Cinzia DEL GIOVANE - personale UniMoRe

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Cinzia DEL GIOVANE

Ricercatore t.d. art. 24 c. 3 lett. B
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

Pubblicazioni

2024 - Dairy Intake and Risk of Cognitive Decline and Dementia: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies [Articolo su rivista]
Villoz, F.; Filippini, T.; Ortega, N.; Kopp-Heim, D.; Voortman, T.; Blum, M. R.; Del Giovane, C.; Vinceti, M.; Rodondi, N.; Chocano-Bedoya, P. O.
abstract

Dairy intake may influence cognition through several molecular pathways. However, epidemiologic studies yield inconsistent results, and no dose-response meta-analysis has been conducted yet. Therefore, we performed a systematic review with a dose-response meta-analysis about the association between dairy intake and cognitive decline or incidence of dementia. We investigated prospective studies with a follow-up ≥6 mo on cognitive decline or dementia incidence in adults without known chronic conditions through a systematic search of Embase, Medline, Cochrane Library, Web of Science, and Google Scholar from inception to 11 July 2023. We evaluated the dose-response association using a random-effects model. We identified 15 eligible cohort studies with >300,000 participants and a median follow-up of 11.4 y. We observed a negative nonlinear association between cognitive decline/dementia incidence and dairy intake as assessed through the quantity of consumption, with the nadir at ∼150 g/d (risk ratio: 0.88; 95% confidence interval: 0.78, 0.99). Conversely, we found an almost linear negative association when we considered the frequency of consumption (risk ratio for linear trend: 0.84; 95% confidence interval: 0.77, 0.92 for 1 time/d increase of dairy products). Stratified analysis by dairy products showed different shapes of the association with linear inverse relationship for milk intake, whereas possibly nonlinear for cheese. The inverse association was limited to Asian populations characterized by generally lower intake of dairy products, compared with the null association reported by European studies. In conclusion, our study suggests a nonlinear inverse association between dairy intake and cognitive decline or dementia, also depending on dairy types and population characteristics, although the heterogeneity was still high in overall and several subgroup analyses. Additional studies should be performed on this topic, including a wider range of intake and types of dairy products, to confirm a potential preventing role of dairy intake on cognitive decline and identify ideal intake doses. This review was registered at PROSPERO as CRD42020192395.

2023 - Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis [Articolo su rivista]
Tabaee Damavandi, P.; Fabin, N.; Giossi, R.; Matricardi, S.; Del Giovane, C.; Striano, P.; Meletti, S.; Brigo, F.; Trinka, E.; Lattanzi, S.
abstract

Introduction: Fenfluramine (FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy. Methods: We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double- or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with ≥ 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and suffered adverse events (AEs). The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) along with the 95% confidence interval (CI) were estimated for each outcome. Results: Three trials were identified and a total of 469 Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) subjects were randomized. All three trials were judged to be at low risk of biases. In patients with DS, the RRs for ≥ 50% and 100% reductions in convulsive seizure frequency for the FFA group compared to placebo were 5.61 (95% CI 2.73–11.54) and 4.71 (95% CI 0.57–39.30), respectively. In patients with LGS, the corresponding RRs for ≥ 50% and 100% reductions in drop seizure frequency were 2.58 (95% CI 1.33–5.02) and 0.50 (95% CI 0.031–7.81), respectively. The drug was withdrawn for any reason in 10.1% and 5.8% of patients receiving FFA and placebo, respectively (RR 1.79, 95% CI 0.89–3.59). Treatment discontinuation due to AEs occurred in 5.4% and 1.2% of FFA- and placebo-treated patients, respectively (RR 3.63, 95% CI 0.93–14.16). Decreased appetite, diarrhoea, fatigue, and weight loss were AEs associated with FFA treatment. Conclusion: Fenfluramine reduces the frequency of seizures in patients with DS and LGS. Decreased appetite, diarrhoea, fatigue, and weight loss are non-cardiovascular AEs associated with FFA.

2023 - Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Russo, E.; Del Giovane, C.; Matricardi, S.; Meletti, S.; Striano, P.; Damavandi, P. T.; Silvestrini, M.; Brigo, F.
abstract

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.

2022 - Atogepant for the Prevention of Episodic Migraine in Adults: A Systematic Review and Meta-Analysis of Efficacy and Safety [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Altamura, C.; Del Giovane, C.; Silvestrini, M.; Brigo, F.; Vernieri, F.
abstract

Introduction: The inhibition of the calcitonin gene-related peptide (CGRP) pathway has attracted interest in pharmacological research on migraine. Atogepant is a potent, selective, orally available antagonist of the CGRP receptor approved as a preventive treatment of episodic migraine. This systematic review with meta-analysis aims to evaluate the efficacy and safety of atogepant for the prevention of episodic migraine in adult patients. Methods: Randomized, placebo-controlled, single or double-blinded trials were identified through a systematic literature search (December week 4, 2021). Main outcomes included the changes from baseline in monthly migraine days and the incidence of adverse events (AEs) and treatment withdrawal due to AEs. Mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs) were estimated. Results: Two trials were included, overall enrolling 1550 patients. A total of 408 participants were randomized to placebo, 314 to atogepant 10 mg, 411 to atogepant 30 mg, and 417 to atogepant 60 mg once daily. The mean age of the patients was 41.0 years and 87.7% were women. The reduction in the mean number of migraine days from baseline across the 12-week treatment period was significantly greater among patients treated with atogepant at either the daily dose of 10 mg (MD − 1.16, 95% CI − 1.60 to − 0.73, p < 0.001), 30 mg (MD − 1.15, 95% CI − 1.54 to − 0.76, p < 0.001), or 60 mg (MD − 1.20, 95% CI − 2.18 to − 0.22, p = 0.016) than with placebo. There were no differences in the occurrence of AEs and drug withdrawal due to AEs between atogepant and placebo groups. Constipation was more commonly observed in patients treated with atogepant at 30 mg/day than placebo (RR 5.19, 95% CI 2.00–13.46; p = 0.001). Treatment with atogepant at the daily dose of 60 mg was associated with a higher risk of constipation (RR 4.92, 95% CI 1.89–12.79; p = 0.001) and nausea (RR 2.73, 95% CI 1.47–5.06; p = 0.001) than placebo. Conclusion: Atogepant is an efficacious and overall well-tolerated treatment for the prevention of episodic migraine in adults.

2022 - Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: A nested study within a randomized placebo controlled trial [Articolo su rivista]
Buchi, A. E.; Feller, M.; Netzer, S.; Blum, M. R.; Gonzalez Rodriguez, E.; Collet, T. -H.; Del Giovane, C.; van Heemst, D.; Quinn, T.; Kearney, P. M.; Westendorp, R. G. J.; Gussekloo, J.; Mooijaart, S. P.; Hans, D.; Bauer, D. C.; Rodondi, N.; Aeberli, D.
abstract

The effect of levothyroxine (LT4) therapy for subclinical hypothyroidism (SHypo) on appendicular bone geometry and volumetric density has so far not been studied. In a nested study within the randomized, placebo-controlled Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST) trial, we assessed the effect of LT4 therapy on bone geometry as measured by peripheral quantitative computed tomography (pQCT). In the TRUST trial, community-dwelling adults aged ≥65 years with SHypo were randomized to LT4 with dose titration vs. placebo with mock titration. We analyzed data from participants enrolled at the TRUST site in Bern, Switzerland who had bone pQCT measured at baseline and at 1 to 2 years follow-up. The primary outcomes were the annual percentage changes of radius and tibia epi- and diaphysis bone geometry (total and cortical cross-sectional area (CSA) and cortical thickness), and of volumetric bone mineral density (bone mineral content (BMC) and total, trabecular and cortical volumetric bone mineral density (vBMD)). We performed linear regression of the annual percentage changes adjusted for sex, LT4 dose at randomization and muscle cross-sectional area. The 98 included participants had a mean age of 73.9 (±SD 5.4) years, 45.9% were women, and 12% had osteoporosis. They were randomized to placebo (n = 48) or LT4 (n = 50). Annual changes in BMC and vBMD were similar between placebo and LT4-treated groups, without significant difference in bone geometry or volumetric bone mineral density changes, neither at the diaphysis, nor at the epiphysis. For example, in the placebo group, epiphyseal BMC (radius) decreased by a mean 0.2% per year, with a similar decrease of 0.5% per year in the LT4 group (between-group difference in %ΔBMC 0.3, 95% CI –0.70 to 1.21, p = 0.91). Compared to placebo, LT4 therapy for an average 14 months had no significant effect on bone mass, bone geometry and volumetric density in older adults with subclinical hypothyroidism. Trial registration: The trial was registered on ClinicalTrials.gov numbers NCT01660126 (TRUST Thyroid trial) and NCT02491008 (Skeletal outcomes).

2022 - Change in colorectal cancer (CRC) testing rates associated with the introduction of the first organized screening program in canton Uri, Switzerland: Evidence from insurance claims data analyses from 2010 to 2018 [Articolo su rivista]
Bissig, S.; Syrogiannouli, L.; Schneider, R.; Tal, K.; Selby, K.; Del Giovane, C.; Bulliard, J. -L.; Senn, O.; Ducros, C.; Schmid, C. P. R.; Marbet, U.; Auer, R.
abstract

The first canton in Switzerland to implement an organized colorectal cancer screening program (OSP) was Uri. Starting in 2013, it offered 50–69-year-olds free testing with colonoscopy every 10 years or fecal occult blood test (FOBT) every 2 years. We tested the association between the OSP and testing rates over time. We analyzed claims data of 50–69-year-olds from Uri and neighboring cantons (NB) provided by a large health insurance and complemented it with data from the OSP. We fitted multivariate adjusted logistic regression models to compare overall testing rates and by method (colonoscopy or FOBT/both) We computed the 2018 rate of the population up-to-date with testing (colonoscopy within 9 years/FOBT within 2 years). Yearly overall testing rates in Uri increased from 8.7% in 2010 to 10.8% in 2018 and from 6.5% to 7.9% in NB. In Uri, the proportion tested with FOBT/both increased from 4.7% to 6.0% but decreased from 2.8% to 1.1% in NB. Testing by FOBT/both increased more between 2015 and 2018 than 2010–2012 in Uri than in NB (OR:2.1[95%CI:1.8–2.4]), it increased less for colonoscopy (OR:0.60[95%CI:0.51–0.70]), with no change in overall CRC testing (OR:0.91[95%CI:0.81–1.02]). In 2018 in Uri, 42.5% were up-to-date with testing (FOBT/both:9.2%, colonoscopy:35.7%); in NBs, 40.7% (FOBT/both:2.7%, colonoscopy:39%). Yearly FOBT rates in Uri were always higher than in NB. Though the OSP in Uri was not associated with a greater increase in overall testing rates, the OSP was associated with increased FOBT.

2022 - Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis [Articolo su rivista]
De Crescenzo, F.; D'Alo, G. L.; Ostinelli, E. G.; Ciabattini, M.; Di Franco, V.; Watanabe, N.; Kurtulmus, A.; Tomlinson, A.; Mitrova, Z.; Foti, F.; Del Giovane, C.; Quested, D. J.; Cowen, P. J.; Barbui, C.; Amato, L.; Efthimiou, O.; Cipriani, A.
abstract

2022 - Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: Systematic review and network meta-Analysis of randomised controlled trials [Articolo su rivista]
Papola, D.; Ostuzzi, G.; Tedeschi, F.; Gastaldon, C.; Purgato, M.; Del Giovane, C.; Pompoli, A.; Pauley, D.; Karyotaki, E.; Sijbrandij, M.; Furukawa, T. A.; Cuijpers, P.; Barbui, C.
abstract

Background Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. Aims To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-Analysis. Method We conducted a systematic review and network meta-Analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-Analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258). Results We included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive-behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. =-0.67, 95% CI-0.95 to-0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI-0.94 to 1.56; CINeMA: moderate) and short-Term psychodynamic therapy (for efficacy: s.m.d. =-0.61, 95% CI-1.15 to-0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54-1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU. Conclusions CBT and short-Term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-Analysis should inform clinicians and guidelines.

2022 - Comparison of 6 Mortality Risk Scores for Prediction of 1-Year Mortality Risk in Older Adults with Multimorbidity [Articolo su rivista]
Schneider, C.; Aubert, C. E.; Del Giovane, C.; Donze, J. D.; Gastens, V.; Bauer, D. C.; Blum, M. R.; Dalleur, O.; Henrard, S.; Knol, W.; O'Mahony, D.; Curtin, D.; Lee, S. J.; Aujesky, D.; Rodondi, N.; Feller, M.
abstract

Importance: The most appropriate therapy for older adults with multimorbidity may depend on life expectancy (ie, mortality risk), and several scores have been developed to predict 1-year mortality risk. However, often, these mortality risk scores have not been externally validated in large sample sizes, and a head-to-head comparison in a prospective contemporary cohort is lacking. Objective: To prospectively compare the performance of 6 scores in predicting the 1-year mortality risk in hospitalized older adults with multimorbidity. Design, Setting, and Participants: This prognostic study analyzed data of participants in the OPERAM (Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People) trial, which was conducted between December 1, 2016, and October 31, 2018, in surgical and nonsurgical departments of 4 university-based hospitals in Louvain, Belgium; Utrecht, the Netherlands; Cork, Republic of Ireland; and Bern, Switzerland. Eligible participants in the OPERAM trial had multimorbidity (≥3 coexisting chronic diseases), were aged 70 years or older, had polypharmacy (≥5 long-term medications), and were admitted to a participating ward. Data were analyzed from April 1 to September 30, 2020. Main Outcomes and Measures: The outcome of interest was any-cause death occurring in the first year of inclusion in the OPERAM trial. Overall performance, discrimination, and calibration of the following 6 scores were assessed: Burden of Illness Score for Elderly Persons, CARING (Cancer, Admissions ≥2, Residence in a nursing home, Intensive care unit admit with multiorgan failure, ≥2 Noncancer hospice guidelines) Criteria, Charlson Comorbidity Index, Gagné Index, Levine Index, and Walter Index. These scores were assessed using the following measures: Brier score (0 indicates perfect overall performance and 0.25 indicates a noninformative model); C-statistic and 95% CI; Hosmer-Lemeshow goodness-of-fit test and calibration plots; and sensitivity, specificity, and positive and negative predictive values. Results: The 1879 patients in the study had a median (IQR) age of 79 (74-84) years and 835 were women (44.4%). The median (IQR) number of chronic diseases was 11 (8-16). Within 1 year, 375 participants (20.0%) died. Brier scores ranged from 0.16 (Gagné Index) to 0.24 (Burden of Illness Score for Elderly Persons). C-statistic values ranged from 0.62 (95% CI, 0.59-0.65) for Charlson Comorbidity Index to 0.69 (95% CI, 0.66-0.72) for the Walter Index. Calibration was good for the Gagné Index and moderate for other mortality risk scores. Conclusions and Relevance: Results of this prognostic study suggest that all 6 of the 1-year mortality risk scores examined had moderate prognostic performance, discriminatory power, and calibration in a large cohort of hospitalized older adults with multimorbidity. Overall, none of these mortality risk scores outperformed the others, and thus none could be recommended for use in daily clinical practice..

2022 - Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis [Articolo su rivista]
Ostuzzi, G.; Vita, G.; Bertolini, F.; Tedeschi, F.; De Luca, B.; Gastaldon, C.; Nose, M.; Papola, D.; Purgato, M.; Del Giovane, C.; Correll, C. U.; Barbui, C.
abstract

Background: Although antipsychotic maintenance treatment is widely recommended to prevent relapse in chronic psychoses, evidence-based guidelines do not provide clear indications on different maintenance treatment strategies, including continuing the antipsychotic at standard doses, reducing the dose, switching to another antipsychotic, or even stopping the antipsychotic. We aimed to compare the effectiveness of these maintenance treatment strategies, hypothesising the superiority of all strategies over stopping, and of continuing at standard doses over both switching and reducing the dose. Methods: We did a systematic review and network meta-analysis of randomized controlled trials (RCTs) that investigated antipsychotics for relapse prevention in adults with schizophrenia-spectrum disorders who were clinically stable, and which compared four treatment strategies: continuing the current antipsychotic at standard doses recommended for acute treatment; reducing the current antipsychotic dose; switching to a different antipsychotic; and stopping the antipsychotic and replacing it with placebo. We excluded RCTs with fewer than 25 individuals, a prerandomisation washout period greater than 4 weeks, a follow-up shorter than 6 weeks, and those recruiting treatment-resistant individuals. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, and online trial registers for published and unpublished RCTs from inception to Sept 1, 2021, combining terms describing all available antipsychotics, and terms describing continuation, maintenance, or long-term treatment for schizophrenia-spectrum disorders. Relative risks (RRs) and standardised mean differences were pooled using random-effects pairwise and network meta-analyses. We assessed risk of bias of each RCT with the Cochrane Risk-of-Bias 2 tool, and confidence of pooled estimates with CINeMA. The primary outcome was relapse prevention. The study protocol was registered in advance in the Open Science Forum registry. Findings: Of 3936 records identified, 119 records, reporting on 101 RCTs, were eligible, 98 of which (including 13 988 individuals) provided data that could be meta-analysed for at least one outcome. The mean proportion of female participants per study was 38% (range 0–100; median 39%, IQR 29–50), whereas for male participants it was 62% (range 0–100; median 61%, IQR 50–71), and the overall mean age was 38·8 years (range 23·2–63·9; median 39·3, IQR 35·0–43·9). Of the 98 RCTs meta-analysed, 89·8% were done in high-income and upper-middle-income countries. The ethnic group White or so-called Caucasian was the most represented (mean 56% participants per study), although this information was relatively scarce. All continuation strategies were significantly more effective in preventing relapse than stopping antipsychotic treatment, with a large risk reduction for continuing at standard doses (RR 0·37, 95% CI 0·32–0·43; number-needed-to-treat [NNT] 3·17, 95% CI 2·94–3·51) and antipsychotic switching (RR 0·44, 0·37–0·53; NNT 3·57, 3·17–4·25), and moderate risk reduction for dose reduction (RR 0·68, 0·51–0·90; NNT 6·25, 4·08–20·00). Continuing and switching antipsychotics did not differ significantly (RR 0·84, 0·69–1·02; with lower values favouring continuing), whereas reducing antipsychotic dose was outperformed by both continuing (RR 0·55, 0·42–0·71; NNT 4·44, 3·45–6·90) and switching (RR 0·65, 0·47–0·89; NNT 5·17, 3·77–18·18). Results were supported by moderate confidence of evidence and confirmed by secondary analyses and by several sensitivity and subgroup analyses, including removing studies with abrupt antipsychotic discontinuation or fast tapering (≤4 weeks). No tolerability differences emerged between treatment strategies. According to the Cochrane Risk-of-Bias tool, version 2, 16·8% of included RCTs had an overall high risk of bias for the primary outcome. We found moderate h

2022 - Determining the Effects of Transcranial Direct Current Stimulation on Tinnitus, Depression, and Anxiety: A Systematic Review [Articolo su rivista]
Labree, B.; Hoare, D. J.; Gascoyne, L. E.; Scutt, P.; Del Giovane, C.; Sereda, M.
abstract

(1) Background: Tinnitus is the awareness of a sound in the absence of an external source. It affects around 10–15% of people, a significant proportion of whom also experience symptoms such as depression or anxiety that negatively affect their quality of life. Transcranial direct current stimulation (tDCS) is a technique involving constant low-intensity direct current delivered via scalp electrodes. It is a potential treatment option for tinnitus, as well as tinnitus-related conditions such as depression and anxiety. This systematic review estimates the effects of tDCS on outcomes relevant to tinnitus. In addition, it sheds light on the relationship between stimulation parameters and the effect of tDCS on these outcomes; (2) Methods: Exhaustive searches of electronic databases were conducted. Randomised controlled trials were included if they reported at least one of the following outcomes: tinnitus symptom severity, anxiety, or depression. Where available, data on quality of life, adverse effects, and neurophysiological changes were also reviewed. GRADE was used to assess the certainty in the estimate; (3) Results: Meta-analyses revealed a statistically significant reduction in tinnitus (moderate certainty) and depression (low certainty)-but not anxiety-following active tDCS compared to sham control. Network meta-analyses revealed potential optimal stimulation parameters; (4) Conclusions: The evidence synthesised in this review suggests tDCS has the potential to reduce symptom severity in tinnitus and depression. It further narrows down the number of potentially optimal stimulation parameters.

2022 - Editorial: Second-Generation Antipsychotics for Bipolar Depression in Youths: The Best Evidence Synthesis Is a Strong Call for Further Evidence [Articolo su rivista]
Cortese, S.; Frazier, J. A.; Del Giovane, C.
abstract

2022 - Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies [Articolo su rivista]
Syrogiannouli, L.; Wildisen, L.; Meuwese, C.; Bauer, D. C.; Cappola, A. R.; Gussekloo, J.; den Elzen, W. P. J.; Trompet, S.; Westendorp, R. G. J.; Jukema, J. W.; Ferrucci, L.; Ceresini, G.; Asvold, B. O.; Chaker, L.; Peeters, R. P.; Imaizumi, M.; Ohishi, W.; Vaes, B.; Volzke, H.; Sgarbi, J. A.; Walsh, J. P.; Dullaart, R. P. F.; Bakker, S. J. L.; Iacoviello, M.; Rodondi, N.; Del Giovane, C.
abstract

Background: In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC). Methods: For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA. Results: Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score. Conclusion: ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

2022 - Incorporating dose effects in network meta-analysis [Articolo su rivista]
Watt, J. A.; Del Giovane, C.; Jackson, D.; Turner, R. M.; Tricco, A. C.; Mavridis, D.; Straus, S. E.; Veroniki, A. -A.
abstract

Systematic reviews with network meta-analysis that ignore potential dose effects could limit the applicability and validity of review findings. This article aims to help content experts (eg, clinicians), methodologists, and statisticians better understand how to incorporate dose effects in network meta-analysis. Three models are described that make different clinical and statistical assumptions about how to model dose effects. This article also illustrates the importance of dose effects in understanding the potential risk of harm in people with dementia from cerebrovascular events associated with atypical antipsychotic drug use (quetiapine, olanzapine, and risperidone) and the potential risk of harm in people with nausea and headache associated with cholinesterase inhibitor use (donepezil, galantamine, and rivastigmine). Finally, important considerations when choosing between different network meta-analysis models incorporating dose effects are discussed.

2022 - Network Meta-Analysis [Capitolo/Saggio]
Watt, J.; Del Giovane, C.
abstract

There are often multiple potential interventions to treat a disease; therefore, we need a method for simultaneously comparing and ranking all of these available interventions. In contrast to pairwise meta-analysis, which allows for the comparison of one intervention to another based on head-to-head data from randomized trials, network meta-analysis (NMA) facilitates simultaneous comparison of the efficacy or safety of multiple interventions that may not have been directly compared in a randomized trial. NMAs help researchers study important and previously unanswerable questions, which have contributed to a rapid rise in the number of NMA publications in the biomedical literature. However, the conduct and interpretation of NMAs are more complex than pairwise meta-analyses: there are additional NMA model assumptions (i.e., network connectivity, homogeneity, transitivity, and consistency) and outputs (e.g., network plots and surface under the cumulative ranking curves [SUCRAs]). In this chapter, we will: (1) explore similarities and differences between pairwise and network meta-analysis; (2) explain the differences between direct, indirect, and mixed treatment comparisons; (3) describe how treatment effects are derived from NMA models; (4) discuss key criteria predicating completion of NMA; (5) interpret NMA outputs; (6) discuss areas of ongoing methodological research in NMA; (7) outline an approach to conducting a systematic review and NMA; (8) describe common problems that researchers encounter when conducting NMAs and potential solutions; and (9) outline an approach to critically appraising a systematic review and NMA.

2022 - Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants [Articolo su rivista]
Ostuzzi, G.; Bertolini, F.; Tedeschi, F.; Vita, G.; Brambilla, P.; del Fabro, L.; Gastaldon, C.; Papola, D.; Purgato, M.; Nosari, G.; Del Giovane, C.; Correll, C.; Barbui, C.
abstract

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia-spectrum disorders, but evidence-based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long-acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head-to-head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta-analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, “high” confidence in the results was found for (in descending order of effect magnitude) amisulpride-oral (OS), olanzapine-OS, aripiprazole-LAI, olanzapine-LAI, aripiprazole-OS, paliperidone-OS, and ziprasidone-OS. “Moderate” confidence in the results was found for paliperidone-LAI 1-monthly, iloperidone-OS, fluphenazine-OS, brexpiprazole-OS, paliperidone-LAI 1-monthly, asenapine-OS, haloperidol-OS, quetiapine-OS, cariprazine-OS, and lurasidone-OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing “moderate” confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia-spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best-performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low- and middle-income countries and constrained-resource settings, where few medications may be selected. Results from this network meta-analysis can inform clinical guidelines and national and international drug regulation policies.

2022 - Pharmacist interventions to improve hypertension management: protocol for a systematic review of randomised controlled trials [Articolo su rivista]
Gastens, V.; Kiszio, B.; Del Giovane, C.; Tsuyuki, R.; Paradis, G.; Chiolero, A.; Santschi, V.
abstract

INTRODUCTION: Hypertension management remains a major public health challenge in primary care. Innovative interventions to improve blood pressure (BP) control are needed. One approach is through community-based models of care with the involvement of pharmacists and other non-physician healthcare professionals. Our objective is to systematically review the evidence of the impact of pharmacist care alone or in collaboration with other healthcare professionals on BP among hypertensive outpatients compared with usual care. Because these interventions can be complex, with various components, the effect size may differ between the type of interventions. One major focus of our study will be to assess carefully the heterogeneity in the effects of these interventions to identify which ones work best in a given healthcare setting. METHODS AND ANALYSIS: Systematic searches of the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica (Embase) and Central Register of Controlled Trials (CENTRAL) databases will be conducted. Randomised controlled trials assessing the effect of pharmacist interventions on BP among outpatients will be included. Examples for pharmacist interventions are patient education, feedback to physician and medication management. The outcome will be the change in BP or BP at follow-up or BP control. Results will be synthesised descriptively and, if appropriate, will be pooled across studies to perform meta-analyses. If feasible, we will also perform a network meta-analysis to compare interventions that have not been compared directly head-to-head by using indirect evidence. Heterogeneity in the effect will be evaluated through prespecified subgroup and stratified analyses, accounting notably for the type and intensity of interventions, patients' characteristics and healthcare setting. ETHICS AND DISSEMINATION: Ethical approval is not required as the results will be drawn from currently available published literature. Outcomes of the review will be shared through peer-reviewed journal and used for implementation policy. PROSPERO REGISTRATION NUMBER: CRD42021279751.

2022 - Pharmacological and non-pharmacological interventions for adults with ADHD: Protocol for a systematic review and network meta-analysis [Articolo su rivista]
Cortese, S.; Del Giovane, C.; Chamberlain, S.; Philipsen, A.; Young, S.; Bilbow, A.; Cipriani, A.
abstract

Introduction It is unclear how pharmacological and non-pharmacological interventions compare with each other in terms of efficacy and tolerability for core symptoms and additional problems in adults with attention-deficit/hyperactivity disorder (ADHD). We aim to conduct the first network meta-analysis (NMA) comparing pharmacological and non-pharmacological interventions (or their combinations) in adults with ADHD. Methods and analysis We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMAs. We will search a broad set of electronic databases/registries and contact drug companies and experts in the field to retrieve published and unpublished randomised controlled trials (RCTs) (parallel or cross-over) of medications (either licensed or unlicensed) and any non-pharmacological intervention in adults (≥18 years) with ADHD. Primary outcomes will be: (1) change in severity of ADHD core symptoms, and (2) acceptability (all-cause discontinuation). Secondary outcomes will include tolerability (drop-out due to side effects) and change in the severity of emotional dysregulation, executive dysfunctions and quality of life. The risk of bias in each individual RCT included in the NMA will be assessed using the Cochrane Risk of Bias tool-version 2. We will evaluate the transitivity assumption comparing the distribution of possible effect modifiers across treatment comparisons. We will perform Bayesian NMA for each outcome with random-effects model in OpenBUGS. Pooled estimates of NMA will be obtained using the Markov Chains Monte Carlo method. We will judge the credibility in the evidence derived from the NMA using the CINeMA tool (which includes assessment of publication bias). We will conduct a series of sensitivity analyses to assess the robustness of the findings. Ethics and dissemination As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-reviewed journals. PROSPERO registration number CRD42021265576.

2022 - Polypharmacy and inappropriate medications in multimorbid elderly patients What OPERAM taught us and will teach us [Articolo su rivista]
Bretagne, L.; Jungo, K. T.; Blum, M. R.; Schwenkglenks, M.; Chiolero, A.; Del Giovane, C.; Gencer, B.; Aujesky, D.; Rodondi, N.
abstract

Polypharmacy and inappropriate medication use are very common in multimorbid older patients. This population has unfortunately been excluded from most large, randomized studies. In a recent multicenter randomized study (OPERAM), we included over 2000 multimorbid patients. We found that 86% of the patients aged 70 years and more had inappropriate medications and that these medications could be discontinued without negative impact on the health of these patients. This cohort of multimorbid patients will be followed for 10 years to evaluate their prognosis, life expectancy, treatments and quality of life, with numerous projects to better understand the inappropriate prescribing of individual drugs and their consequences on the health of this population.

2022 - Ten-year changes in colorectal cancer screening in Switzerland: The Swiss Health Interview Survey 2007, 2012 and 2017 [Articolo su rivista]
Schneider, R.; Syrogiannouli, L.; Bissig, S.; Scharf, T.; Bulliard, J. -L.; Ducros, C.; Del Giovane, C.; Tal, K.; Zwahlen, M.; Selby, K.; Auer, R.
abstract

Recent recommendations for colorectal cancer (CRC) screening suggest fecal occult blood test (FOBT) or colonoscopy. Since 2013, mandatory health insurance in Switzerland reimburse CRC screening. We set out to determine if CRC testing rate and type of CRC screening changed in Switzerland from 2007 to 2017 and between the three main language regions. We extracted data on 50–75-year-olds from the Swiss Health Interview Survey (SHIS) 2007, 2012 and 2017 to determine rates of self-reported testing with FOBT within last 2 years and colonoscopy within last 10 years. We estimated prevalence ratio (PR) in multivariate-adjusted logistic regression models and compared rates in German-, French- and Italian-speaking regions, adjusting for sociodemographic, self-rated health and insurance variables. Overall testing rates (FOBT or colonoscopy) increased in all regions from 2007 to 2017 (German-speaking 33.6% to 48.3%; French-speaking 30.8% to 48.8%; Italian-speaking 37.9% to 46.8%), mainly because of an increase in colonoscopy rate for screening reasons (p < 0.001 in all regions). Rates of FOBT testing fell significantly in the German-speaking region (11.9% to 4.4%, p < 0.001), but not in the Italian- (13.9% to 8.5%, p = 0.052) and French-speaking regions (7.6% to 7.4%, p = 0.138). Overall CRC testing rate rose from 33.2% in 2007 to 48.4% in 2017, mainly because of an increase of colonoscopy rate for screening reasons. Coverage remains below the 65% target of European guidelines. Organized screening programs encouraging FOBT screening could contribute to further increasing the CRC testing rate.

2022 - Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Zaccara, G.; Striano, P.; Russo, E.; Del Giovane, C.; Silvestrini, M.; Brigo, F.
abstract

Background: Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs. Objective: We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA). Methods: We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA). Results: Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11–3.66], ESL (OR 1.93, 95% CI 1.07–3.48), LCM (OR 1.86, 95% CI 1.04–3.32), and PER (OR 2.07, 95% CI 1.16–3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44–0.86) and LCM (OR 0.60, 95% CI 0.40–0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02–1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments. Conclusions: Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

2022 - Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials [Articolo su rivista]
Lyko, C.; Blum, M. R.; Abolhassani, N.; Stuber, M. J.; Del Giovane, C.; Feller, M.; Moutzouri, E.; Oberle, J.; Jungo, K. T.; Collet, T. -H.; den Elzen, W. P. J.; Poortvliet, R. K. E.; Du Puy, R. S.; Dekkers, O. M.; Trompet, S.; Jukema, J. W.; Aujesky, D.; Quinn, T.; Westendorp, R.; Kearney, P. M.; Gussekloo, J.; Van Heemst, D.; Mooijaart, S. P.; Bauer, D. C.; Rodondi, N.
abstract

Background: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between-group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

2021 - A network meta-analysis of psychosocial interventions for refugees and asylum seekers with PTSD [Articolo su rivista]
Turrini, G.; Tedeschi, F.; Cuijpers, P.; Del Giovane, C.; Kip, A.; Morina, N.; Nose, M.; Ostuzzi, G.; Purgato, M.; Ricciardi, C.; Sijbrandij, M.; Tol, W.; Barbui, C.
abstract

Introduction Refugees and asylum seekers are vulnerable to common mental disorders, including post-traumatic stress disorder (PTSD). Using a network meta-analysis (NMA) approach, the present systematic review compared and ranked psychosocial interventions for the treatment of PTSD in adult refugees and asylum seekers. Methods Randomised studies of psychosocial interventions for adult refugees and asylum seekers with PTSD were systematically identified. PTSD symptoms at postintervention was the primary outcome. Standardised mean differences (SMDs) and ORs were pooled using pairwise and NMA. Study quality was assessed with the Cochrane Risk of Bias (RoB) tool, and certainty of evidence was assessed through the Confidence in Network Meta-Analysis application. Results A total of 23 studies with 2308 participants were included. Sixteen studies were conducted in high-income countries, and seven in low-income or middle-income countries. Most studies were at low risk of bias according to the Cochrane RoB tool. NMA on PTSD symptoms showed that cognitive behavioural therapy (CBT) (SMD=-1.41; 95% CI -2.43 to -0.38) and eye movement desensitisation and reprocessing (EMDR) (SMD=-1.30; 95% CI -2.40 to -0.20) were significantly more effective than waitlist (WL). CBT was also associated with a higher decrease in PTSD symptoms than treatment as usual (TAU) (SMD -1.51; 95% CI -2.67 to -0.36). For all other interventions, the difference with WL and TAU was not significant. CBT and EMDR ranked best according to the mean surface under the cumulative ranking. Regarding acceptability, no intervention had less dropouts than inactive interventions. Conclusion CBT and EMDR appeared to have the greatest effects in reducing PTSD symptoms in asylum seekers and refugees. This evidence should be considered in guidelines and implementation packages to facilitate dissemination and uptake in refugee settings.

2021 - A review of methods for addressing components of interventions in meta-analysis [Articolo su rivista]
Petropoulou, M.; Efthimiou, O.; Rucker, G.; Schwarzer, G.; Furukawa, T. A.; Pompoli, A.; Koek, H. L.; Del Giovane, C.; Rodondi, N.; Mavridis, D.
abstract

Many healthcare interventions are complex, consisting of multiple, possibly interacting, components. Several methodological articles addressing complex interventions in the metaanalytical context have been published. We hereby provide an overview of methods used to evaluate the effects of complex interventions with meta-analytical models. We summarized the methodology, highlighted new developments, and described the benefits, drawbacks, and potential challenges of each identified method. We expect meta-analytical methods focusing on components of several multicomponent interventions to become increasingly popular due to recently developed, easy-to-use, software tools that can be used to conduct the relevant analyses. The different meta-analytical methods are illustrated through two examples comparing psychotherapies for panic disorder. Copyright:

2021 - Antihypertensive Drugs for Secondary Prevention after Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis [Articolo su rivista]
Boncoraglio, G. B.; Del Giovane, C.; Tramacere, I.
abstract

Background and Purpose: Approximately 30% of ischemic strokes occur after a previous stroke or transient ischemic attack. Arterial hypertension is one of the best established risk factors for first and recurrent stroke, both ischemic and hemorrhagic. Guidelines for the secondary prevention of ischemic stroke support the use of blood pressure (BP)-lowering drugs in most patients. However, the evidence for these recommendations comes from meta-analyses that included both ischemic and hemorrhagic stroke patients, whereas these 2 conditions differ quantitatively in several aspects. With this systematic review and meta-analysis, we aimed at summarizing the current evidence on BP-lowering drugs for secondary prevention in patients with ischemic stroke or transient ischemic attack. Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to January 31, 2020. We included randomized controlled trials comparing any specific BP-lowering drug, as monotherapy or combination, with either a control or another BP-lowering drug. Results: Eight studies that enrolled 33 774 patients with ischemic stroke or transient ischemic attack were included in the meta-analysis. Mean follow-up was 25 months (range, 3-48). Moderate-quality evidence indicated that a subsequent stroke occurred in 7.9% (ischemic in 7.4% or hemorrhagic in 0.6%) of patients taking any type of BP-lowering drug compared with 9.7% of patients taking placebo (odds ratio, 0.79 [95% CI, 0.66-0.94]; absolute risk difference, -1.9% [95% CI, -3.1% to -0.5%]). Moderate-quality evidence indicated that mortality occurred similarly in patients taking any type of BP-lowering treatment compared with placebo, with an absolute risk of 7.3% and 7.9%, respectively (odds ratio, 1.01 [95% CI, 0.92-1.10]; absolute risk difference, 0.1% [95% CI, -0.6% to 0.7%]). Conclusions: The use of BP-lowering drugs in patients with ischemic stroke or transient ischemic attack is associated with a 1.9% risk reduction of stroke but does not affect the all-cause mortality risk.

2021 - Antiplatelet drugs for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis [Articolo su rivista]
Del Giovane, C.; Boncoraglio, G. B.; Bertu, L.; Banzi, R.; Tramacere, I.
abstract

Background: Antiplatelet drugs may prevent recurrent ischemic events after ischemic stroke but their relative effectiveness and harms still need to be clarified. Within this network meta-analysis we aimed to summarize the current evidence for using antiplatelet drugs for secondary stroke prevention. Methods: We searched MEDLINE, EMBASE and CENTRAL up to September 2020. Randomized controlled trials (RCTs) assessing antiplatelet drugs for secondary stroke prevention were included. We did pairwise meta-analyses and network meta-analyses using random-effects models. Primary outcomes were all strokes (ischemic or hemorrhagic) and all-cause mortality. Results: The review included 57 RCTs, 50 (n = 165,533 participants) provided data for the meta-analyses. Compared to placebo/no treatment, moderate to high-confidence evidence indicated that cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day significantly reduced the risk of all strokes (odds ratios, ORs and absolute risk difference, ARD): cilostazol 0.51 (95 % confidence interval, CI, 0.37 to 0.71; 3.6 % fewer), clopidogrel 0.63 (95 % CI, 0.49 to 0.79; 2.7 % fewer), dipyridamole + aspirin 0.65 (95 % CI, 0.55 to 0.78; 2.5 % fewer), ticagrelor 0.68 (95 % CI, 0.50 to 0.93; 2.3 % fewer), ticlopidine 0.74 (95 % CI 0.59 to 0.93; 1.9 % fewer), aspirin ≤ 150 mg/day 0.79 (95 % CI, 0.66 to 0.95; 1.5 % fewer). Aspirin > 150 mg/day and the combinations clopidogrel/aspirin, ticagrelor/aspirin, also decrease all strokes but increase the risk of hemorrhagic events. Only aspirin > 150 mg/day significantly reduced all-cause mortality (OR 0.86, 95 % CI 0.76 to 0.97; ARD 0.9 %, 95 %CI 1.5–0.2 % fewer, moderate confidence). Compared to aspirin ≤ 150 mg/day, clopidogrel significantly reduced the risk of all strokes, cardiovascular events, and intracranial hemorrhage outcomes. Cilostazol also appeared to provide advantages but data are limited to the Asian population. Conclusions: Considering the benefits and harms ratio, cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day appear to be the best choices as antiplatelet drugs for secondary prevention of patients with ischemic stroke or TIA. Systematic review registration: PROSPERO CRD42020159896.

2021 - Comparative efficacy and acceptability of psychological interventions for the treatment of adult outpatients with anorexia nervosa: a systematic review and network meta-analysis [Articolo su rivista]
Solmi, M.; Wade, T. D.; Byrne, S.; Del Giovane, C.; Fairburn, C. G.; Ostinelli, E. G.; De Crescenzo, F.; Johnson, C.; Schmidt, U.; Treasure, J.; Favaro, A.; Zipfel, S.; Cipriani, A.
abstract

Background: No consistent first-option psychological interventions for adult outpatients with anorexia nervosa emerges from guidelines. We aimed to compare stand-alone psychological interventions for adult outpatients with anorexia nervosa with a specific focus on body-mass index, eating disorder symptoms, and all-cause dropout rate. Methods: In this systematic review and network meta-analysis, we assessed randomised controlled trials about stand-alone pharmacological or non-pharmacological treatments of adult outpatients with anorexia nervosa, defined according to standardised criteria, with data for at least two timepoints relating to either body-mass index or global eating disorder psychopathology. We searched Cochrane CENTRAL, CINAHL, MEDLINE, and PsychINFO for published and unpublished literature from inception until March 20, 2020. The primary outcomes were the change in body mass index and clinical symptoms, and the secondary outcome was all-cause dropout rate, which were all assessed for treatment as usual, cognitive behavioural therapy (CBT), Maudsley anorexia treatment for adults, family-based treatment, psychodynamic-oriented psychotherapies, a form of CBT targeting compulsive exercise, and cognitive remediation therapy followed by CBT. Global and local inconsistencies for the network meta-analysis were measured, and CINeMA was used to assess the confidence in evidence for primary outcomes. The protocol is registered in PROSPERO (CRD42017064429). Findings: Of 14 003 studies assessed for their title and abstract, 16 (0·1%) randomised controlled trials for psychological treatments were included in the systematic review, of which 13 (0·1%) contributed to the network meta-analysis, with 1047 patients in total (of whom 1020 [97·4%] were female). None of the interventions outperformed treatment as usual in our primary outcomes, but the all-cause dropout rate was lower for CBT than for psychodynamic-oriented psychotherapies (OR 0·54, 95% CI 0·31–0·93). Heterogeneity or inconsistency emerged only for a few comparisons. Confidence in the evidence was low to very low. Interpretation: Compared with treatment as usual, specific psychological treatments for adult outpatients with anorexia nervosa can be associated with modest improvements in terms of clinical course and quality of life, but no reliable evidence supports clear superiority or inferiority of the specific treatments that are recommended by clinical guidelines internationally. Our analysis is based on the best data from existing clinical studies, but these findings should not be seen as definitive or universally applicable. There is an urgent need to fund new research to develop and improve therapies for adults with anorexia nervosa. Meanwhile, to better understand the effects of available treatments, participant-level data should be made freely accessible to researchers to eventually identify whether specific subgroups of patients are more likely to respond to specific treatments. Funding: Flinders University, National Institute for Health Research Oxford Health Biomedical Research Centre.

2021 - Development and validation of a life expectancy estimator for multimorbid older adults: A cohort study protocol [Articolo su rivista]
Gastens, V.; Del Giovane, C.; Anker, D.; Feller, M.; Syrogiannouli, L.; Schwab, N.; Bauer, D. C.; Rodondi, N.; Chiolero, A.
abstract

Background Older multimorbid adults have a high risk of mortality and a short life expectancy (LE). Providing high-value care and avoiding care overuse, including of preventive care, is a serious challenge among multimorbid patients. While guidelines recommend to tailor preventive care according to the estimated LE, there is no tool to estimate LE in this specific population. Our objective is therefore to develop an LE estimator for older multimorbid adults by transforming a mortality prognostic index, which will be developed and internally validated in a prospective cohort. Methods and analysis We will analyse data of the Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People cohort study in Bern, Switzerland. 822 participants were included at hospitalisation with age of 70 years or older, multimorbidity (three or more chronic medical conditions) and polypharmacy (use of five drugs or more for >30 days). All-cause mortality will be assessed during 3 years of follow-up. We will apply a flexible parametric survival model with backward stepwise selection to identify the mortality risk predictors. The model will be internally validated using bootstrapping techniques. We will derive a point-based risk score from the regression coefficients. We will transform the 3-year mortality prognostic index into an LE estimator using the Gompertz survival function. We will perform a qualitative assessment of the clinical usability of the LE estimator and its application. We will conduct the development and validation of the mortality prognostic index following the Prognosis Research Strategy (PROGRESS) framework and report it following the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. Ethics and dissemination Written informed consent by patients themselves or, in the case of cognitive impairment, by a legal representative, was required before enrolment. The local ethics committee (Kantonale Ethikkommission Bern) has approved the study. We plan to publish the results in peer-reviewed journals and present them at national and international conferences.

2021 - Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults with Subclinical Hypothyroidism: An Ancillary Study of a Randomized Clinical Trial [Articolo su rivista]
Wildisen, L.; Feller, M.; Del Giovane, C.; Moutzouri, E.; Du Puy, R. S.; Mooijaart, S. P.; Collet, T. -H.; Poortvliet, R. K. E.; Kearney, P.; Quinn, T. J.; Kloppel, S.; Bauer, D. C.; Peeters, R. P.; Westendorp, R.; Aujesky, D.; Gussekloo, J.; Rodondi, N.
abstract

Importance: Previous trials on the effect of levothyroxine on depressive symptom scores in patients with subclinical hypothyroidism were limited by small sample sizes (N = 57 to 94) and potential biases. Objective: To assess the effect of levothyroxine on the development of depressive symptoms in older adults with subclinical hypothyroidism in the largest trial on this subject and to update a previous meta-analysis including the results from this study. Design, Setting, and Participants: This predefined ancillary study analyzed data from participants in the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial, a double-blind, randomized, placebo-controlled, parallel-group clinical trial conducted from April 2013 to October 31, 2016. The TRUST trial included adults aged 65 years or older diagnosed with subclinical hypothyroidism, defined as the presence of persistently elevated thyroid-stimulating hormone (TSH) levels (4.6-19.9 mIU/L) with free thyroxine (T4) within the reference range. Participants were identified from clinical and general practitioner laboratory databases and recruited from the community in Switzerland, the Netherlands, Ireland, and the UK. This ancillary study included a subgroup of 472 participants from the Netherlands and Switzerland; after exclusions, a total of 427 participants (211 randomized to levothyroxine and 216 to placebo) were analyzed. This analysis was conducted from December 1, 2019, to September 1, 2020. Interventions: Randomization to either levothyroxine or placebo. Main Outcomes and Measures: Depressive symptom scores after 12 months measured with the Geriatric Depression Scale (GDS-15), with higher scores indicating more depressive symptoms (minimal clinically important difference = 2). Results: A total of 427 participants with subclinical hypothyroidism (mean [SD] age, 74.52 [6.29] years; 239 women [56%]) were included in this analysis. The mean (SD) TSH level was 6.57 (2.22) mIU/L at baseline and decreased after 12 months to 3.83 (2.29) mIU/L in the levothyroxine group; in the placebo group, it decreased from 6.55 (2.04) mIU/L to 5.91 (2.66) mIU/L. At baseline, the mean (SD) GDS-15 score was 1.26 (1.85) in the levothyroxine group and 0.96 (1.58) in the placebo group. The mean (SD) GDS-15 score at 12 months was 1.39 (2.13) in the levothyroxine and 1.07 (1.67) in the placebo group with an adjusted between-group difference of 0.15 for levothyroxine vs placebo (95% CI, -0.15 to 0.46; P =.33). In a subgroup analysis including participants with a GDS-15 of at least 2, the adjusted between-group difference was 0.61 (95% CI, -0.32 to 1.53; P =.20). Results did not differ according to age, sex, or TSH levels. A previous meta-analysis (N = 278) on the association of levothyroxine with depressive symptoms was updated to include these findings, resulting in an overall standardized mean difference of 0.09 (95% CI, -0.05 to 0.22). Conclusions and Relevance: This ancillary study of a randomized clinical trial found that depressive symptoms did not differ after levothyroxine therapy compared with placebo after 12 months; thus, these results do not provide evidence in favor of levothyroxine therapy in older persons with subclinical hypothyroidism to reduce the risk of developing depressive symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT01853579.

2021 - Is dairy intake associated with less cognitive decline? A systematic review and meta-analysis of longitudinal studies [Abstract in Rivista]
Villoz, Fanny; Filippini, Tommaso; Blum, Manuel; DEL GIOVANE, Cinzia; Vinceti, Marco; Rodondi, Nicolas; Chocano-Bedoya, Patricia
abstract

Introduction: With aging population, prevention of cognitive de- cline is a major concern in primary care. Nutrition is a modifiable factor that could have a clinical impact in this prevention. In par- ticular, the effects of the dairy intake on cognition are still contro- versial. We conducted a systematic review and meta-analysis on association between the dairy intake and cognitive decline or inci- dence of dementia with dose-response analysis. Methods: We included longitudinal studies with community-dwell- ing adults ≥ 18 years unselected on the basis of chronic conditions. Our primary outcomes were the decline of cognitive function as de- fined in studies and incidence of dementia at end of follow-up. We identified relevant literature through a systematic search of Em- base, Medline Ovid, Cochrane, Web of Science and Google Scholar from inception to end of July 2020. Two investigators conducted abstract and full-text screenings, data extractions, and risk-of-bias assessments using the Academy of Nutrition and Dietetics Quality Criteria Checklist (QCC). We performed a meta-analysis using a random-effects model. Results: We included 11 prospective studies with 46,896 partici- pants. We rated all studies at low risk of bias. Mean follow-up time was 11.7 years. Seven studies assessed cognitive decline through decrease in scores of various neuropsychological tests including MMSE (Mini-Mental State Examination). Three studies assessed dementia incidence using either MMSE threshold or DSM-IIIR/ DSM-IV criteria. Comparing highest vs. lowest dairy intake, we found no association between dairy and cognitive decline. (Sum- mary risk ratio-sRR=0.97; 95%CI 0.82, 1.16; 7 studies) although with large statistical heterogeneity (I2=76.75%). The dose-response anal- yses using g/day with 4 studies showed U-shaped curve, with low- est risk at approximately 120-130 g/day. We found an inverse asso- ciation between the dairy intake and dementia incidence (sRR=0.61; 95%CI 0.44, 0.86; I2 =43.65%; 3 studies)

2021 - Maintenance treatment with long-acting injectable antipsychotics for people with nonaffective psychoses: A network meta-analysis [Articolo su rivista]
Ostuzzi, G.; Bertolini, F.; Del Giovane, C.; Tedeschi, F.; Bovo, C.; Gastaldon, C.; Nose, M.; Ogheri, F.; Papola, D.; Purgato, M.; Turrini, G.; Correll, C. U.; Barbui, C.
abstract

Objective: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. Methods: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation (“acceptability”). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Results: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). Conclusions: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

2021 - Novel bleeding risk score for patients with atrial fibrillation on oral anticoagulants, including direct oral anticoagulants [Articolo su rivista]
Adam, L.; Feller, M.; Syrogiannouli, L.; Del-Giovane, C.; Donze, J.; Baumgartner, C.; Segna, D.; Floriani, C.; Roten, L.; Fischer, U.; Aeschbacher, S.; Moschovitis, G.; Schlapfer, J.; Shah, D.; Amman, P.; Kobza, R.; Schwenkglenks, M.; Kuhne, M.; Bonati, L. H.; Beer, J.; Osswald, S.; Conen, D.; Aujesky, D.; Rodondi, N.
abstract

Objective: Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs. Methods: We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the β-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel's c-statistics for model discrimination. Results: We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 ± 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19–0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63–0.80). Conclusion: In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination.

2021 - Prevalence and factors associated with chronic use of levothyroxine: A cohort study [Articolo su rivista]
Janett-Pellegri, C.; Wildisen, L.; Feller, M.; Del Giovane, C.; Moutzouri, E.; Grolimund, O.; Walter, P.; Waeber, G.; Marques-Vidal, P.; Vollenweider, P.; Rodondi, N.
abstract

Importance Levothyroxine prescriptions are rising worldwide. However, there are few data on factors associated with chronic use. Objective To assess the prevalence of chronic levothyroxine use, its rank among other chronic drugs and factors associated with chronic use. To assess the proportion of users outside the therapeutic range of thyroid-stimulating hormone (TSH). Design Cohort study (CoLaus|PsyCoLaus) with recruitment from 2003 to 2006. Follow-ups occurred 5 and 10 years after baseline. Participants A random sample of Lausanne (Switzerland) inhabitants aged 35-75 years. Main outcomes We evaluated the prevalence of chronic levothyroxine use and we then ranked it among the other most used chronic drugs. The ranking was compared to data from health insurance across the country. We assessed the association between each factor and chronic levothyroxine use in multivariable logistic regression models. The proportion of chronic levothyroxine users outside the usual TSH therapeutic range was assessed. Results 4,334 participants were included in the analysis (mean±SD age 62.8±10.4 years, 54.9% women). 166 (3.8%) participants were chronic levothyroxine users. Levothyroxine was the second most prescribed chronic drug after aspirin in the cohort (8.2%) and the third most prescribed when using Swiss-wide insurance data. In multivariable analysis, chronic levothyroxine use was associated with increasing age [odds ratio 1.03, 95% confidence interval 1.01-1.05 per 1-year increase]; female sex [11.87 (5.24-26.89)]; BMI [1.06 (1.02- 1.09) per 1-kg/m2 increase]; number of concomitant drugs [1.22 (1.16-1.29) per 1-drug increase]; and family history of thyroid pathologies [2.18 (1.37-3.48)]. Among chronic levothyroxine users with thyroid hormones assessment (n = 157), 42 (27%) were outside the TSH therapeutic range (17% overtreated and 10% undertreated). Conclusions In this population-based study, levothyroxine ranked second among chronic drugs. Age, female sex, BMI, number of drugs and family history of thyroid pathologies were associated with chronic levothyroxine use. More than one in four chronic users were over- or undertreated.

2021 - Rituximab for people with multiple sclerosis [Articolo su rivista]
Filippini, G.; Kruja, J.; Del Giovane, C.
abstract

BACKGROUND: Multiple sclerosis (MS) is the most common neurological cause of disability in young adults. Off-label rituximab for MS is used in most countries surveyed by the International Federation of MS, including high-income countries where on-label disease-modifying treatments (DMTs) are available.  OBJECTIVES: To assess beneficial and adverse effects of rituximab as 'first choice' and as 'switching' for adults with MS. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registers for completed and ongoing studies on 31 January 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled non-randomised studies of interventions (NRSIs) comparing rituximab with placebo or another DMT for adults with MS. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. We used the Cochrane Collaboration's tool for assessing risk of bias. We rated the certainty of evidence using GRADE for: disability worsening, relapse, serious adverse events (SAEs), health-related quality of life (HRQoL), common infections, cancer, and mortality. We conducted separate analyses for rituximab as 'first choice' or as 'switching', relapsing or progressive MS, comparison versus placebo or another DMT, and RCTs or NRSIs. MAIN RESULTS: We included 15 studies (5 RCTs, 10 NRSIs) with 16,429 participants of whom 13,143 were relapsing MS and 3286 progressive MS. The studies were one to two years long and compared rituximab as 'first choice' with placebo (1 RCT) or other DMTs (1 NRSI), rituximab as 'switching' against placebo (2 RCTs) or other DMTs (2 RCTs, 9 NRSIs). The studies were conducted worldwide; most originated from high-income countries, six from the Swedish MS register. Pharmaceutical companies funded two studies. We identified 14 ongoing studies. Rituximab as 'first choice' for relapsing MS Rituximab versus placebo: no studies met eligibility criteria for this comparison. Rituximab versus other DMTs: one NRSI compared rituximab with interferon beta or glatiramer acetate, dimethyl fumarate, natalizumab, or fingolimod in active relapsing MS at 24 months' follow-up. Rituximab likely results in a large reduction in relapses compared with interferon beta or glatiramer acetate (hazard ratio (HR) 0.14, 95% confidence interval (CI) 0.05 to 0.39; 335 participants; moderate-certainty evidence). Rituximab may reduce relapses compared with dimethyl fumarate (HR 0.29, 95% CI 0.08 to 1.00; 206 participants; low-certainty evidence) and natalizumab (HR 0.24, 95% CI 0.06 to 1.00; 170 participants; low-certainty evidence). It may make little or no difference on relapse compared with fingolimod (HR 0.26, 95% CI 0.04 to 1.69; 137 participants; very low-certainty evidence). The study reported no deaths over 24 months. The study did not measure disability worsening, SAEs, HRQoL, and common infections. Rituximab as 'first choice' for progressive MS One RCT compared rituximab with placebo in primary progressive MS at 24 months' follow-up. Rituximab likely results in little to no difference in the number of participants who have disability worsening compared with placebo (odds ratio (OR) 0.71, 95% CI 0.45 to 1.11; 439 participants; moderate-certainty evidence). Rituximab may result in little to no difference in recurrence of relapses (OR 0.60, 95% CI 0.18 to 1.99; 439 participants; low-certainty evidence), SAEs (OR 1.25, 95% CI 0.71 to 2.20; 439 participants; low-certainty evidence), common infections (OR 1.14, 95% CI 0.75 to 1.73; 439 participants; low-certainty evidence), cancer (OR 0.50, 95% CI 0.07 to 3.59; 439 participants; low-certainty evidence), and mortality (OR 0.25, 95% CI 0.02 to 2.77; 439 participants; low-certainty evidence). The study did not measure HRQoL. Rituximab versus other DMTs: no studies met eligibility criteria for this comparison. Rituximab as 'switching' for relapsing MS  One RCT compared rituximab with placebo in relapsing MS

2021 - Rituximab for people with multiple sclerosis [Articolo su rivista]
Filippini, G.; Kruja, J.; He, D.; Del Giovane, C.
abstract

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The main objective is to assess the benefits and harms of rituximab compared to placebo or another DMT for people with multiple sclerosis. Specific comparisons include:. rituximab compared with placebo or other DMTs as first choice treatment for relapsing forms of MS; rituximab when switching from another DMT compared with placebo or other DMTs for relapsing forms of MS; rituximab compared with placebo or other DMTs as first choice treatment for progressive forms of MS; and rituximab when switching from another DMT compared with placebo or other DMTs for progressive forms of MS.

2021 - Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation [Articolo su rivista]
Moutzouri, E.; Lyko, C.; Feller, M.; Blum, M. R.; Adam, L.; Blum, S.; Aeschbacher, S.; Fischer, U.; Roten, L.; Del Giovane, C.; Meyer-Zuern, C. S.; Conte, G.; Bonati, L. H.; Moschovitis, G.; Kuhne, M.; Beer, J.; Aujesky, D.; Osswald, S.; Conen, D.; Rodondi, N.
abstract

Objective: To evaluate if subclinical thyroid dysfunction is associated with cardiovascular (CV) risk in patients with atrial fibrillation (AF). Methods: Swiss-AF is a prospective cohort of community-dwelling participants aged ≥ 65 years with AF. Primary outcome was a composite endpoint of CV events (myocardial infarctions, stroke/transitory ischemic events, systemic embolism, heart failure (HF) hospitalizations, CV deaths). Secondary outcomes were component endpoints, total mortality, and AF-progression. Exposures were thyroid dysfunction categories, TSH and fT4. Sensitivity analyses were performed for amiodarone use, thyroid hormones use, and competing events. Results: 2415 patients were included (mean age: 73.2 years; 27% women). 196 (8.4%) had subclinical hypothyroidism and 53 (2.3%) subclinical hyperthyroidism. Subclinical thyroid dysfunction was not associated with CV events, during a median follow-up of 2.1 years (max 5 years): age- and sex-adjusted hazard ratio (adjHR) of 0.99 (95% CI: 0.69-1.41) for subclinical hypothyroidism and 0.55 (95% CI: 0.23-1.32) for subclinical hyperthyroidism. Results remained robust following multivariable adjustment and sensitivity analyses. In euthyroid patients, fT4 levels were associated with an increased risk for the composite endpoint and HF (adjHR: 1.46, 95% CI: 1.04-2.05; adjHR: 1.70, 95% CI: 1.08-2.66, respectively, for the highest quintile vs the middle quintile). Results remained similar following multivariable adjustment and remained significant for HF in sensitivity analyses. No association between subclinical thyroid dysfunction and total mortality or AF-progression was found. Conclusions: Subclinical hypothyroidism was not associated with increased CV risk in AF patients. Higher levels of fT4 with normal TSH were associated with a higher risk for HF.

2021 - The gut-microbiome as a target for the treatment of schizophrenia: A systematic review and meta-analysis of randomised controlled trials of add-on strategies [Articolo su rivista]
Minichino, A.; Brondino, N.; Solmi, M.; Del Giovane, C.; Fusar-Poli, P.; Burnet, P.; Cipriani, A.; Lennox, B. R.
abstract

The gut-microbiome has been hypothesised as a novel potential target for intervention for schizophrenia. We tested this hypothesis with a systematic review and meta-analysis of studies investigating the efficacy and acceptability of add-on strategies known to affect the gut-microbiome for the treatment of schizophrenia. Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobials, pre/probiotics, and faecal transplant in schizophrenia. Primary outcomes were severity of negative symptoms and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. We identified 28 eligible trials: 21 investigated antibiotics, 4 antimicrobials (Artemisinin, Artemether, and Sodium Benzoate), 3 pre/probiotics, none faecal transplant. Results showed no effect of D-Cycloserine (10 studies; SMD, −0.16; 95% CI −0.40, 0.08; P = .20; I2: 28.2%), Minocycline (7 studies; SMD: −0.35; 95% CI −0.70, 0.00; P = .05, I2:77.7%), other antibiotics (2 studies), probiotics alone (1 study), and Artemisinin (1 study) on negative symptoms of schizophrenia when compared to placebo. Limited evidence suggests efficacy on negative symptoms for Sodium benzoate (2 studies; SMD, −0.63; 95%CI −1.03, −0.23; P < .001; I2:0%), Artemether (1 study), and probiotics combined with Vitamin D (1 study) when compared to placebo. Acceptability of intervention was similar to placebo. Negative findings were mainly led by antibiotics trials, with paucity of evidence available on pre/probiotics. There is a need of expanding our knowledge on the clinical relevance of gut-microbiome-host interaction in psychosis before engaging in further trials.

2021 - Tolerability of statin-based management of patients with a history of statin-associated muscle symptoms: Protocol for a systematic review [Articolo su rivista]
Villoz, F.; Lyko, C.; Del Giovane, C.; Rodondi, N.; Blum, M. R.
abstract

Introduction Statin-associated muscle symptoms (SAMSs) are a major clinical issue in the primary and secondary prevention of cardiovascular events. Current guidelines advise various approaches mainly based on expert opinion. We will lead a systematic review and meta-analysis to explore the tolerability and acceptability and effectiveness of statin-based therapy management of patients with a history of SAMS. We aim to provide evidence on the tolerability and different strategies of statin-based management of patients with a history of SAMS. Methods and analysis We will conduct a systematic review of randomised controlled trials (RCTs) and non-randomised studies with a control group. We will search in Data sources MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest from inception until April 2021. Two independent reviewers will carry out the study selection based on eligibility criteria. We will extract data following a standard data collection form. The reviewers will use the Cochrane Collaboration's tools and Newcastle-Ottawa Scale to appraise the study risk of bias. Our primary outcome will be tolerability and our secondary outcomes will be acceptability and effectiveness. We will conduct a qualitative analysis of all included studies. In addition, if sufficient and homogeneous data are available, we will conduct quantitative analysis. We will synthesise dichotomous data using OR with 95% CI and continuous outcomes by using mean difference or standardised mean difference (with 95% CI). We will determine heterogeneity visually with forest plots and quantitatively with I 2 and Q-test. We will summarise the confidence in the quantitative estimate by using Grading of Recommendations Assessment, Development and Evaluation approach. Ethics and dissemination As a systematic review of literature without collection of new clinical data, there will be no requirement for ethical approval. We will disseminate findings through peer-reviewed publications. PROSPERO registration number CRD42020202619.

2021 - Treating insomnia in Swiss primary care practices: A survey study based on case vignettes [Articolo su rivista]
Linder, S.; Duss, S. B.; Dvorak, C.; Merlo, C.; Essig, S.; Tal, K.; Del Giovane, C.; Syrogiannouli, L.; Heinzer, R.; Nissen, C.; Bassetti, C. L. A.; Auer, R.; Maire, M.
abstract

Guidelines recommend cognitive behavioural therapy for insomnia (CBT-I) as first-line treatment for chronic insomnia, but it is not clear how many primary care physicians (PCPs) in Switzerland prescribe this treatment. We created a survey that asked PCPs how they would treat chronic insomnia and how much they knew about CBT-I. The survey included two case vignettes that described patients with chronic insomnia, one with and one without comorbid depression. PCPs also answered general questions about treating chronic insomnia and about CBT-I and CBT-I providers. Of the 820 Swiss PCPs we invited, 395 (48%) completed the survey (mean age 54 years; 70% male); 87% of PCPs prescribed sleep hygiene and 65% phytopharmaceuticals for the patient who had only chronic insomnia; 95% prescribed antidepressants for the patient who had comorbid depression. In each case, 20% of PCPs prescribed benzodiazepines or benzodiazepine receptor agonists, 8% prescribed CBT-I, 68% said they knew little about CBT-I, and 78% did not know a CBT-I provider. In the clinical case vignettes, most PCPs treated chronic insomnia with phytopharmaceuticals and sleep hygiene despite their lack of efficacy, but PCPs rarely prescribed CBT-I, felt they knew little about it, and usually knew no CBT-I providers. PCPs need more information about the benefits of CBT-I and local CBT-I providers and dedicated initiatives to implement CBT-I in order to reduce the number of patients who are prescribed ineffective or potentially harmful medications.

2021 - Treatment of depression in children and adolescents – Authors' reply [Articolo su rivista]
Zhou, X.; Teng, T.; Del Giovane, C.; Furukawa, T. A.; Weisz, J. R.; Cipriani, A.; Xie, P.
abstract

2020 - Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety [Articolo su rivista]
Lattanzi, S.; Brigo, F.; Trinka, E.; Zaccara, G.; Striano, P.; Del Giovane, C.; Silvestrini, M.
abstract

Background: Dravet syndrome (DS) is one of the most severe forms of drug-resistant epilepsy and available interventions fail to control seizures in most patients. Cannabidiol (CBD) is the first in a new class of antiepileptic drugs with a distinctive chemical structure and mechanism of action. Objective: The aim of this systematic review was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with DS using meta-analytical techniques. Methods: We searched for randomized, placebo-controlled, single- or double-blinded trials. Main outcomes included ≥ 50% reduction in baseline convulsive seizure frequency and the incidence of treatment withdrawal and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (95% CIs) were estimated through the inverse variance method. Results: Three trials were included involving 359 participants, 228 for CBD and 131 for placebo groups. In all trials, the active treatment was a plant-derived pharmaceutical formulation of purified CBD oral solution. The pooled RR for 50% response during the treatment was 1.69 (95% CI 1.21–2.36; p = 0.002). Across the trials, treatment was discontinued in 20 (9.0%) and 3 (2.3%) cases in the add-on CBD and placebo groups, respectively; the RR for CBD withdrawal was 3.12 (95% CI 1.07–9.10; p = 0.037). The RR to develop any AE during add-on CBD treatment was 1.06 (95% CI 0.87–1.28; p = 0.561). AEs significantly associated with adjunctive CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Conclusions: Adjunctive CBD resulted in a greater reduction in convulsive seizure frequency than placebo and a higher rate of AEs in patients with DS presenting with seizures uncontrolled by concomitant antiepileptic therapy.

2020 - Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Zaccara, G.; Striano, P.; Del Giovane, C.; Silvestrini, M.; Brigo, F.
abstract

Background: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABAA receptors, binding at a non-benzodiazepine site. Objective: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. Methods: We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. Results: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67–2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93–7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85–2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08–4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02–1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. Conclusions: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

2020 - An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms [Articolo su rivista]
Wildisen, L.; Del Giovane, C.; Moutzouri, E.; Beglinger, S.; Syrogiannouli, L.; Collet, T. -H.; Cappola, A. R.; Asvold, B. O.; Bakker, S. J. L.; Yeap, B. B.; Almeida, O. P.; Ceresini, G.; Dullaart, R. P. F.; Ferrucci, L.; Grabe, H.; Jukema, J. W.; Nauck, M.; Trompet, S.; Volzke, H.; Westendorp, R.; Gussekloo, J.; Kloppel, S.; Aujesky, D.; Bauer, D.; Peeters, R.; Feller, M.; Rodondi, N.
abstract

In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck’s Depression Inventory (BDI) scale (range 0–63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = − 0.17 to 0.76, I2 = 15.6) or subclinical hyperthyroidism (− 0.10, 95% confidence interval = − 0.67 to 0.48, I2 = 3.2) compared to euthyroidism. This systematic review and IPD analysis of six prospective cohort studies found no clinically relevant association between subclinical thyroid dysfunction at baseline and depressive symptoms during follow-up. The results were robust in all sensitivity and subgroup analyses. Our results are in contrast with the traditional notion that subclinical thyroid dysfunction, and subclinical hypothyroidism in particular, is associated with depressive symptoms. Consequently, our results do not support the practice of prescribing levothyroxine in patients with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

2020 - Association between colorectal cancer testing and insurance type: Evidence from the Swiss Health Interview Survey 2012 [Articolo su rivista]
Braun, A. L.; Kassner, A.; Syrogiannouli, L.; Selby, K.; Bulliard, J. -L.; Martin, Y.; Guessous, I.; Tal, K.; Del Giovane, C.; Zwahlen, M.; Auer, R.
abstract

Both colonoscopy and fecal occult blood test (FOBT) are commonly used for colorectal cancer (CRC) screening, but colonoscopy costs much more than FOBT. Swiss insurance offers high or low deductibles and choice of basic or private insurance. We hypothesized that high deductibles and basic insurance discourage colonoscopy, but do not change FOBT rates. We determined the proportion of patients tested for CRC in Switzerland (colonoscopy within 10 years, FOBT within 2 years), and determined associations with health insurance type. We extracted data on 50–75-year-olds from the Swiss Health Interview Surveys of 2012 to determine colonoscopy and FOBT testing rates (n = 7335). Multivariate logistic regression models estimated prevalence ratios (PRs) of CRC testing associated with health insurance type (deductible and private insurance), adjusted for socio-demographic factors (age, gender, education, income) and self-rated health. The weighted proportion of individuals tested for CRC within recommended intervals was 39.5%. Testing with colonoscopy was significantly associated with private insurance (PR 1.85, 95% CI: 1.46–2.35) and low deductible (PR 2.00, 95% CI: 1.56–2.57). Testing with FOBT was significantly associated with deductible (PR 1.71, 95%CI:1.09–2.68) but not with private insurance. About 60% of the Swiss population was not current with CRC testing. After adjusting for covariates, private insurance and low deductible was significantly associated with higher prevalence of CRC testing, indicating that waiving the deductible could increase CRC screening uptake and reduce health inequality.

2020 - Cannabidiol efficacy and clobazam status: A systematic review and meta-analysis [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Striano, P.; Zaccara, G.; Del Giovane, C.; Nardone, R.; Silvestrini, M.; Brigo, F.
abstract

Objective: To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques. Methods: We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated. Results: Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P =.015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P <.001). Significance: CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.

2020 - Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis [Articolo su rivista]
Zhou, X.; Teng, T.; Zhang, Y.; Del Giovane, C.; Furukawa, T. A.; Weisz, J. R.; Li, X.; Cuijpers, P.; Coghill, D.; Xiang, Y.; Hetrick, S. E.; Leucht, S.; Qin, M.; Barth, J.; Ravindran, A. V.; Yang, L.; Curry, J.; Fan, L.; Silva, S. G.; Cipriani, A.; Xie, P.
abstract

Background: Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents. Methods: We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841. Findings: From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (–0·78, 95% CrI −1·55 to −0·01) and psychodynamic therapy (–1·14, −2·20 to −0·08), but not more effective than fluoxetine alone (–0·22, −0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from −1·73 to −0·51); and only interpersonal therapy was more effective than all psychological controls (–1·37 to −0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as “low” to “very low” in terms of confidence of evidence according to Confidence In Network Meta-Analysis. Interpretation: Despite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. Funding: National Key Research and Development Program of China.

2020 - Effect of Thyroid Hormone Therapy on Fatigability in Older Adults with Subclinical Hypothyroidism: A Nested Study within a Randomized Placebo-Controlled Trial [Articolo su rivista]
Stuber, M. J.; Moutzouri, E.; Feller, M.; Del Giovane, C.; Bauer, D. C.; Blum, M. R.; Collet, T. -H.; Gussekloo, J.; Mooijaart, S. P.; McCarthy, V. J. C.; Aujesky, D.; Westendorp, R.; Stott, D. J.; Glynn, N. W.; Kearney, P. M.; Rodondi, N.; Newman, A.
abstract

Background: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue. Method: This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged =65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 µg (25 µg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose. Results: Among 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p <. 001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p =. 88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p =. 26). In participants with higher fatigability at baseline (=15 points for the physical score [n = 88] or =13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p =. 79) and -2.2 (95% CI -8.8 to 4.5, p =. 51). Conclusions: Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.

2020 - Low reporting of cointerventions in recent cardiovascular clinical trials: A systematic review [Articolo su rivista]
Moutzouri, E.; Adam, L.; Feller, M.; Syrogiannouli, L.; Da Costa, B. R.; Del Giovane, C.; Bauer, D. C.; Aujesky, D.; Chiolero, A.; Rodondi, N.
abstract

BACKGROUND: A cointervention in a randomized clinical trial (RCT) is medical care given in addition to the tested intervention. If cointerventions are unbalanced between trial arms, the results may be biased. We hypothesized that cointerventions would be more adequately reported in RCTs without full blinding or at risk of bias. METHODS AND RESULTS: To describe the reporting of cointerventions and to evaluate the factors associated with their reporting, we did a systematic search of all RCTs evaluating pharmacological interventions on cardiovascular outcomes published in 5 high-impact journals. The reporting of cointerventions, blinding, and risk of bias were extracted and evaluated independently by 2 reviewers (E.M., L.A.). Cointerventions were inadequately reported in 87 of 123 RCTs (70.7%), with 56 (45.5%) providing no information on cointerventions and 31 (25.2%) providing only partial information. Of the RCTs, 52 (42.3%) had inadequate blinding of participants and/or personnel and 63 (51.2%) of the RCTs were judged at risk of bias. In univariable analysis, the reporting of cointerventions was not associated with blinding of participants and/or personnel (odds ratio [OR], 1.04; 95% CI, 0.47–2.27 for adequately versus inadequately blinded trials) or with risk of bias (OR, 1.47; 95% CI, 0.67–3.21 for at low risk of bias versus trials at risk of bias). In multivariable analysis, only a follow-up of <1 month was associated with the adequate reporting of cointerventions (OR, 3.63; 95% CI, 1.21–10.91). CONCLUSIONS: More than two-thirds of recent major cardiovascular trials did not adequately report cointerventions. The quality of reporting was not better among trials that were not fully blinded or at risk for bias.

2020 - Prevalence and management of chronic insomnia in Swiss primary care: Cross-sectional data from the “Sentinella” practice-based research network [Articolo su rivista]
Maire, M.; Linder, S.; Dvorak, C.; Merlo, C.; Essig, S.; Tal, K.; Del Giovane, C.; Syrogiannouli, L.; Duss, S. B.; Heinzer, R.; Nissen, C.; Bassetti, C. L. A.; Auer, R.
abstract

We investigated the prevalence and treatment of patients with chronic insomnia presenting to Swiss primary care physicians (PCPs) part of “Sentinella”, a nationwide practice-based research network. Each PCP consecutively asked 40 patients if they had sleep complaints, documented frequency, duration, comorbidities, and reported ongoing treatment. We analysed data of 63% (83/132) of the PCPs invited. The PCPs asked 76% (2,432/3,216) of included patients about their sleep (51% female); 31% (761/2,432) of these had had insomnia symptoms; 36% (875/2,432) had current insomnia symptoms; 11% (269/2,432) met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for chronic insomnia (61% female). In all, 75% (201/269) of patients with chronic insomnia had comorbidities, with 49% (99/201) reporting depression. Chronic insomnia was treated in 78% (209/269); 70% (188/268) took medication, 38% (102/268) benzodiazepines or benzodiazepine receptor agonists, 32% (86/268) took antidepressants. Only 1% (three of 268) had been treated with cognitive behavioural therapy for insomnia (CBT-I). A third of patients presenting for a non-urgent visit in Swiss primary care reported insomnia symptoms and 11% met the DSM-5 criteria for chronic insomnia. Hypnotics were the most common treatment, but almost no patients received first-line CBT-I. Reducing the burden of insomnia depends on disseminating knowledge about and access to CBT-I, and encouraging PCPs to discuss it with and offer it as a first-line treatment to patients with chronic insomnia.

2020 - Retrospective Analysis of Factors Associated with Long-Stay Hospitalizations in an Acute Psychiatric Ward [Articolo su rivista]
DI LORENZO, Rosaria; Montardi, Giulia; Panza, Leda; DEL GIOVANE, Cinzia; Saraceni, Serena; Rovesti, Sergio; Ferri, Paola
abstract

Purpose: To evaluate the longest hospitalizations in an acute psychiatric ward [Service of Psychiatric Diagnosis and Treatment (SPDT)] and the related demographic, clinical and organizational variables to understand the factors that contribute to long-stay (LOS) phenomenon. The term “long stay” indicates clinical, social and organizational problems responsible for delayed discharges. In psychiatry, clinical severity, social dysfunction and/or health-care system organization appear relevant factors in prolonging stays. Patients and Methods: We divided all the SPDT hospitalizations from 1 January 2010 to 31 December 2015 into two groups based on the 97.5th percentile of duration: ≤36 day (n=3254) and >36 day (n=81) stays, in order to compare the two groups for the selected variables. Comparisons were made using Pearson’s chi-square for categorical data and t-test for continuous variables, the correlation between the LOS, as a dependent variable, and the selected variables was analyzed in stepwise multiple linear regression and in multiple logistic regression models. Results: The longest hospitalizations were significantly related to the diagnosis of “schizophrenia and other psychosis” (Pearson Chi2=17.24; p=0.045), the presence of moderate and severe aggressiveness (Pearson chi2=29; p=0.000), compulsory treatment (Pearson Chi2=8.05; p=0.005), parenteral or other route administration of psycho-pharmacotherapy (Pearson Chi2=12.91; p=0.007), poli-therapy (Pearson Chi2=6.40; p=0.041), complex psychiatric activities (Pearson Chi2=12.26; p=0.002) and rehabilitative programs (Pearson Chi2=37.05; p=0.000) during the hospitalization and at discharge (Pearson Chi2=29.89; p=0.000). Many demographic and clinical variables were statistically significantly correlated to the LOS at our multiple linear and logistic regression model. Conclusion: In our sample, clinical illness severity and need for complex therapeutic and rehabilitative treatments were associated with prolonged psychiatric hospitalizations. Understanding this phenomenon can have not only economic but also clinical, ethical and social relevance.

2020 - Second-line treatments in benzodiazepine-resistant convulsive status epilepticus: An updated network meta-analysis including the ESET Trial – What did change? [Articolo su rivista]
Brigo, F.; Del Giovane, C.; Nardone, R.; Trinka, E.; Lattanzi, S.
abstract

2020 - The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles [Articolo su rivista]
La Marca, A.; Capuzzo, M.; Donno, V.; Mignini Renzini, M.; Giovane, C. D.; D'Amico, R.; Sunkara, S. K.
abstract

Research Question: How much the variability in patients’ response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients’ basal characteristics? Design: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. Results: Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients’ characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). Conclusions: The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients’ characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

2020 - Which psychotherapy is effective in panic disorder? And which delivery formats are supported by the evidence? Study protocol for two systematic reviews and network meta-analyses [Articolo su rivista]
Papola, D.; Ostuzzi, G.; Gastaldon, C.; Purgato, M.; Del Giovane, C.; Pompoli, A.; Karyotaki, E.; Sijbrandij, M.; Furukawa, T. A.; Cuijpers, P.; Barbui, C.
abstract

Introduction Panic disorder is among the most prevalent anxiety diseases. Although psychotherapy is recommended as first-line treatment for panic disorder, little is known about the relative efficacy of different types of psychotherapies. Moreover, there is little evidence concerning the effectiveness of different formats of major psychotherapeutic types, such as cognitive-behavioural therapy (CBT). In this protocol, we present an overarching project consisting of two systematic reviews and network meta-analyses (NMA) to shed light on which psychotherapy (NMA-1), and specifically, which CBT delivery format (NMA-2) should be considered most effective for adults suffering from panic disorder with or without agoraphobia. Methods and analyses Starting from a common pool of data, we will conduct two systematic reviews and NMA of randomised controlled trials examining panic disorder. A comprehensive search will be performed in electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Register of Controlled Trials - CENTRAL from database inception to 1 January 2021 to identify relevant studies. A systematic approach to searching, screening, reviewing and data extraction will be applied. Titles, abstract and - whenever necessary - full texts will be examined independently by at least two reviewers. The quality of the included studies will be assessed using the revised Cochrane risk of bias tool V.2. The primary efficacy outcome will be anxiety symptoms at study endpoint. The primary acceptability outcome will be all-cause discontinuation, as measured by the proportion of patients who had discontinued treatment for any reason at endpoint. Data will be pooled using a random-effects model. Pairwise and NMA will be conducted. Ethics and dissemination No ethical approval is necessary for these two studies, as there will be no collection of primary data. The results will be disseminated through peer-reviewed publications and presentations at national and international conferences and meetings.

2019 - Antiepileptic drug monotherapy for epilepsy in the elderly: A systematic review and network meta-analysis [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Del Giovane, C.; Nardone, R.; Silvestrini, M.; Brigo, F.
abstract

Objective: To estimate the comparative efficacy and safety of antiepileptic drugs (AEDs) in the elderly with new-onset epilepsy. Methods: We searched electronic databases for randomized controlled trials (RCTs) of monotherapy AEDs to treat epilepsy in elderly. The following outcomes were analyzed: seizure freedom and withdrawal from the study for any cause at 6 and 12 months; withdrawal from the study for any adverse event (AE) at 12 months; and occurrence of any AE at 12 months. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA) and mean ranks. Results: Five RCTs (1425 patients) were included. Included AEDs were carbamazepine immediate- and controlled-release (CBZ-IR, CBZ-CR), gabapentin (GBP), lacosamide (LCM), lamotrigine (LTG), levetiracetam (LEV), phenytoin (PHT), and valproic acid (VPA). At the pairwise and network meta-analyses, there were no differences in any of the comparison according to 6- and 12-month seizure freedom. The treatment with CBZ-IR and CBZ-CR was associated with a higher risk of withdrawal than LTG, LEV, or VPA, and CBZ-IR had the overall highest probability of discontinuation across all AEDs. According to SUCRA, the following had the greatest likelihood ranking best for seizure freedom at 6 and 12 months: LCM, LTG, and LEV. CBZ-CR and CBZ-IR had the highest probabilities of being worst for the 12-month retention. CBZ-IR, CBZ-CR, and GBP had the highest probabilities of withdrawal from the study for AEs, and VPA had the highest probability of being the best-tolerated option. Significance: Although no significant difference in efficacy was found across treatments, LCM, LTG, and LEV had the highest probability of ranking best for achieving seizure freedom. CBZ-IR and CBZ-CR showed a poor tolerability profile, leading to higher withdrawal rates compared to LEV and VPA.

2019 - Combining Pharmacological and Nonpharmacological Interventions in Network Meta-analysis in Psychiatry [Articolo su rivista]
Del Giovane, C.; Cortese, S.; Cipriani, A.
abstract

2019 - Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: A systematic review and network meta-analysis [Articolo su rivista]
Tramacere, I.; Boncoraglio, G. B.; Banzi, R.; Del Giovane, C.; Kwag, K. H.; Squizzato, A.; Moja, L.
abstract

Background: Statins may prevent recurrent ischemic events after ischemic stroke. Determining which statin to use remains controversial. We aimed to summarize the evidence for the use of statins in secondary prevention for patients with ischemic stroke by comparing benefits and harms of various statins. Methods: We searched for randomized controlled trials (RCTs) assessing statins in patients with ischemic stroke or transient ischemic attack (TIA) in MEDLINE, EMBASE, and CENTRAL up to July 2017. Two authors extracted data and appraised risks of bias. We performed pairwise meta-analyses and trial sequential analyses (TSA) to compare statins versus placebo/no statin, and network meta-analyses using frequentist random-effects models to compare statins through indirect evidence. We used GRADE to rate the overall certainty of evidence. Primary outcomes were all-cause mortality and all strokes. Secondary outcomes were different types of strokes, cardiovascular events, and adverse events. Results: We identified nine trials (10,741 patients). No head-to-head RCTs were found. The median follow-up period was 2.5 years. Statins did not seem to modify all stroke and all-cause mortality outcomes; they were associated with a decreased risk of ischemic stroke (odds ratio, OR, 0.81 [95% CI, 0.70 to 0.93]; absolute risk difference, ARD, - 1.6% [95% CI, - 2.6 to - 0.6%]), ischemic stroke or TIA (OR, 0.75 [95% CI, 0.64 to 0.87]; ARD, - 4.2% [95% CI, - 6.2 to - 2.1%]), and cardiovascular event (OR, 0.75 [95% CI, 0.69 to 0.83]; ARD, - 5.4% [95% CI, - 6.8 to - 3.6%]), and did not seem to modify rhabdomyolysis, myalgia, or rise in creatine kinase. In the comparison of different statins, moderate- to high-quality evidence indicated that differences between pharmaceutical products seemed modest, with high doses (e.g., atorvastatin 80 mg/day and simvastatin 40 mg/day) associated with the greatest benefits. TSA excluded random error as a cause of the findings for ischemic stroke and cardiovascular event outcomes. Evidence for increased risk of hemorrhagic stroke was sensitive to the exclusion of the SPARCL trial. Conclusions: Evidence strongly suggests that statins are associated with a reduction in the absolute risk of ischemic strokes and cardiovascular events. Differences in effects among statins were modest, signaling potential therapeutic equivalence. Trial registration: PROSPERO CRD42018079112

2019 - Different Types and Acceptability of Psychotherapies for Acute Anxiety Disorders in Children and Adolescents: A Network Meta-analysis [Articolo su rivista]
Zhou, X.; Zhang, Y.; Furukawa, T. A.; Cuijpers, P.; Pu, J.; Weisz, J. R.; Yang, L.; Hetrick, S. E.; Del Giovane, C.; Cohen, D.; James, A. C.; Yuan, S.; Whittington, C.; Jiang, X.; Teng, T.; Cipriani, A.; Xie, P.
abstract

Importance: Anxiety disorders are common in children and adolescents, and uncertainty remains regarding the optimal strategy of psychotherapies in this population. Objective: To compare and rank the different types of psychotherapies and the different ways of delivering psychological treatments for anxiety disorders in children and adolescents. Data Sources: PubMed, Cochrane Central Register of Controlled Trials, EMBASE, PsycINFO, Web of Science, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ProQuest Dissertations, LILACS (Literatura Latino Americana em Ciências da Saúde), international trial registers, and US Food and Drug Administration reports were searched from inception to November 30, 2017. Study Selection: Randomized clinical trials that compared any structured psychotherapy with another psychotherapy or a control condition for anxiety disorders in children and adolescents were selected. Data Extraction and Synthesis: Four researchers independently performed data extraction and quality assessment. Pairwise meta-analyses and Bayesian network meta-analysis within the random-effects model were used to synthesize data. Main Outcomes and Measures: Efficacy (change in anxiety symptoms) posttreatment and at follow-up, acceptability (all-cause discontinuation), and quality of life and functional improvement were measured. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Results: A total of 101 unique trials including 6625 unique participants compared 11 different psychotherapies with 4 specific control conditions. The certainty of evidence was rated as low or very low for most comparisons. For efficacy, most psychotherapies were significantly more effective than the wait list condition posttreatment (standardized mean difference [SMD], -1.43 to -0.61) and at the longest follow-up (SMD, -1.84 to -1.64). However, only group cognitive behavioral therapy (CBT) was significantly more effective than the other psychotherapies and all control conditions posttreatment. For acceptability, bibliotherapy CBT had significantly more all-cause discontinuations than some psychotherapies and control conditions (range of odds ratios, 2.48-9.32). In terms of quality of life and functional improvement, CBT (delivered in different ways) was significantly beneficial compared with psychological placebo and the wait list condition (SMDs, 0.73 to 1.99). Conclusions and Relevance: Group CBT would be the more appropriate choice of psychotherapy for anxiety disorders in children and adolescents, based on these findings. Other types of psychotherapies and different ways of delivering psychological treatment can be alternative options. Further research is needed to explore specific anxiety disorders, disorder-specific psychotherapy, and moderators of treatment effect.

2019 - Intravenous antiepileptic drugs in adults with benzodiazepine-resistant convulsive status epilepticus: A systematic review and network meta-analysis [Articolo su rivista]
Brigo, F.; Del Giovane, C.; Nardone, R.; Trinka, E.; Lattanzi, S.
abstract

Aim: The aim of this study was to estimate the comparative efficacy and safety of antiepileptic drugs (AEDs) in adults with benzodiazepine-resistant convulsive status epilepticus (SE). Methods: MEDLINE, CENTRAL, ClinicalTrials.gov, and Opengrey.eu were searched (from inception to 3rd April, 2018) for randomized controlled trials (RCTs) of AEDs used intravenously to treat benzodiazepine-resistant SE in adults. Efficacy outcomes were SE cessation within 1 h from drug administration and seizure freedom at 24 h. Safety outcomes were respiratory depression and hypotension. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA) and mean ranks. Results: Five RCTs were considered, involving 349 patients. Included interventions were valproate (VPA; 20–30 mg/kg), phenytoin (PHT; 20 mg/kg), diazepam (DZP; 0.2 mg/kg, then 4 mg/h), phenobarbital (PHB; 20 mg/kg, then 100 mg every 6 h), lacosamide (LCM; 400 mg), and levetiracetam (LEV; 20 mg/kg); PHB was superior to PHT, VPA, DZP, LEV, and LCM with respect to SE cessation and performed better than VPA, DZP, and LCM in the achievement of seizure freedom at 24 h. No differences were noted between drugs in the occurrence of respiratory depression and hypotension. According to SUCRA, PHB had the greatest probabilities of being best in the achievement of SE control and seizure freedom, whereas VPA and LCM ranked best for the safety outcomes. Conclusions: Our study suggests that high-dose PHB is effective in controlling SE and preventing seizure recurrence, and LCM and VPA could be better tolerated options. Further head-to-head comparative studies are strongly required to provide more definitive evidence. This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

2019 - Stem cell transplantation for ischemic stroke [Articolo su rivista]
Boncoraglio, G. B.; Ranieri, M.; Bersano, A.; Parati, E. A.; Giovane, C. D.
abstract

Background Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010. Objectives To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke. Search methods We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MED-LINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018). Selection criteria We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation). Data collection and analysis Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach. Main results In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial. Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD]-1.49, 95% confidence interval [CI]-2.65 to-0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD-0.42, 95% CI-0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI-1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants. No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence). We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias. Authors’ conclusions Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neuro

2019 - Subclinical thyroid dysfunction and depressive symptoms: protocol for a systematic review and individual participant data meta-analysis of prospective cohort studies [Articolo su rivista]
Wildisen, L.; Moutzouri, E.; Beglinger, S.; Syrogiannouli, L.; Cappola, A. R.; Asvold, B. O.; Bakker, S. J. L.; Ceresini, G.; Dullaart, R.; Ferrucci, L.; Grabe, H.; Jukema, J. W.; Nauck, M.; Trompet, S.; Volzke, H.; Westendorp, R. G. J.; Gussekloo, J.; Peeters, R. P.; Kloppel, S.; Aujesky, D.; Bauer, D. C.; Rodondi, N.; Del Giovane, C.; Feller, M.
abstract

INTRODUCTION: Prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms have yielded conflicting findings, possibly because of differences in age, sex, thyroid-stimulating hormone cut-off levels or degree of baseline depressive symptoms. Analysis of individual participant data (IPD) may help clarify this association. METHODS AND ANALYSIS: We will conduct a systematic review and IPD meta-analysis of prospective studies on the association between subclinical thyroid dysfunction and depressive symptoms. We will identify studies through a systematic search of the literature in the Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to April 2019 and from the Thyroid Studies Collaboration. We will ask corresponding authors of studies that meet our inclusion criteria to collaborate by providing IPD. Our primary outcome will be depressive symptoms at the first available individual follow-up, measured on a validated scale. We will convert all the scores to the Beck Depression Inventory scale. For each cohort, we will estimate the mean difference of depressive symptoms between participants with subclinical hypothyroidism or hyperthyroidism and control adjusted for depressive symptoms at baseline. Furthermore, we will adjust our multivariable linear regression analyses for age, sex, education and income. We will pool the effect estimates of all studies in a random-effects meta-analysis. Heterogeneity will be assessed by I2. Our secondary outcomes will be depressive symptoms at a specific follow-up time, at the last available individual follow-up and incidence of depression at the first, last and at a specific follow-up time. For the binary outcome of incident depression, we will use a logistic regression model. ETHICS AND DISSEMINATION: Formal ethical approval is not required as primary data will not be collected. Our findings will have considerable implications for patient care. We will seek to publish this systematic review and IPD meta-analysis in a high-impact clinical journal. PROSPERO REGISTRATION NUMBER: CRD42018091627.

2018 - Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis [Articolo su rivista]
De Crescenzo, F.; Ciabattini, M.; D'Alo, G. L.; De Giorgi, R.; Del Giovane, C.; Cassar, C.; Janiri, L.; Clark, N.; Ostacher, M. J.; Cipriani, A.
abstract

Background: Clinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction. Methods and findings: We searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24–6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03–28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33–7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02–5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32–8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13–14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased. Conclusions: To our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-makers.

2018 - Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: Study protocol for a systematic review and network meta-analysis [Articolo su rivista]
Zhang, Y.; Zhou, X.; Yang, L.; Hetrick, S. E.; Weisz, J. R.; Cuijpers, P.; Barth, J.; Del Giovane, C.; Yuan, S.; Cohen, D.; Gillies, D.; Jiang, X.; Teng, T.; Xie, P.
abstract

Introduction Post-traumatic stress disorder (PTSD) is common among children and adolescents who are exposed to trauma, and it is often associated with significant negative impacts on their psychosocial functioning and quality of life. Many types of psychotherapies have been found to be effective for PTSD in children and adolescents. However, due to the lack of direct comparisons between different psychotherapies, the hierarchy of treatment efficacy is still unclear. Therefore, we plan to conduct a systematic review and network meta-analysis to evaluate the efficacy and acceptability of various types of psychotherapies for PTSD in children and adolescents. Methods and analysis A systematic search will be conducted among eight electronic databases, including PubMed, Cochrane, Embase, Web of Science, PsycINFO, Cumulative Index of Nursing and Allied Health, Published International Literature on Traumatic Stress (PILOTS) and ProQuest Dissertations, from inception to October 2017. Randomised controlled trials, regardless of language, publication year and publication type, comparing any psychotherapies for PTSD to any control condition or alternative treatment in children and adolescents (18 years old or less) diagnosed with full or subclinical PTSD will be included. Study duration and the number of treatment sessions will not be limited. The primary outcome will be PTSD symptom severity at post-treatment as measured by a rating scale reported by the child, parent or a clinician. The secondary outcomes will include: (1) efficacy at follow-up; (2) acceptability (all-cause discontinuation); (3) anxiety symptom severity; (4) depressive symptom severity and (5) quality of life and functional improvement. Bayesian network meta-analyses for all relative outcome measures will be performed. We will conduct subgroup and sensitivity network meta-analyses to determine whether the findings are affected by study characteristics. The quality of the evidence contributing to network estimates of the primary outcome will be evaluated by the Grading of Recommendations, Assessment, Development and Evaluations framework. Ethics and dissemination No ethical issues are foreseen. The results will be published in a peer-reviewed journal, which will be disseminated electronically and in print. This network meta-analysis may be updated to inform and guide the clinical management of PTSD in children and adolescents. PROSPERO registration number CRD42016051786.

2018 - Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis [Articolo su rivista]
Cortese, S.; Adamo, N.; Del Giovane, C.; Mohr-Jensen, C.; Hayes, A. J.; Carucci, S.; Atkinson, L. Z.; Tessari, L.; Banaschewski, T.; Coghill, D.; Hollis, C.; Simonoff, E.; Zuddas, A.; Barbui, C.; Purgato, M.; Steinhausen, H. -C.; Shokraneh, F.; Xia, J.; Cipriani, A.
abstract

Background: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. Methods: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. Findings: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints. Interpretation: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment o

2018 - Comparative efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents: Protocol of an individual patient data meta-analysis [Articolo su rivista]
Zhou, X.; Cipriani, A.; Furukawa, T. A.; Cuijpers, P.; Zhang, Y.; Hetrick, S. E.; Pu, J.; Yuan, S.; Del Giovane, C.; Xie, P.
abstract

Introduction Although previous conventional meta-analyses and network meta-analyses have provided some important findings about pharmacological treatments for children and adolescents with depressive disorders in the past decades, several questions still remain unsolved by the aggregate data from those meta-analyses. Individual participant data meta-analysis (IPD-MA) enables exploration of the impacts of individual characteristics on treatment effects, allowing matching of treatments to specific subgroups of patients. We will perform an IPD-MA to assess the efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents. Methods and analysis We will systematically search for all double-blind randomised controlled trials (RCTs) that have compared any new-generation antidepressant with placebo for the acute treatment of major depressive disorder in children and adolescents, in the following databases: PubMed, EMBASE, the Cochrane Library, PsycINFO, Web of Science, CINAHL, LILACS and ProQuest Dissertations. We will contact all corresponding authors of included RCTs and ask for their cooperation in this project by providing individual participant data from the original trials. The primary outcomes will include efficacy, measured as the mean change of depression symptoms by Children's Depression Rating Scale Revised (CDRS-R), and tolerability, measured as the proportion of patients who withdrew from the trials early due to adverse effects. The secondary outcomes will include response rates, remission rates, deterioration rate, all-cause discontinuation, suicidal-related outcomes and global functioning outcome. Using the raw de-identified study data, we will use mixed-effects logistic and linear regression models to perform the IPD-MAs. The risk of bias of included studies will be assessed using the Cochrane risk of bias tool. We will also detect the publication bias and effects of non-participation of eligible studies. Dissemination Ethical approval is not required given that informed consent has already been obtained from the patients by the trial investigators before the included trials were conducted. This study may have considerable implications for practice and help improve patient care.

2018 - Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis [Articolo su rivista]
Lattanzi, S.; Brigo, F.; Trinka, E.; Zaccara, G.; Cagnetti, C.; Del Giovane, C.; Silvestrini, M.
abstract

Background: Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability. Objective: The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques. Methods: Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs). Results: Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Conclusions: Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

2018 - Psychometric properties of the Patient Dignity Inventory in an acute psychiatric ward: an extension study of the preliminary validation [Articolo su rivista]
DI LORENZO, Rosaria; Ferri, Paola; Biffarella, Carlotta; Cabri, Giulio; Carretti, Eleonora; Pollutri, Gabriella; Spattini, Ludovica; DEL GIOVANE, Cinzia; Chochinov Harvey, Max
abstract

Background: During the last decades, dignity has been an emerging issue in mental health since its ethical and therapeutic implications became known. This study is an extension of the preliminary validation of the Patient Dignity Inventory (PDI) in a psychiatric setting, originally designed for assessing perceived dignity in terminal cancer patients. Methods: From October 21, 2015 to December 31, 2016, we administered the Italian PDI to all patients hospitalized in an acute psychiatric ward, who provided their consent and completed it at discharge (n=165). We performed Cronbach’s alpha coefficient and principal factor analysis. We administered other scales concomitantly to analyze the concurrent validity of PDI. We applied stepwise multiple linear regression to identify the patients’ demographic and clinical variables related to the PDI score. Results: Our response rate was 93%, with excellent internal consistency (Cronbach’s alpha coefficient=0.94). The factorial analysis showed three factors with eigenvalue .1, which explained .80% of total variance: 1) “loss of self-identity and anxiety for the future”, 2) “concerns for social dignity and spiritual life”, and 3) “loss of personal autonomy”. The PDI and the three factor scores were positively and significantly correlated with the Hamilton Scales for Depression and Anxiety but not with other scale scores. Among patients’ variables, “suicide risk” and “insufficient social and economic condition” were positively and significantly correlated with the PDI total score. Conclusion: The PDI can be a reliable tool to assess patients’ dignity perception in a psychiatric setting, which suggests that both social and clinical severe conditions are closely related to dignity loss.

2018 - Screening and treatment of hypertension in older adults: Less is more? [Articolo su rivista]
Anker, D.; Santos-Eggimann, B.; Santschi, V.; Del Giovane, C.; Wolfson, C.; Streit, S.; Rodondi, N.; Chiolero, A.
abstract

Screening and treatment of hypertension is a cornerstone of cardiovascular disease (CVD) prevention. Hypertension causes a large proportion of cases of stroke, coronary heart disease, heart failure, and associated disability and is highly prevalent especially among older adults. On the one hand, there is robust evidence that screening and treatment of hypertension prevents CVD and decreases mortality in the middle-aged population. On the other hand, among older adults, observational studies have shown either positive, negative, or no correlation between blood pressure (BP) and cardiovascular outcomes. Furthermore, there is a lack of high quality evidence for a favorable harm-benefit balance of antihypertensive treatment among older adults, especially among the oldest-old (i.e., above the age of 80 years), because very few trials have been conducted in this population. The optimal target BP may be higher among older treated hypertensive patients than among middle-aged. In addition, among frail or multimorbid older individuals, a relatively low BP may be associated with worse outcomes, and antihypertensive treatment may cause more harm than benefit. To guide hypertension screening and treatment recommendations among older patients, additional studies are needed to determine the most efficient screening strategies, to evaluate the effect of lowering BP on CVD risk and on mortality, to determine the optimal target BP, and to better understand the relationship between BP, frailty, multimorbidity, and health outcomes.

2018 - Selenium for preventing cancer [Articolo su rivista]
Vinceti, Marco; Filippini, Tommaso; Del Giovane, Cinzia; Dennert, Gabriele; Zwahlen, Marcel; Brinkman, Maree; Zeegers, Maurice P. A.; Horneber, Markus; D'Amico, Roberto; Crespi, Catherine M.
abstract

Background: This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer. Objectives: To gather and present evidence needed to address two research questions: 1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans. Search methods: We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries. Selection criteria: We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants. Data collection and analysis: We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach. Main results: We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk. Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed. In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individu

2018 - Supplementary Data [Articolo su rivista]
Amato, L.; Vecchi, S.; Barbui, C.; Cruciani, F.; D'Amico, R.; Del Giovane, C.; Minozzi, S.; Mitrova, Z.; Saulle, R.; Davoli, M.
abstract

2018 - Unbalanced risk-benefit analysis of ADHD drugs – Authors' reply [Articolo su rivista]
Cipriani, A.; Adamo, N.; Giovane, C. D.; Coghill, D.; Banaschewski, T.; Hollis, C.; Zuddas, A.; Simonoff, E.; Cortese, S.
abstract

2017 - A preliminary study of Patient Dignity Inventory validation among patients hospitalized in an acute psychiatric ward [Articolo su rivista]
Di Lorenzo, Rosaria; Cabri, Giulio; Carretti, Eleonora; Galli, Giacomo; Giambalvo, Nina; Rioli, Giulia; Saraceni, Serena; Spiga, Giulia; DEL GIOVANE, Cinzia; Ferri, Paola
abstract

Purpose: To investigate the perception of dignity among patients hospitalized in a psychiatric setting using the Patient Dignity Inventory (PDI), which had been first validated in oncologic field among terminally ill patients. Patients and methods: After having modified two items, we administered the Italian version of PDI to all patients hospitalized in a public psychiatric ward (Service of Psychiatric Diagnosis and Treatment of a northern Italian town), who provided their consent and completed it at discharge, from October 21, 2015 to May 31, 2016. We excluded minors and patients with moderate/severe dementia, with poor knowledge of Italian language, who completed PDI in previous hospitalizations and/or were hospitalized for ,72 hours. We collected the demographic and clinical variables of our sample (n=135). We statistically analyzed PDI scores, performing Cronbach’s alpha coefficient and principal factor analysis, followed by orthogonal and oblique rotation. We concomitantly administered to our sample other scales (Hamilton Rating Scales for Depression and Anxiety, Global Assessment of Functioning and Health of the Nation Outcome Scales) to analyze the PDI concurrent validity. Results: With a response rate of 93%, we obtained a mean PDI score of 48.27 (±19.59 SD) with excellent internal consistency (Cronbach’s alpha coefficient =0.93). The factorial analysis showed the following three factors with eigenvalue .1 (Kaiser’s criterion), which explained .80% of total variance with good internal consistency: 1) “Loss of self-identity and social role”, 2) “Anxiety and uncertainty for future” and 3) “Loss of personal autonomy”. The PDI and the three-factor scores were statistically significantly positively correlated with the Hamilton Scales for Depression and Anxiety but not with other scale scores. Conclusion: Our preliminary research suggests that PDI can be a reliable tool to assess patients’ dignity perception in a psychiatric setting, until now little investigated, helping professionals to improve quality of care and patients to accept treatments.

2017 - Comparative efficacy and acceptability of antidepressants, psychological interventions, and their combination for depressive disorder in children and adolescents: Protocol for a network meta-analysis [Articolo su rivista]
Zhou, X.; Cipriani, A.; Zhang, Y.; Cuijpers, P.; Hetrick, S. E.; Weisz, J. R.; Pu, J.; Giovane, C. D.; Furukawa, T. A.; Barth, J.; Coghill, D.; Leucht, S.; Yang, L.; Ravindran, A. V.; Xie, P.
abstract

Introduction Depressive disorder is common in children and adolescents, with important consequences and serious impairments in terms of personal and social functioning. While both pharmacological and psychological interventions have been shown to be effective, there is still uncertainty about the balance between these and what treatment strategy should be preferred in clinical practice. Therefore, we aim to compare and rank in a network meta-analysis (NMA) the commonly used psychological, pharmacological and combined interventions for depressive disorder in children and adolescents. Methods and analysis We will update the literature search of two previous NMAs for the identification of trials of antidepressant and psychotherapy alone for depressive disorder in children and adolescents. For identification of trials of combination interventions, seven databases (PubMed, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, CINAHL, LiLACS) will be searched from date of inception. We will also search ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and check relevant reports on the US Food and Drug Administration website for unpublished data. Building on our previous findings in the field, we will include any commonly prescribed oral antidepressants and any manualised or structured psychotherapies, as well as their combinations. Randomised controlled trials assessing any active intervention against active comparator or pill placebo/psychological controls in acute treatment for depressive disorder in children and adolescents will be included. The primary outcomes will be efficacy (mean change in depressive symptoms), and acceptability of treatment (dropout rate due to any cause). The secondary outcomes will be remission rate, tolerability of treatment (dropouts for adverse events), as well as suicide-related outcomes (suicidal behaviour or ideation). We will perform Bayesian NMAs for all relative outcome measures. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings. Dissemination This NMA will provide the most up to date and clinically useful information about the comparative efficacy and acceptability of antidepressants, psychological intervention and their combination in the acute treatment of children and adolescents with depressive disorder. This is the newest NMA and therefore these results are very important in terms of evidence-based medicine. The results will be disseminated through peer-reviewed publication. Protocol registration PROSPERO CRD42015020841.

2017 - Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: Protocol for a systematic review and network meta-analysis [Articolo su rivista]
Cortese, S.; Adamo, N.; Mohr-Jensen, C.; Hayes, A. J.; Bhatti, S.; Carucci, S.; Del Giovane, C.; Atkinson, L. Z.; Banaschewski, T.; Simonoff, E.; Zuddas, A.; Barbui, C.; Purgato, M.; Steinhausen, H. -C.; Shokraneh, F.; Xia, J.; Cipriani, A.; Coghill, D.
abstract

Introduction Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. Methods and analysis We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. Ethics and dissemination No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences.

2017 - Medication-related visits in a pediatric emergency department: an 8-years retrospective analysis [Articolo su rivista]
Rosafio, Cristiano; Paioli, Serena; DEL GIOVANE, Cinzia; Cenciarelli, Valentina; Viani, Nilla; Bertolani, Paolo; Iughetti, Lorenzo
abstract

There are limited data on the characterization of medication-related visits (MRVs) to the emergency department (ED) in pediatric patients in Italy. We have estimated the frequency, severity, and classification of MRVs to the ED in pediatric patients.

2017 - Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease): An attempted network meta-analysis [Articolo su rivista]
Buzzetti, E.; Kalafateli, M.; Thorburn, D.; Davidson, B. R.; Thiele, M.; Gluud, L. L.; Del Giovane, C.; Askgaard, G.; Krag, A.; Tsochatzis, E.; Gurusamy, K. S.
abstract

Background: Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol-related liver disease remains controversial. Objectives: To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol-related liver disease through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta-analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol-related liver diseases. Selection criteria: Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol-related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co-existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. Data collection and analysis: Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. Main results: We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes. Alcoholic hepatitis Fifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow-up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta-analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health-related quality of life or incidence of hepatocellular carcinoma. Severe alcoholic hepatitis Of the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow-up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis. Source of funding: Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials. Other alcohol-related liver diseases Thirty-one randomised clinical trials included 3695 participants with other alcohol-related liver diseases (with a wide spectrum of alcohol-related liver diseases). Th

2017 - Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis [Articolo su rivista]
Filippini, G.; Del Giovane, C.; Clerico, M.; Beiki, O.; Mattoscio, M.; Piazza, F.; Fredrikson, S.; Tramacere, I.; Scalfari, A.; Salanti, G.
abstract

Background: The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions. Objectives: 1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment; 2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety; 3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment'). Search methods: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016). Selection criteria: We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide. Data collection and analysis: Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system. Main results: We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-up There was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glati

2016 - A modified prediction model for VBAC, in a European population [Articolo su rivista]
Annessi, E.; Del Giovane, C.; Magnani, L.; Carossino, E.; Baldoni, G.; Battagliarin, G.; Accorsi, P.; Facchinetti, F.
abstract

Objective: The first aim of the study is to validate the Grobmans Nomogram on Italian population, and then to include other variables with the purpose to increase the accuracy of the Nomogram.Methods: This is a multicenter study in which eligible subjects were pregnant women reaching term having one prior cesarean section (CS) and then choosing for a trial of labor. Multivariate logistic regression model have been performed, and then the predicted percentages of vaginal delivery (VD) success were divided into 10 groups and compared with the observed ones.Results: Among 1161 women, 1100 were enrolled, of which 857 (77.9%) delivered vaginally. At the multivariate logistic regression, the variables predicting vaginal birth after cesarean (VBAC) in the validation were maternal age (p < 0.001), maternal body mass index (p = 0.007), having had a VD (p = 0.008) and recurring indication for CS (p < 0.001). By adding the two new variables in the proposed model, was reached the significance of "African ethnicity" (p = 0.037) and especially "years of education" (p = 0.032).Conclusions: The Grobmans Nomogram seems to be applicable to Italian population too, even if with less accuracy than in the US population. The addition of the level of maternal education increases the accuracy of the model, underlining the importance of the social context in the choice of VBAC.

2016 - Adverse effects of immunotherapies for multiple sclerosis: A network meta-analysis [Articolo su rivista]
Tramacere, I.; Benedetti, M. D.; Capobussi, M.; Castellini, G.; Citterio, A.; Del Giovane, C.; Frau, S.; Gonzalez-Lorenzo, M.; La Mantia, L.; Moja, L.; Nuzzo, S.; Filippini, G.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: To compare adverse effects of immunotherapies for people with multiple sclerosis (MS) or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects.

2016 - Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study [Articolo su rivista]
Ferraro, Diana; Consonni, D.; Fini, N.; Fasano, Antonio; DEL GIOVANE, Cinzia; Emilia Romagna Registry for ALS, Group; Mandrioli, Jessica
abstract

Background and purpose: To compare two recently developed staging systems for amyotrophic lateral sclerosis (ALS) [King's College and Milano-Torino staging (MITOS) systems] in an incident, population-based cohort of patients with ALS. Methods: Since 2009, a prospective registry has been recording all incident cases of ALS in the Emilia Romagna region in Italy. For each patient, detailed clinical information, including the ALS functional rating scale score, is collected at each follow-up. Results: Our study on 545 incident cases confirmed that King's College stages occurred at predictable times and were quite evenly spaced out throughout the disease course (occurring at approximately 40%, 60% and 80% of the disease course), whereas MITOS stages were mostly skewed towards later phases of the disease. In the King's College system there was a decrease in survival and an increase in deaths with escalating stages, whereas in the MITOS system survival curves pertaining to intermediate stages overlapped and the number of deaths was fairly homogenous throughout most stages. Conclusions: The King's College staging system had a higher homogeneity (i.e. smaller differences in survival among patients in the same stage) and a higher discriminatory ability (i.e. greater differences in survival among patients in different stages), being more suitable for individualized prognosis and for measuring efficacy of therapeutic interventions.

2016 - Association of immunotherapies with outcomes in relapsing-remitting multiple sclerosis [Articolo su rivista]
Tramacere, I.; Del Giovane, C.; Filippini, G.
abstract

CLINICAL QUESTION: What immunotherapies for multiple sclerosis are associated with the greatest benefit and highest risk of discontinuation due to adverse events in patients with relapsing-remitting multiple sclerosis? BOTTOM LINE: Alemtuzumab, natalizumab, and fingolimod were associated with the greatest benefit with regard to relapse prevention. Their association with prevention of disability worsening was unclear. Fingolimod was associated with a high risk of treatment discontinuation due to adverse events.

2016 - Clinical outcome is not affected by total knee arthroplasty alignment [Articolo su rivista]
Mugnai, Raffaele; Zambianchi, Francesco; Digennaro, Vitantonio; Marcovigi, Andrea; Tarallo, Luigi; DEL GIOVANE, Cinzia; Catani, Fabio
abstract

Purpose: This study aims to analyse the influence on total knee arthroplasty (TKA) clinical outcomes of biomechanical intra-operative computer-assisted surgery-measured parameters, together with radiographic and demographical data. Methods: Between 2007 and 2009, 227 computer-assisted surgery (CAS) primary TKAs were performed in 219 consecutive patients. Information about gender, age and body mass index (BMI) was collected for each patient. Before knee replacement, all patients underwent a complete radiographic examination and passive flexion–extension range of motion was recorded. All TKAs were implanted using an image-free knee navigation system. Patients included in the study were evaluated at 3, 6 and 12Â months of follow-up and then yearly. At each follow-up, subjects were asked to answer the validated Italian version of the Knee Injury and Osteoarthritis Outcome Score. Results: One hundred and eighty patients (187 knees) had data available for analysis. Complications were reported in 13 patients (7.0Â %). Intra-operative CAS-measured parameters, together with age, BMI, gender, pre- and post-operative radiographic alignment, did not influence TKA clinical results at a mean 2Â years of follow-up. On the other hand, higher post-operative flexion arc of movement was suggestive of better clinical outcomes. Conclusion: TKA clinical outcome is influenced by post-operative knee flexion, other than neutral mechanical limb alignment. Therefore, it is recommended to prefer TKA designs that allow high flexion and to encourage early physical rehabilitation. Level of evidence: IV.

2016 - Comparative efficacy and acceptability of pharmacological treatments for insomnia in adults: A systematic review and network meta-analysis [Articolo su rivista]
De Crescenzo, F.; Foti, F.; Ciabattini, M.; Del Giovane, C.; Watanabe, N.; Sane Schepisi, M.; Quested, D. J.; Cipriani, A.; Barbui, C.; Amato, L.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: 1) To compare individual pharmacological treatments for insomnia in adults in terms of: efficacy, measured as self-rated quality of sleep or satisfaction with sleep; and acceptability of treatment. 2) To generate a clinically-useful hierarchy of available pharmacological treatments for insomnia in adults, according to their efficacy and acceptability.

2016 - Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis [Articolo su rivista]
Cipriani, A.; Zhou, X.; Del Giovane, C.; Hetrick, S. E.; Qin, B.; Whittington, C.; Coghill, D.; Zhang, Y.; Hazell, P.; Leucht, S.; Cuijpers, P.; Pu, J.; Cohen, D.; Ravindran, A. V.; Liu, Y.; Michael, K. D.; Yang, L.; Liu, L.; Xie, P.
abstract

Background Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. Methods We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. Findings We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference −0·51, 95% credible interval [CrI] −0·99 to −0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2 values were 33·21% for efficacy and 0% for tolerability. Interpretation When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. Funding National Basic Research Program of China (973 Program).

2016 - Mucorales-specific T cells in patients with hematologic malignancies [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Gilioli, Andrea; Forghieri, Fabio; Candoni, Anna; Cesaro, Simone; Quadrelli, Chiara; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Codeluppi, Mauro; Mussini, Cristina; Colaci, Elisabetta; Messerotti, Andrea; Paolini, Ambra; Maccaferri, Monica; Fantuzzi, Valeria; DEL GIOVANE, Cinzia; Stefani, Alessandro; Morandi, Uliano; Maffei, Rossana; Marasca, Roberto; Narni, Franco; Fanin, Renato; Comoli, Patrizia; Romani, Luigina; Beauvais, Anne; Viale, Pier Luigi; Latgè, Jean Paul; Lewis, Russell E.; Luppi, Mario
abstract

Background: Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. Methods and Findings: By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during highdose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD):2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Conclusions: Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.

2016 - Predictive role of haemoglobin on disease response to neoadjuvant chemotherapy in breast cancer. [Abstract in Atti di Convegno]
Omarini, Claudia; Iattoni, Elena; Filieri, Maria Elisabetta; Toss, Angela; Grizzi, Giulia; DEL GIOVANE, Cinzia; Valentina Tamma, Antonella; Cascinu, Stefano; Piacentini, Federico
abstract

Background: Tumour hypoxia has been shown to play an important role in the outcome of cancer patients. Data on the predictive role of haemoglobin (Hb) on disease response to primary therapies in breast cancer (BC) are lacking. The purpose of this study is to evaluate the influence of Hb level throughout treatment course in predicting the response to neoadjuvant chemotherapy. Methods: 252 patients diagnosed with stage I-III BC treated with anthracycline-taxane based primary chemotherapy were evaluated. Patient and tumor characteristics and treatment information were collected. Standard biological parameters (Ki67, nuclear grade, hormone receptors and HER2 status) were correlated with pathologic complete response (pCR). We focused on Hb (baseline and after therapy levels, drop in Hb throughout treatment) and its correlation to pCR rate. The Hb cut-off to discriminate anaemic vs non-anaemic patients was set at 12,0 g/dl. Results: Globally, pCR was achieved in 58 patients (23%), mainly in case of younger age ( < 50 years = 29%, ≥ 50 years = 17%; p = 0.01), high nuclear grade (Grade1-2 = 0%, grade 3 = 27%; p < 0.0001), high ki67 ( > 20% = 26%, < 20% = 12%; p = 0.02) and hormone receptor negative status (Luminal B/HER2 negative = 9%, Luminal B/HER2 positive = 32%, HER2 enriched = 46%, triple negative = 37%; p < 0.0001). Median baseline Hb was 13,3 g/dl while median Hb level after chemotherapy was 11.6 g/dl: pCR was not influenced by Hb level before and after primary chemotherapy. No difference in Hb levels were observed stratifying patients according to nuclear grade, tumour stage and cancer subtypes. Anaemia due to chemotherapy was reported in 56% of patients. The decrease in Hb levels from baseline was greater in patients with lower response rate. On univariate analysis, a decrease in Hb ≥ 2 g/dl was associated with a significantly lower rate of pCR (15% vs 43%; p = 0.047). This correlation was even more evident in the subgroup of anaemic patients (17% vs 32%; p = 0.037). Conclusions: A decrease in Hb ≥ 2 g/dl during neoadjuvant chemotherapy may negatively affect the rate of pCR in BC patients, thus suggesting that anaemia should be avoided in order to obtain the best response to primary treatments.

2016 - The Revolving Door Phenomenon in an Italian Acute Psychiatric Ward: A 5-Year Retrospective Analysis of the Potential Risk Factors [Articolo su rivista]
Di Lorenzo, R.; Sagona, M.; Landi, G.; Martire, L.; Piemonte, C.; Del Giovane, C.
abstract

To highlight the revolving door (RD) phenomenon in an acute psychiatric ward, we retrospectively identified the patients hospitalized three or more times in a calendar year from 1/1/2009 to 31/12/2013 as RD patients (RDP). We collected sociodemographic and clinical variables of RDP and statistically analyzed the potential RD risk factors. We divided RDP into "high" and "extremely high" utilizers and evaluated the variables related to more frequent readmissions. RDP represented 5.68% of all patients and their hospitalizations (RDH) 25% of all admissions. The statistically significant risk factors for all RDH were "disability pension," "substance abuse/dependence," "mild/severe aggressiveness," and "psychiatric and social rehabilitative programs". The comparison between "high" and "extremely high" utilizers showed that "manic episodes" and "personality disorders," among the diagnoses, "familial relational conflicts" and "violence/suicidality", among the hospitalization reasons, were statistically significant risk factors for more frequent readmissions. RD phenomenon was greatly affected by severe clinical conditions with social disability.

2016 - Treatment with disease modifying drugs for people with a first clinical attack suggestive of multiple sclerosis [Articolo su rivista]
Filippini, G.; Clerico, M.; Beiki, O.; Mattoscio, M.; Piazza, F.; Del Giovane, C.; Fredrikson, S.; Tramacere, I.; Scalfari, A.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: To estimate the benefit and safety of all DMDs that have been evaluated in all studies (randomised and non-randomised) for early treatment. We will employ novel, high-quality methods for systematic reviews and network meta-analysis in collaboration with the Cochrane Multiple Interventions Group. To evaluate the quality of the evidence provided by existing studies. We will consider the credibility of included studies and other characteristics of the evidence base as we characterise conclusions pertaining to high, low or very low quality of evidence. We will undertake this review in accordance with the methods described by the template protocol published online and will use this template as we prepare the review.

2016 - iNKT cells in secondary progressive multiple sclerosis patients display pro-inflammatory profiles [Articolo su rivista]
DE BIASI, Sara; Simone, ANNA MARIA; Nasi, Milena; Bianchini, Elena; Ferraro, Diana; Vitetta, Francesca; Gibellini, Lara; Pinti, Marcello; DEL GIOVANE, Cinzia; Sola, Patrizia; Cossarizza, Andrea
abstract

Background. Multiple Sclerosis (MS), an autoimmune disease with neurodegeneration and inflammation, is characterized by several alterations of different T cell subsets. However, few data exist on the role of iNKT lymphocytes. Objective. To identify possible changes in the phenotype of iNKT cells in patients with different clinical forms of MS, and find alterations in their polyfunctionality (i.e., ability to produce simultaneously up to 4 cytokines such as IL‐17, TNF‐α, IFN‐γ, IL‐4). Methods. We studied a total of 165 patients, 91 with a Relapsing Remitting form [RR; 31 were treated with interferon (IFN)1‐β, 25 with natalizumab (Nat), 29 with glatiramer acetate (Gla); 17 were newly-diagnosed RR without treatment, 19 not active RR without treatment]. Forty-four patients had a Progressive MS: 20 Primary Progressive (PP), 24 Secondary Progressive (SP). A total of 55 age- and sex-matched subjects represented healthy controls (CTR). Among fresh peripheral blood mononuclear cells (PBMC) iNKT cells were identified by flow cytometry. Moreover, the capability of iNKT cells to produce different cytokines (IL‐17, TNF‐α, IFN‐γ, and IL‐4) after in vitro stimulation were evaluated in 18 RR (11 treated with Nat and 7 with IFN), 4 PP, 6 SP and 16 CTR. Results. No main differences were found in iNKT cell phenotype among MS patients with different MS forms, or during different treatments. However, the polyfunctional response of iNKT cells showed Th1 and Th17 profiles. This was well evident in patients with secondary progressive form, who are characterized by high levels of inflammation and neurodegeneration, and exhibited a sustained increase in the production of Th17 cytokines. Patients treated with natalizumab displayed lower levels of iNKT cells producing IL‐17, TNF‐α and IFN‐γ. Conclusion. Our data suggest that the progressive phase of the disease is characterized by permanent iNKT activation and a skewing towards an inflammatory phenotype. Compared to other treatments, natalizumab was able to modulate iNKT cell function.

2015 - A review and meta-analysis of outdoor air pollution and risk of childhood leukemia [Articolo su rivista]
Filippini, Tommaso; Heck, J. E.; Malagoli, Carlotta; DEL GIOVANE, Cinzia; Vinceti, Marco
abstract

Leukemia is the most frequent malignant disease affecting children. To date, the etiology of childhood leukemia remains largely unknown. Few risk factors (genetic susceptibility, infections, ionizing radiation, etc.) have been clearly identified, but they appear to explain only a small proportion of cases. Considerably more uncertain is the role of other environmental risk factors, such as indoor and outdoor air pollution.We sought to summarize and quantify the association between traffic-related air pollution and risk of childhood leukemia, and further examined results according to method of exposure assessment, study quality, leukemia subtype, time period, and continent where studies took place. After a literature search yielded 6 ecologic and 20 case-control studies, we scored the studies based on the Newcastle-Ottawa Scale. The studies assessed residential exposure to pollutants from motorized traffic by computing traffic density in the neighboring roads or vicinity to petrol stations, or by using measured or modeled nitrogen dioxide and benzene outdoor air levels. Because heterogeneity across studies was observed, random-effects summary odds ratios (OR) and 95% confidence intervals (CI) were reported. Whenever possible we additionally conducted stratified analyses comparing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Limiting the analysis to high-quality studies (Newcastle-Ottawa Scale ≥ 7), those using traffic density as the exposure assessment metric showed an increase in childhood leukemia risk in the highest exposure category (OR = 1.07, 95% CI 0.93–1.24). However, we observed evidence of publication bias. Results for NO2 exposure and benzene showed an OR of 1.21 (95% CI 0.97–1.52) and 1.64 (95% CI 0.91–2.95) respectively. When stratifying by leukemia type, the results based upon NO2 were 1.21 (95% CI 1.04–1.41) for ALL and 1.06 (95% CI 0.51–2.21) for AML; based upon benzene were 1.09 (95% CI 0.67–1.77) for ALL and 2.28 (95% CI 1.09–4.75) for AML. Estimates were generally higher for exposures in the postnatal period compared to the prenatal period, and for European studies compared to North American studies. Overall, our results support a link between ambient exposure to traffic pollution and childhood leukemia risk, particularly due to benzene.

2015 - Atypical antipsychotic augmentation for treatment-resistant depression: A systematic review and network meta-analysis [Articolo su rivista]
Zhou, X.; Keitner, G. I.; Qin, B.; Ravindran, A. V.; Bauer, M.; Del Giovane, C.; Zhao, J.; Liu, Y.; Fang, Y.; Zhang, Y.; Xie, P.
abstract

Background: Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD). Methods: Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review. Results: All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from-0.27 to-0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250-350 mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD =-0.38; SMD =-0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250-350 mg daily). Conclusions: All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.

2015 - Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis [Articolo su rivista]
Ferraro, Diana; Galli, Veronica; Vitetta, Francesca; Simone, Anna Maria; Bedin, Roberta; Del Giovane, Cinzia; Morselli, Franca; Filippini, Maria Maddalena; Nichelli, Paolo Frigio; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) CXCL13 was shown to correlate with markers of intrathecal inflammation and CSF oligoclonal IgM bands (IgMOB) have been associated with a more severe Multiple Sclerosis (MS) course.We correlated CSF CXCL13 levels with clinical, MRI and CSF parameters, including CSF IgMOB, in 110 Clinically Isolated Syndrome (CIS) patients.CSF CXCL13 levels correlated with CSF cell count, total protein, IgG Index and with the presence of CSF IgGOB and IgMOB.CSF CXCL13 levels ≥. 15.4. pg/ml showed a good positive predictive value and specificity for a MS diagnosis and for a clinical relapse within one year from onset.

2015 - Comparative efficacy and acceptability of psychotherapies for acute anxiety disorders in children and adolescents: Study protocol for a network metaanalysis [Articolo su rivista]
Zhang, Y.; Zhou, X.; James, A. C.; Qin, B.; Whittington, C. J.; Cuijpers, P.; Giovane, C. D.; Liu, Y.; Cohen, D.; Weisz, J. R.; Xie, P.
abstract

Introduction: Anxiety disorders are associated with significant public health burden in young individuals. Cognitive-behavioural therapy (CBT) is the most commonly used psychotherapy for anxiety disorders in children and adolescents, but previous reviews were hindered by a limited number of trials with direct comparisons between different psychotherapies and their deliveries. Consequently, the main aim of this research was to investigate the comparative efficacy and acceptability of various types and deliveries of psychotherapies for anxiety disorders in children and adolescents. Methods and analysis: We will systematically search PubMed, EMBASE, Cochrane, Web of Science, PsycINFO, CINAHL, ProQuest Dissertations and LiLACS for randomised controlled trials, regardless of whether participants received blinding or not, published from 1 January 1966 to 30 January 2015 (updated to 1 July 2015), that compared any psychotherapy with either a control condition or an active comparator with different types and/or different delivery formats for the acute treatment of anxiety disorders in children and adolescents. Data extraction, risk of bias and quality assessments will be independently extracted by two reviewers. The primary outcome for efficacy will be mean overall change scores in anxiety symptoms (self-rated or assessor-rated) from baseline to post-treatment between two groups. The acceptability of treatment will be measured as the proportion of patients who discontinued treatment during the acute phase of treatment. We will assess efficacy, based on the standardised mean difference (SMD), and acceptability, based on the OR, using a random-effects network meta-analysis within a Bayesian framework. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. Ethics and dissemination: No ethical issues are foreseen. The results will be published in a peer-reviewed journal and will be disseminated electronically and in print. The meta-analysis may be updated to inform and guide management of anxiety in children and adolescents.

2015 - Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: A systematic review and network meta-analysis [Articolo su rivista]
Zhou, X.; Hetrick, S. E.; Cuijpers, P.; Qin, B.; Barth, J.; Whittington, C. J.; Cohen, D.; Del Giovane, C.; Liu, Y.; Michael, K. D.; Zhang, Y.; Weisz, J. R.; Xie, P.
abstract

Previous meta-analyses of psychotherapies for child and adolescent depression were limited because of the small number of trials with direct comparisons between two treatments. A network meta-analysis, a novel approach that integrates direct and indirect evidence from randomized controlled studies, was undertaken to investigate the comparative efficacy and acceptability of psychotherapies for depression in children and adolescents. Systematic searches resulted in 52 studies (total N=3805) of nine psychotherapies and four control conditions. We assessed the efficacy at post-treatment and at follow-up, as well as the acceptability (all-cause discontinuation) of psychotherapies and control conditions. At post-treatment, only interpersonal therapy (IPT) and cognitive-behavioral therapy (CBT) were significantly more effective than most control conditions (standardized mean differences, SMDs ranged from -0.47 to -0.96). Also, IPT and CBT were more beneficial than play therapy. Only psychodynamic therapy and play therapy were not significantly superior to waitlist. At follow-up, IPT and CBT were significantly more effective than most control conditions (SMDs ranged from -0.26 to -1.05), although only IPT retained this superiority at both short-term and long-term follow-up. In addition, IPT and CBT were more beneficial than problem-solving therapy. Waitlist was significantly inferior to other control conditions. With regard to acceptability, IPT and problem-solving therapy had significantly fewer all-cause discontinuations than cognitive therapy and CBT (ORs ranged from 0.06 to 0.33). These data suggest that IPT and CBT should be considered as the best available psychotherapies for depression in children and adolescents. However, several alternative psychotherapies are understudied in this age group. Waitlist may inflate the effect of psychotherapies, so that psychological placebo or treatment-as-usual may be preferable as a control condition in psychotherapy trials.

2015 - Comparative efficacy and tolerability of first-generation and newer-generation antidepressant medications for depressive disorders in children and adolescents: Study protocol for a systematic review and network meta-analysis [Articolo su rivista]
Zhou, X.; Qin, B.; Whittington, C.; Cohen, D.; Liu, Y.; Del Giovane, C.; Michael, K. D.; Zhang, Y.; Xie, P.
abstract

Introduction: Depressive disorders are among the most common psychiatric disorders in children and adolescents, and have adverse effects on their psychosocial functioning. Questions concerning the efficacy and safety of antidepressant medications in the treatment of depression in children and adolescents, led us to integrate the direct and indirect evidence using network meta-analysis to create hierarchies of these drugs. Methods and analysis: Seven databases with PubMed, EMBASE, the Cochrane Library, Web of Science, CINAHL, LiLACS and PsycINFO will be searched from 1966 to December 2013 (updated to May, 2015). There are no restrictions on language or type of publication. Randomised clinical trials assessing first-generation and newer-generation antidepressant medications against active comparator or placebo as acute treatment for depressive disorders in children and adolescents (under 18 years of age) will be included. The primary outcome for efficacy will be mean improvement in depressive symptoms, as measured by the mean change score of a depression rating scale from baseline to post-treatment. The tolerability of treatment will be defined as side effect discontinuation, as defined by the proportion of patients who discontinued treatment due to adverse events during the trial. We will also assess the secondary outcome for efficacy (response rate), acceptability (all-cause discontinuation) and suiciderelated outcomes. We will perform the Bayesian network meta-analyses for all relative outcome measures. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings. Dissemination: The network meta-analysis will provide useful information on antidepressant treatment for child and adolescent depression. The results will be disseminated through peer-reviewed publication or conference presentations.

2015 - Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: Systematic review and network meta-analysis [Articolo su rivista]
Zhou, X.; Ravindran, A. V.; Qin, B.; Del Giovane, C.; Li, Q.; Bauer, M.; Liu, Y.; Fang, Y.; Da Silva, T.; Zhang, Y.; Fang, L.; Wang, X.; Xie, P.
abstract

Objective: To comparatively analyze the efficacy, acceptability, and tolerability of various augmentation agents in adult patients with treatment-resistant depression. Data Sources: An electronic literature search of PubMed, EMBASE, the Cochrane Library, Web of Science, EBSCO, PsycINFO, EAGLE, and NTIS for trials published up to December 2013 was conducted. Several clinical trial registry agencies and US Food and Drug Administration reports were also reviewed. No language, publication date, or publication status restrictions were imposed. Study Selection: Randomized controlled trials comparing 11 augmentation agents (aripiprazole, bupropion, buspirone, lamotrigine, lithium, methylphenidate, olanzapine, pindolol, quetiapine, risperidone, and thyroid hormone) with each other and with placebo for adult treatment-resistant depression were included. Data Extraction: The proportion of patients who responded to treatment was defined as primary efficacy, and the proportion of all-cause discontinuation and side-effects discontinuation were respectively defined as acceptability and tolerability, which were assessed with odds ratios (ORs) and a Bayesian random-effects model with 95% credible intervals (CrIs). Results: A total of 48 trials consisting of 6,654 participants were eligible. In terms of the primary efficacy, quetiapine (OR = 1.92; 95% CrI, 1.39-3.13), aripiprazole (OR = 1.85; 95% CrI, 1.27-2.27), thyroid hormone (OR = 1.84; 95% CrI, 1.06-3.56), and lithium (OR = 1.56; 95% CrI, 1.05-2.55) were significantly more effective than placebo. Sensitivity analyses indicated that efficacy estimates for aripiprazole and quetiapine were more robust than those for thyroid hormone and lithium. In terms of acceptability, no significant difference was found between active agents and placebo. In terms of tolerability, compared to placebo, quetiapine (OR = 3.85; 95% CrI, 1.92-8.33), olanzapine (OR = 3.36; 95% CrI, 1.60-8.61), aripiprazole (OR = 2.51; 95% CrI, 1.11-7.69), and lithium (OR = 2.30; 95% CrI, 1.04-6.03) were significantly less well tolerated. Conclusions: Quetiapine and aripiprazole appear to be the most robust evidence-based options for augmentation therapy in patients with treatment-resistant depression, but clinicians should interpret these findings cautiously in light of the evidence of potential treatment-related side effects.

2015 - Distance as a barrier to cancer diagnosis and treatment: Review of the literature [Articolo su rivista]
Ambroggi, M.; Biasini, C.; Giovane, C. D.; Fornari, F.; Cavanna, L.
abstract

The burden of travel from a patient’s residence to health care providers is an important issue that can influence access to diagnosis and treatment ofcancer.Although several studies have shown that the travel burden can result in delays in diagnosis and treatment of many common cancers, its role appears underestimated in the treatment of patients in clinical practice. Therefore, we performed a review of the published data on the role of travel burden influencing four items: delay of diagnosis, adequate treatment of cancer, outcome, and quality of life of cancer patients. Forty-seven studies published up to December 2014 were initially identified. Twenty studies were excluded because they did not regard specifically the four items of our review.Twenty-seven studies formed the basis of our study and involved 716,153 patients. The associations between travel burden and (a) cancer stage at diagnosis (12 studies), (b) appropriate treatment (8 studies), (c) outcome (4 studies), and (d) quality of life (1 study) are reported. In addition, in two studies,therelationbetween travel burden and compliance with treatment was examined. The results of our review show that increasing travel requirements are associated with more advanced disease at diagnosis, inappropriatetreatment, aworse prognosis, and a worse quality of life. These results suggest that clinical oncologists should remember the specific travel burden problem for cancer patients, who often need health care services every week or every month for many years.

2015 - Efficacy and tolerability of antidepressants in the treatment of adolescents and young adults with depression and substance use disorders: A systematic review and meta-analysis [Articolo su rivista]
Zhou, X.; Qin, B.; Del Giovane, C.; Pan, J.; Gentile, S.; Liu, Y.; Lan, X.; Yu, J.; Xie, P.
abstract

Aims: To measure the effectiveness of antidepressants for adolescents and young adults with co-occurring depression and substance use disorder. Design, Setting and Participants: Meta-analysis of randomized controlled clinical trials. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science and PsychINFO was conducted (from 1970 to 2013). Prospective, parallel groups, double-blind, controlled trials with random assignment to an antidepressant or placebo on young patients (age≤25 years) who met diagnostic criteria of both substance use and unipolar depressive disorder were included. Five trials were selected for this analysis and included 290 patients. Measurements: Our efficacy outcome measures were depression outcomes (dichotomous and continuous measures) and substance-use outcomes (change of frequency or quantity of substance-use). Secondary analysis was conducted to access the tolerability of antidepressant treatment. Findings: For dichotomous depression outcome, antidepressants group was significantly more effective than placebo group [risk ratio (RR)=1.21; 95% confidence interval (CI) 1.01-1.45], with low heterogeneity (I2=0%). Although no statistically significant effects for continuous depression outcome [standardized mean differences (SMD)=-0.13; 95% CI, -0.55 to 0.30] were found with moderate heterogeneity (I2=63%), subgroup analysis showed that the medicine group with a sample size of more than 50 showed statistically significant efficacy compared with the placebo group (SMD -0.53, 95% CI -0.82 to -0.25). Moreover, there was no significant difference for substance-use outcomes and tolerability outcomes between the medication and placebo groups. Conclusions: Antidepressant medication has a small overall effect in reducing depression in young patients with combined depressive and substance-use disorders, but does not appear to improve substance use outcomes.

2015 - Exploring inconsistencies between observational and experimental studies of selenium and diabetes risk. [Abstract in Rivista]
Vinceti, Marco; Filippini, Tommaso; DEL GIOVANE, Cinzia; Crespi, Cm
abstract

Background: Observational and experimental epidemiologic studies that have addressed the relation between intake of the trace element selenium and cancer risk have yielded strongly conflicting results, as recently reported by a Cochrane review. Most observational studies suggest an inverse association, while randomized controlled trials (RCTs) have indicated a null or direct relation. Little is known about the replication of such inconsistencies when dealing with the risk of other chronic disease. Objectives: We investigated the results of observational and experimental studies linking selenium exposure to the occurrence of type 2 diabetes. Methods: After a literature search we identified 12 observational studies (8 cross-sectional and 4 cohort) and 5 RCTs. Using a random-effects model, we computed the summary relative risk (RR) of type-2 diabetes along with its 95% confidence interval (CI) in subjects with the highest versus the lowest selenium exposure category in observational studies, and in subjects allocated to selenium compared to placebo in the RCTs. Results: Summary RRs were 1.98 (95% CI 1.22-3.23) and 1.13 (0.15-8.45) for cross-sectional studies using serum and toenail selenium for exposure assessment, respectively. Cohort studies based on toenail selenium yielded a summary RR of 0.78 (0.62-0.98), while the only study assessing dietary selenium intake gave a RR of 2.39, (1.32-4.32). For RCTs, summary RR was 1.10 (1.00-1.21) among selenium-supplemented versus placebo. The distinctive feature of the two observational studies (one cross-sectional and one prospective) that failed to find an excess diabetes risk associated with higher selenium exposure was that the subjects were health professionals. Age, gender, study area and other demographic characteristics did not appear to have influenced the results. Conclusions: These results suggest that the ability of observational studies to predict results of RCTs when addressing the health effects of selenium may differ on the basis of the outcome studied (diabetes versus cancer) as well as the indicator used for exposure assessment and the type of population under study.

2015 - Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis [Articolo su rivista]
Tramacere, Irene; DEL GIOVANE, Cinzia; Salanti, Georgia; D'Amico, Roberto; Filippini, Graziella
abstract

Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biologics. Although there is consensus that these therapies reduce the frequency of relapses, their relative benefit in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison trials.

2015 - Induction of labor in women that had a previous cesarean delivery [Articolo su rivista]
Facchinetti, Fabio; DEL GIOVANE, Cinzia; Petrella, Elisabetta; Annessi, Eleonora
abstract

This study aims to evaluate factors that predict the likelihood of the success of induction of labor (IOL) in women that had a previous cesarean section (pCS).

2015 - Post-transplantation hepatocellular carcinoma recurrence: Patterns and relation between vascularity and differentiation degree [Articolo su rivista]
Pecchi, Annarita; Besutti, Giulia; de Santis, Mario; DEL GIOVANE, Cinzia; Nosseir, Sofia; Tarantino, Giuseppe; DI BENEDETTO, Fabrizio; Torricelli, Pietro
abstract

Aim: To evaluate the relationship between hepatocellular carcinoma (HCC) vascularity and grade; to describe patterns and vascular/histopathological variations of post-transplantation recurrence. Methods: This retrospective study included 165 patients (143 men, 22 women; median age 56.8 years, range 28-70.4 years) transplanted for HCC who had a follow-up period longer than 2 mo. Pre-transplantation dynamic computed tomography or magnetic resonance examinations were retrospectively reviewed, classifying HCC imaging enhancement pattern into hypervascular and hypovascular based on presence of wash-in during arterial phase. All pathologic reports of the explanted livers were reviewed, collecting data about HCC differentiation degree. The association between imaging vascular pattern and pathological grade was estimated using the Fisher exact test. All follow-up clinical and imaging data were reviewed for evidence of recurrence. Recurrence rate was calculated and imaging features of recurrent tumor were collected, classifying early and late recurrences based on timing (< or ≥ 2 years after transplantation) and intrahepatic, extrahepatic and both intrahepatic and extrahepatic recurrences based on location. All intrahepatic recurrences were classified as hypervascular or hypovascular and the differentiation degree was collected where available. The presence of variations in imaging enhancement pattern and pathological grade between the primary tumor and the intrahepatic recurrence was evaluated and the association between imaging and histopatholgical variations was estimated by using the χ2 test. Results: Of the 163 patients with imaging evidence of viable tumor, 156 (95.7%) had hypervascular and 7 (4.3%) hypovascular HCC. Among the 125 patients with evidence of viable tumor in the explanted liver, 19 (15.2%) had grade 1, 56 (44.8%) grade 2, 40 (32%) grade 3 and 4 (3.2%) grade 4 HCC, while the differentiation degree was not assessable for 6 patients (4.8%). A significant association was found between imaging vascularity and pathological grade (P = 0.035). Post-transplantation recurrence rate was 14.55% (24/165). All recurrences occurred in patients who had a hypervascular primary tumor. Three patients (12.5%) experienced late recurrence; the location of the first recurrence was extrahepatic in 14 patients (58.3%), intrahepatic in 7 patients (29.2%) and both intrahepatic and extrahepatic in 3 patients (12.5%). Two patients had a variation in imaging characteristics between the primary HCC (hypervascular) and the intrahepatic recurrent HCC (hypovascular), while 1 patient had a variation of histopathological characteristics (from moderate to poor differentiation), however no association was found between imaging and histopathological variations. Conclusion: A correlation was found between HCC grade and vascularity; some degree of variability may exist between the primary and the recurrence imaging/histopathological characteristics, apparently not correlated.

2015 - Prediction risk chart for scleroderma digital ulcers: A composite predictive model based on capillaroscopic, demographic and clinico-serological parameters [Articolo su rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Carraro, Valeria; Iudici, Michele; Bocci, Mario; Vukatana, Gentiana; Gerli, Roberto; De Angelis, Rossella; Del Medico, Patrizia; Praino, Emanuela; Lo Monaco, Andrea; D'Amico, Roberto; DEL GIOVANE, Cinzia; Mazzuca, Salvatore; Colaci, Michele; Giuggioli, Dilia; Ferri, Clodoveo
abstract

BACKGROUND: Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY: To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS: Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS: A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (≤19.3%); medium (>19.3%, ≤58.6%); high (>58.6%, ≤89.2%), and very high risk (>89.2%). CONCLUSIONS: The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy.

2015 - Retrospective analysis on safety and efficacy of everolimus in treatment of metastatic renal cancer patients receiving dialysis [Articolo su rivista]
Guida, A.; Masini, C.; Milella, M.; Di Lorenzo, G.; Santoni, M.; Prati, V.; Porta, C.; Cosmai, L.; Donati, D.; Del Giovane, C.; Mighali, P.; Sabbatini, R.
abstract

Aims: This retrospective study aimed to investigate safety and efficacy of everolimus in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring dialysis. Patients & methods: From November 2009 to December 2012, 11 mRCC patients undergoing dialysis were treated with everolimus after failure of anti-VEGF therapy at six Italian institutions. Patient characteristics, safety and outcomes were collected. Results: Progression-free survival and overall survival were determined using the Kaplan-Meier method. Median progression-free survival and overall survival were 9.01 and 15.7 months, respectively. No unexpected adverse events were reported. Conclusion: Everolimus appears to be safe in mRCC patients with renal impairment or end-stage renal disease requiring dialysis. Larger prospective studies are required to confirm these findings.

2015 - Systematic review with network meta-analysis: Comparative efficacy and safety of budesonide and mesalazine (mesalamine) for Crohn's disease [Articolo su rivista]
Moja, L.; Danese, S.; Fiorino, G.; Del Giovane, C.; Bonovas, S.
abstract

Background Budesonide and mesalazine (mesalamine) are commonly used in the medical management of patients with mild to moderate Crohn's disease. Aim To assess their comparative efficacy and harm using the methodology of network meta-analysis. Methods A comprehensive search of Medline, Embase, the Cochrane Library and ClinicalTrials.gov, through October 2014, was performed to identify randomised controlled trials (RCTs) that recruited adult patients with active or quiescent Crohn's disease, and compared budesonide or mesalazine with placebo, or against each other, or different dosing strategies of one drug. Results Twenty-five RCTs were combined using Bayesian network meta-analysis. Budesonide 9 mg/day, or at higher doses (15 or 18 mg/day), was shown superior to placebo for induction of remission [odds ratio (OR), 2.93; 95% credible interval (CrI), 1.52-5.39, and OR, 3.28; CrI, 1.46-7.55 respectively] and ranks at the top of the hierarchy of the competing treatments. For maintenance of remission, budesonide 6 mg/day demonstrated superiority over placebo (OR, 1.69; CrI, 1.05-2.75), being also at the best ranking position among all compared treatment strategies. No other comparisons (i.e. different doses of mesalazine vs. placebo or budesonide, for induction or maintenance of remission) reached significance. The occurrence of withdrawals due to adverse events was not shown different between budesonide, mesalazine and placebo, in both the induction and maintenance phases. Conclusions Budesonide, at the doses of 9 mg/day, or higher, for induction of remission in active mild or moderate Crohn's disease, and at 6 mg/day for maintenance of remission, appears to be the best treatment choice.

2015 - The impact of the Italian guidelines on antibiotic prescription practices for acute otitis media in a paediatric emergency setting [Articolo su rivista]
Palma, Silvia; Rosafio, Cristiano; DEL GIOVANE, Cinzia; Patianna, VIVIANA DORA; Lucaccioni, Laura; Genovese, Elisabetta; Bertolani, Paolo; Iughetti, Lorenzo
abstract

Acute otitis media (AOM) is one of the most common childhood infectious diseases. The recent Italian Pediatric Guidelines for the treatment of AOM constitutes a step forward in the management of children with uncomplicated AOM. The aim of this study was to evaluate antibiotic prescription patterns for AOM in a Pediatric Emergency Department (PED) after those guidelines were introduced and to assess the relationship between implementation of the "watchful waiting" strategy and the incidence of acute mastoiditis in the PED.

2014 - Acceptability, efficacy and safety of pharmacological interventions for cocaine dependence: An overview of Cochrane reviews [Articolo su rivista]
Amato, L.; Del Giovane, C.; Ferri, M.; Minozzi, S.; Schifano, P.; Davoli, M.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: To conduct an overview of Cochrane systematic reviews that assessed the effectiveness of any pharmacological treatments, alone or in combination with others, to treat cocaine abuse or dependence. Any pharmacological treatment will be assessed in terms of effectiveness in reducing symptoms, acceptability and safety and will be ranked according to their effectiveness and acceptability.

2014 - Efficacy, quality of life, and acceptability outcomes of atypical antipsychotic augmentation treatment for treatment-resistant depression: Protocol for a systematic review and network meta-analysis [Articolo su rivista]
Liu, Y.; Zhou, X.; Qin, B.; Del Giovane, C.; Zhang, Y.; Xie, P.
abstract

Background: Major depressive disorder (MDD) is a debilitating and costly mental disorder. Although commercially available antidepressants have proliferated over the last 20 years, a substantial number of patients either do not respond adequately to these drugs or are unable to tolerate their adverse effects. One common approach has been to augment conventional antidepressants with an adjunctive agent, but the optimal selection of atypical antipsychotic agents for adjunctive treatment of treatment-resistant depression (TRD) remains controversial. Methods/Design: An electronic literature search of PubMed, the Cochrane Library, Embase, Web of Science, LiLACS, CINAHL, and PsycINFO for studies will be conducted with no restrictions on language, publication year, or publication type. Several clinical trial registry agencies, pharmaceutical company websites, and FDA reports will also be reviewed. Randomized clinical trials (RCTs) with atypical antipsychotic augmentation treatment for treatment-resistant depression will be considered. Data will be independently extracted by two reviewers. Traditional pairwise meta-analyses will be performed for RCTs that directly compare different treatment arms. Then, Bayesian network meta-analyses will be performed to compare the relative efficacy and acceptability of different atypical antipsychotic agents (and doses). A sensitivity analysis will be performed by excluding studies classified as a small sample size, having a high placebo effect. Discussion: This systematic review and network meta-analysis will comparatively analyze the efficacy, quality of life, and acceptability profiles of atypical antipsychotic medications used for the adjunctive treatment of TRD. The findings should provide clinically relevant implications for comprehensively understanding the risk-benefit profiles of these adjunctive treatments. Systematic review registration: PROSPERO CRD 42014009666.

2014 - Evaluating the quality of evidence from a network meta-analysis [Articolo su rivista]
Salanti, G.; Giovane, C. D.; Chaimani, A.; Caldwell, D. M.; Higgins, J. P. T.
abstract

Systematic reviews that collate data about the relative effects of multiple interventions via network meta-analysis are highly informative for decision-making purposes. A network meta-analysis provides two types of findings for a specific outcome: the relative treatment effect for all pairwise comparisons, and a ranking of the treatments. It is important to consider the confidence with which these two types of results can enable clinicians, policy makers and patients to make informed decisions. We propose an approach to determining confidence in the output of a network meta-analysis. Our proposed approach is based on methodology developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group for pairwise meta-analyses. The suggested framework for evaluating a network meta-analysis acknowledges (i) the key role of indirect comparisons (ii) the contributions of each piece of direct evidence to the network meta-analysis estimates of effect size; (iii) the importance of the transitivity assumption to the validity of network meta-analysis; and (iv) the possibility of disagreement between direct evidence and indirect evidence. We apply our proposed strategy to a systematic review comparing topical antibiotics without steroids for chronically discharging ears with underlying eardrum perforations. The proposed framework can be used to determine confidence in the results from a network meta-analysis. Judgements about evidence from a network meta-analysis can be different from those made about evidence from pairwise meta-analyses. © 2014 Salanti et al.

2014 - HRCT Patterns Of Usual Interstitial Pneumonia In Rheumatoid Lung [Abstract in Rivista]
Tonelli, Roberto; Sverzellati, Nicola; DELLA CASA, Giovanni; Spagnolo, Paolo; Cerri, Stefania; Manfredi, Andreina Teresa; Sebastiani, Marco; Cocconcelli, Elisabetta; DEL GIOVANE, Cinzia; Balduzzi, Sara; Richeldi, Luca; Torricelli, Pietro; Ferri, Clodoveo; Luppi, Fabrizio
abstract

RATIONALE. Interstitial lung disease (ILD) is a well-recognized complication of rheumatoid arthritis (RA) and can present with different patterns on high-resolution computed tomography (HRCT) of the chest. It has been recently shown that a definite HRCT usual interstitial pneumonia (UIP) pattern is highly specific and moderately sensitive for a histopathologic UIP pattern. The aims of the present study were: i) to evaluate the prevalence of the UIP pattern on HRCT in patients with RA-ILD, as compared with patients with idiopathic pulmonary fibrosis (IPF) and ii) to assess the level of agreement between two experienced chest radiologists in detecting the UIP pattern in the two groups of patients. METHODS. 30 patients with RA and at least one chest HRCT showing interstitial changes were retrospectively identified from a single-center cohort of RA patients. Fifty-two patients with IPF based on current diagnostic criteria served as diseased controls. For patients who had more than one HRCT the more recent HRCT was selected. Two experienced thoracic radiologists (radiologist A and B) blinded to patient diagnosis scored all HRCT images independently. Radiologic patterns were categorized as definite UIP, possible UIP or inconsistent with UIP according to the most current international guidelines. The prevalence of the different patterns was assessed for both groups and compared by using the chi square test. The concordance between radiologists was determined using the Cohen kappa score. RESULTS. Radiologist A detected 4 definite UIP (13%), 10 possible UIP (33%) and 16 inconsistent with UIP patterns (53%) among patients with RA-ILD and 16 definite UIP (30%), 24 possible UIP (46%) and 12 inconsistent with UIP patterns (23%) among patients with IPF (chi square 0.016). Radiologist B identified 6 definite UIP (20%), 9 possible UIP (30%) and 15 inconsistent with UIP patterns (50%) in the RA-ILD group and 23 definite UIP (44%), 16 possible UIP (30%) and 13 inconsistent with UIP patterns (25%) in the IPF group (chi square 0.036). Diagnostic agreement in UIP pattern detection was 71.2% (κ= 0.57) for the IPF group and 76.7% (κ =0.62) for the RA-ILD group. CONCLUSIONS. A definite UIP pattern can be identified in chest HRCT of a sizeable fraction of patients with RA-ILD. Moreover, the possible UIP pattern appears to be almost equally distributed in patients with RA-ILD and IPF. Of note, the level of agreement between two experienced chest radiologists in detecting the UIP pattern is higher in patients with RA-ILD than in IPF.

2014 - Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: A network meta-analysis [Articolo su rivista]
Tramacere, I.; Del Giovane, C.; Salanti, G.; D'Amico, R.; Pacchetti, I.; Filippini, G.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: We aim to compare the efficacy and acceptability of immunomodulators and immunosuppressants to treat participants with RRMS and to generate a clinically useful hierarchy of available immunotherapies according to their efficacy and acceptability.

2014 - Long term effectiveness on prescribing of two multifaceted educational interventions: Results of two large scale randomized cluster trials [Articolo su rivista]
Magrini, N.; Formoso, G.; Capelli, O.; Maestri, E.; Nonino, F.; Paltrinieri, B.; Del Giovane, C.; Voci, C.; Magnano, L.; Daya, L.; Marata, A. M.
abstract

Introduction: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. Objectives: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. Methods: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach - TEA, with information materials on osteoporosis or prostatic hyperplasia - and a single drug oriented approach - SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. Results: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. Interpretation: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. Trial Registration: Controlled-Trials.com ISRCTN05866587.

2014 - Prevalence Of Subclinical Liver Fibrosis Among Patients With Idiopathic Pulmonary Fibrosis [Abstract in Rivista]
Cocconcelli, Elisabetta; Cerri, Stefania; Spagnolo, Paolo; Tonelli, Roberto; Ventura, Paolo; Abbati, Gianluca; Vegetti, Alberto; Pileri, Francesca; DEL GIOVANE, Cinzia; Balduzzi, Sara; Pietrangelo, Antonello; Richeldi, Luca; Luppi, Fabrizio
abstract

Rationale Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive fibrosing interstitial pneumonia of unknown cause. Common pathogenic mechanisms with chronic fibrotic disorders involving other organs are likely. Yet, data on the co-existence of subclinical fibrotic disease across multiple organs in patients with IPF are lacking. The present study aimed to investigate the prevalence of subclinical liver fibrosis among patients with IPF. Methods Patients referred to the Center for Rare Lung Disease of the University Hospital of Modena, with a diagnosis of IPF according to recent guidelines and without previous history of liver diseases underwent hepatic transient elastography (FibroScan®), a non-invasive technique measuring liver stiffness, which routinely used for the assessment of hepatic fibrosis in patients with chronic liver diseases. Hepatic fibrotic status is expressed in a scale from 0 (absence of hepatic fibrosis) to 4 (severe liver fibrosis / cirrhosis). Patients with body mass index (BMI) ≥29 (confidence limit of the instrument) were excluded. Patients, in which any degree of hepatic fibrosis was detected, underwent screening for possible secondary causes of liver fibrosis. Results Among 48 IPF patients (34 males, mean age 69 years), 11 (23%) were excluded because of high BMI. In 8 out 37 patients (22%) it was not possible to obtain successful measurements due to the excess of subcutaneous adipose tissue in the chest wall, or narrow intercostal spaces. Thirteen of 37 patients (35%) had abnormal hepatic transient elastography results: 4 patients fell within the range F1-F2 (6.1-7.6 kPa), 6 in F2 (7.4-8.4 kPa), one in F2-F3 (9.5 kPa), 1 in F4 (14.3 kPa) and 1 was identified as probable fibrosis not otherwise classifiable. In all cases, secondary causes of hepatic fibrosis were excluded. Minor impairment of markers of liver injury was found in a minority of patients with liver fibrosis, with AST and ALT values exceeding the threshold value respectively in 2 and 3 patients with liver fibrosis, detected on elastography. Conclusions Over one third of patients in this IPF cohort had a concomitant fibrosing subclinical process in the liver. These preliminary data prompt the need for a large prospective study aimed at clarifying the correlation between the fibrosing processes in the lung and in the liver and the possibility of shared pathogenic mechanisms.

2014 - RARE-Bestpractices: A platform for sharing best practices for the management of rare diseases [Articolo su rivista]
Taruscio, D.; Morciano, C.; Laricchiuta, P.; Mincarone, P.; Palazzo, F.; Leo, C. G.; Sabina, S.; Guarino, R.; Auld, J.; Sejersen, T.; Gavhed, D.; Ritchie, K.; Hilton-Boon, M.; Manson, J.; Kanavos, P. G.; Tordrup, D.; Tzouma, V.; Le Cam, Y.; Senecat, J.; Filippini, G.; Minozzi, S.; Del Giovane, C.; Schunemann, H.; Meerpohl, J. J.; Prediger, B.; Schell, L.; Stefanov, R.; Iskrov, G.; Miteva-Katrandzhieva, T.; Serrano-Aguilar, P.; Perestelo-Perez, L.; Trujillo-Martin, M. M.; Perez-Ramos, J.; Rivero-Santana, A.; Brand, A.; Van Kranen, H.; Bushby, K.; Atalaia, A.; Ramet, J.; Siderius, L.; Posada, M.; Abaitua-Borda, I.; Ferreira, V. A.; Hens-Perez, M.; Manzanares, F. J.
abstract

2014 - Selenium for preventing cancer. [Articolo su rivista]
Vinceti, Marco; Dennert, G; Crespi, Cm; Zwahlen, M; Brinkman, M; Zeegers, Mp; Horneber, M; D'Amico, Roberto; DEL GIOVANE, Cinzia
abstract

BACKGROUND: This review is an update of the first Cochrane publication on selenium for preventing cancer (Dennert 2011).Selenium is a metalloid with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers. OBJECTIVES: Two research questions were addressed in this review: What is the evidence for:1. an aetiological relation between selenium exposure and cancer risk in humans? and2. the efficacy of selenium supplementation for cancer prevention in humans? SEARCH METHODS: We conducted electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 1), MEDLINE (Ovid, 1966 to February 2013 week 1), EMBASE (1980 to 2013 week 6), CancerLit (February 2004) and CCMed (February 2011). As MEDLINE now includes the journals indexed in CancerLit, no further searches were conducted in this database after 2004. SELECTION CRITERIA: We included prospective observational studies (cohort studies including sub-cohort controlled studies and nested case-control studies) and randomised controlled trials (RCTs) with healthy adult participants (18 years of age and older). DATA COLLECTION AND ANALYSIS: For observational studies, we conducted random effects meta-analyses when five or more studies were retrieved for a specific outcome. For RCTs, we performed random effects meta-analyses when two or more studies were available. The risk of bias in observational studies was assessed using forms adapted from the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies; the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate the risk of bias in RCTs. MAIN RESULTS: We included 55 prospective observational studies (including more than 1,100,000 participants) and eight RCTs (with a total of 44,743 participants). For the observational studies, we found lower cancer incidence (summary odds ratio (OR) 0.69, 95% confidence interval (CI) 0.53 to 0.91, N = 8) and cancer mortality (OR 0.60, 95% CI 0.39 to 0.93, N = 6) associated with higher selenium exposure. Gender-specific subgroup analysis provided no clear evidence of different effects in men and women (P value 0.47), although cancer incidence was lower in men (OR 0.66, 95% CI 0.42 to 1.05, N = 6) than in women (OR 0.90, 95% CI 0.45 to 1.77, N = 2). The most pronounced decreases in risk of site-specific cancers were seen for stomach, bladder and prostate cancers. However, these findings have limitations due to study design, quality and heterogeneity that complicate interpretation of the summary statistics. Some studies suggested that genetic factors may modify the relation between selenium and cancer risk-a hypothesis that deserves further investigation.In RCTs, we found no clear evidence that selenium supplementation reduced the risk of any cancer (risk ratio (RR) 0.90, 95% CI 0.70 to 1.17, two studies, N = 4765) or cancer-related mortality (RR 0.81, 95% CI 0.49 to 1.32, two studies, N = 18,698), and this finding was confirmed when the analysis was restricted to studies with low risk of bias. The effect on prostate cancer was imprecise (RR 0.90, 95% CI 0.71 to 1.14, four studies, N = 19,110), and when the analysis was limited to trials with low risk of bias, the interventions showed no effect (RR 1.02, 95% CI 0.90 to 1.14, three studies, N = 18,183). The risk of non-melanoma skin cancer was increased (RR 1.44, 95% CI 0.95 to 1.17, three studies, N = 1900). Results of two trials-the Nutritional Prevention of Cancer Trial (NPCT) and the Selenium and Vitamin E Cancer Trial (SELECT)-also raised concerns about possible increased risk of type 2 diabetes, alopecia and dermatitis due to selenium supplements. An early hypothesis generated by NPCT that individuals with the lowest blood selenium levels at baseline could reduce their risk of cancer, particularly of prostate cancer, by increasing selenium in

2014 - Systematic review of management for treatment-resistant depression in adolescents [Articolo su rivista]
Zhou, X.; Michael, K. D.; Liu, Y.; Del Giovane, C.; Qin, B.; Cohen, D.; Gentile, S.; Xie, P.
abstract

Background: Current guidelines for treatment-resistant depression in adolescents remain inadequate. This study aimed to systematically review the management of treatment-resistant depression in adolescent patients. Methods: We conducted an electronic database search of PUBMED, EMBASE, Cochrane, Web of Science and PsycINFO for studies with adolescent treatment-resistant depression published up to January 2014. Treatment-resistant depression was defined as failure to respond to at least one course of psychological or pharmacological treatment for depression with an adequate dosage, duration, and appropriate compliance during the current illness episode. The Cochrane risk-of-bias method was used to assess the quality of randomized controlled trials. A meta-analysis of all active treatments was conducted. Results: Eight studies with 411 depressed adolescents that fit predetermined criteria investigated pharmacological treatments and psychotherapies. Six were open-label studies, and two were randomized controlled trials. The overall response rate for all active treatments investigated was 46% (95% CI 33 to 59; N = 411) with a moderately high degree of heterogeneity (I2 = 76.1%, 95% CI = 47%-86%). When only the two randomized trials were included, the overall response rate of active treatment was 53% (95% CI = 38-67; N = 347). In these randomized trials, SSRI therapy plus CBT was significantly more effective than SSRI therapy alone, while amitriptyline was not more effective than placebo. Conclusions: Approximately half of the adolescents who presented with treatment-refractory depression responded to active treatment, which suggests that practitioners should remain persistent in managing these challenging cases. The combination of antidepressant medication and psychotherapy should be recommended for adolescents who present with treatment-resistant depression.

2014 - The undergraduate nursing student evaluation of clinical learning environment: an Italian survey [La valutazione dell'ambiente di apprendimento clinico da parte degli studenti del Corso di Laurea in Infermieristica: una indagine italiana] [Articolo su rivista]
Magnani, Daniela; DI LORENZO, Rosaria; Bari, Alessia; Pozzi, Samantha; DEL GIOVANE, Cinzia; Ferri, Paola
abstract

BACKGROUND: Nursing students have to deal with many different clinical and practical aspects of knowledge to become skilled professionals. Student perception may be considered an indicator of teaching quality, since positive perception of students is strictly related to their effective professional learning. The Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale is considered the gold standard psychometric instrument to evaluate both the quality and the climate of clinical learning environment. AIMS: To evaluate the quality of nurse teaching by means of CLES+T scale and to highlight significant correlations between CLES+T scale and selected characteristics of both students and clinical environments. METHODS: On 4 March 2013, a cross-sectional survey was conducted at University of Modena: CLES+T scale was administered during a plenary convocation to 242 nursing students who attended the second and third years of Nursing Degree. All 34 items of the scale were statistically analysed using the median test. RESULTS: The median values were uniformly represented by "4" level (on the Likert scale). The final marks of clinical learning experience were the only variable statistically significantly related to the scale scores. The paediatrics and emergency areas obtained the highest scale scores. CONCLUSIONS: The nursing student evaluations were uniformly positive and related to their positive final marks. A positive ward atmosphere was identified as especially important in this study. These data indicate that a non-hostile and hospitable environment can favour the best clinical learning. We conclude that CLES+T scale can be a useful instrument to explore the clinical climate in all hospital areas and to highlight critical clinical situations.

2013 - A LITERARY WORKSHOP FOR INCREASING ASSERTIVENESS IN PATIENTS WITH EATING DISORDERS: A RANDOMIZED CONTROLLED TRIAL [Articolo su rivista]
Pingani, Luca; Fulvio, Arnone; Maria Laura, Chierici; Elena De, Bernardis; Sara, Donelli; DEL GIOVANE, Cinzia; Vera, Vinci; Giuliano, Turrini; Rigatelli, Marco; Ferrari, Silvia
abstract

Objectives: To assess the effectiveness of a literary workshop activity for increasing linguistic skills and assertiveness in patients with eating disorders (ED).Methods: Twenty-four patients consequently admitted to the ED In-patient Unit at the Private Clinic “Villa Maria Luigia” (Parma, Northern Italy) were enrolled in the study. Of these, 8 were randomly assigned to treatment and 16 to care as usual (being the difference between treatment and care as usual only represented by the literary workshop activity). The literary workshop consisted in 15 weekly 60-minute group sessions. Linguistic and expressive skills were provided and tested during the sessions. The Rathus Assertiveness Schedule and the Verbal Fluency Test (phonemic and semantic) were administered to all patients at the beginning and at the end of hospitalization. Results: A significant improvement of semantic skills, phonetic skills and assertiveness (p<.01) was registered in the treatment group. A positive correlation was also found between variations of linguistic skills and assertiveness in the treatment group, but not in the control group. Conclusions: Effectiveness of a literary workshop activity within a rehabilitation program for patients suffering from ED was suggested: improved communication and language skills might have a positive and significant impact on patients' levels of assertiveness

2013 - Characterization of Specific Immune Responses to Different Aspergillus Antigens during the Course of Invasive Aspergillosis in Hematologic Patients [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Forghieri, Fabio; Beauvais, Anne; Beau, Remi; Candoni, Anna; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Zanetti, Eleonora; Quadrelli, Chiara; Codeluppi, Mauro; Guaraldi, Giovanni; Pagano, Livio; Caira, Morena; DEL GIOVANE, Cinzia; Maccaferri, Monica; Stefani, Alessandro; Morandi, Uliano; Tazzioli, Giovanni; Girardis, Massimo; Delia, Mario; Specchia, Giorgina; Longo, Giuseppe; Marasca, Roberto; Narni, Franco; Merli, Francesco; Imovilli, Annalisa; Apolone, Giovanni; Carvalho, Agostinho; Comoli, Patrizia; Romani, Luigina; Latgè, Jean Paul; Luppi, Mario
abstract

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, β1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA. © 2013 Potenza et al.

2013 - Friend or foe? The current epidemiologic evidence on selenium and human cancer risk [Articolo su rivista]
Vinceti, Marco; Crespi, Cm; Malagoli, Carlotta; DEL GIOVANE, Cinzia; Krogh, V.
abstract

Scientific opinion on the relationship between selenium and the risk of cancer has undergone radical change over the years, with selenium first viewed as a possible carcinogen in the 1940s then as a possible cancer preventive agent in the 1960s-2000s. More recently, randomized controlled trials have found no effect on cancer risk but suggest possible low-dose dermatologic and endocrine toxicity, and animal studies indicate both carcinogenic and cancer-preventive effects. A growing body of evidence from human and laboratory studies indicates dramatically different biological effects of the various inorganic and organic chemical forms of selenium, which may explain apparent inconsistencies across studies. These chemical form-specific effects also have important implications for exposure and health risk assessment. Overall, available epidemiologic evidence suggests no cancer preventive effect of increased selenium intake in healthy individuals and possible increased risk of other diseases and disorders.

2013 - Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis [Articolo su rivista]
Filippini, Graziella; DEL GIOVANE, Cinzia; Vacchi, Laura; D'Amico, Roberto; Di Pietrantonj, Carlo; Beecher, Deirdre; Salanti, Georgia
abstract

Different therapeutic strategies are available for treatment of multiple sclerosis (MS) including immunosuppressants, immunomodulators, and monoclonal antibodies. Their relative effectiveness in the prevention of relapse or disability progression is unclear due to the limited number of direct comparison trials. A summary of the results, including both direct and indirect comparisons of treatment effects, may help to clarify the above uncertainty.

2013 - Network meta-analysis models to account for variability in treatment definitions: Application to dose effects [Articolo su rivista]
Giovane, C. D.; Vacchi, L.; Mavridis, D.; Filippini, G.; Salanti, G.
abstract

For a network meta-analysis, an interlinked network of nodes representing competing treatments is needed. It is often challenging to define the nodes as these typically refer to similar but rarely identical interventions. The objectives of this paper are as follows: (i) to present a series of network meta-analysis models that account for variation in the definition of the nodes and (ii) to exemplify the models where variation in the treatment definitions relates to the dose. Starting from the model that assumes each node has a 'fixed' definition, we gradually introduce terms to explain variability by assuming that each node has several subnodes that relate to different doses. The effects of subnodes are considered monotonic, linked with a 'random walk', random but exchangeable, or have a linear pattern around the treatment mean effect. Each model can be combined with different assumptions for the consistency of effects and might impact on the ranking of the treatments. Goodness of fit, heterogeneity and inconsistency were assessed. The models are illustrated in a star network for the effectiveness of fluoride toothpaste and in a full network comparing agents for multiple sclerosis. The fit and parsimony measures indicate that in the fluoride network the impact of the dose subnodes is important whereas in the multiple sclerosis network the model without subnodes is the most appropriate. The proposed approach can be a useful exploratory tool to explain sources of heterogeneity and inconsistency when there is doubt whether similar interventions should be grouped under the same node. © 2012 John Wiley & Sons, Ltd.

2013 - New approaches to the design of clinical trials in idiopathic pulmonary fibrosis [Articolo su rivista]
Cerri, Stefania; DEL GIOVANE, Cinzia; Balduzzi, Sara; Soncini, Francesco; Sdanganelli, Antonia; Richeldi, Luca
abstract

Idiopathic pulmonary fibrosis (IPF) is one of the major challenges for respiratory medicine since prognosis is particularly poor and few therapeutic options are available - in fact, at present to the only approved drug is pirfenidone. Winning this challenge will be based on successful design and completion of randomized clinical trials. The last decade witnessed an unprecedented increase in quality and quantity of trials in IPF: nonetheless, most have been negative and potential obstacles did emerge. In particular, the choice of the best endpoint, i.e. clinically meaningful and feasible at the same time, and the management of missing data still represent issues not fully resolved. The increasingly competitive environment and the heterogeneity in approach by different regulatory agencies also need to be considered. In the next few years more and more trials will be designed and completed, in the hope of taking quicker and safer treatments to IPF patients.

2013 - Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection. [Articolo su rivista]
Nasi, Milena; Riva, A; Borghi, V; D'Amico, Roberto; DEL GIOVANE, Cinzia; Casoli, C; Galli, M; Vicenzi, E; Gibellini, Lara; DE BIASI, Sara; Clerici, M; Mussini, Cristina; Cossarizza, Andrea; Pinti, Marcello
abstract

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. METHODS: We analyzed 47 Caucasian LTNPs infected for >9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. RESULTS: The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). CONCLUSIONS: The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation.

2013 - Prevalence and Risk Factors of PTSD in Children and Adolescents after the 2012 Earthquake in the Emilia Romagna Region: implications for intervention [Abstract in Rivista]
Forresi, Barbara; DEL GIOVANE, Cinzia; Soncini, Francesco; Aggazzotti, Gabriella; D'Amico, Roberto; Parmelli, Elena; Righi, Elena; Caffo, Ernesto
abstract

PTSD is one of the psychological disorders that occurs after natural disasters. Many cases will remit within a few months, however in some estimates nearly one-third of cases have a chronic course. Delay-onset PTSD and progressive increase of symptoms seem to be very common. Given the significant rates of PTSD among children and adolescents after earthquakes and the long-term impact on their mental health, it is of primary importance to identify and treat symptoms effectively. The authors will present preliminary data from a cross-sectional study aimed at evaluating the prevalence of PTSD in a sample of children and adolescents nine months after the 2012 earthquake that hit the Emilia Romagna region in northern Italy. Data concerning risk (e.g., level of trauma exposure and parental psychopathology) and protective factors for the development and the persistence of the disorder will be also presented. Children and adolescents (age range: 9–14 years), randomly selected from schools in the Province of Modena, have been assessed using an exposure questionnaire on objective/subjective experiences during the earthquake, the UCLA PTSD index for DSM-IV (UPID), and the strengths and difficulties questionnaire (SDQ). Parental symptomatology has been also assessed, in order to evaluate the influence of parental psychopathology on offspring's adjustment. Given the few studies conducted in Italy about the long-term psychological impact of natural disaster on children and adolescents, the present research has important implications for the prevention and treatment of traumatized children and adolescents in Italy, as well as for the development of effective posttrauma interventions.

2013 - Prevalence and risk factors of Post-Traumatic Stress Disorder in children and adolescents after the 2012 earthquake affecting the Emilia Romagna Region (Italy). [Abstract in Rivista]
Righi, Elena; Forresi, Barbara; Soncini, Francesco; DEL GIOVANE, Cinzia; D'Amico, Roberto; Caffo, Ernesto; Fantuzzi, Guglielmina; Aggazzotti, Gabriella
abstract

On May 2012, two major earthquakes hit the Province of Modena (Emilia Romagna Region, Northern Italy): the country suffered 27 deaths and several hundred injured citizen; 15000 local resident were left homeless. Post-Traumatic Stress Disorder (PTSD) is a major debilitating psychological disorder that frequently occurs after natural disasters, including earthquakes, with a prevalence ranging, according to different authors, from 28 to 70%. Many cases will remit within 12 months, however about one-third of cases will have a chronic course. Given the high PTSD rates in children and adolescents, the long term impact on their well-being and the relevant social costs of chronic mental disorders, it is of primary importance to recognize and effectively treat cases as soon as possible and to identify potential individual and social risk and protective factors to be addressed in future effective preventive interventions. An epidemiological cross-sectional study has been set up and is on progress in a randomly selected sample of school children and adolescents (9-14 years) exposed to the earthquake with the aim to assess the PTSD prevalence and to explore potential risk (demographic, parental factors and level of trauma exposure) and protective factors (e.g. social support) associated to PTSD development and persistence. The assessment protocol includes the administration of an exposure questionnaire on objective/subjective experiences during the earthquake, the UCLA PTSD Index for DSM-IV questionnaire, and the Strengths and Difficulties Questionnaire. Parental symptomatology will be also assessed using the Symptom Checklist-90-R questionnaire, in order to evaluate the influence of parental psychopathology on children conditions. The present research will have important implications for the prevention in Italy of chronic PTSD, for treatment of traumatized children and adolescents, as well as for the development of effective post-trauma interventions.

2012 - Immunological advantages of everolimus versus cyclosporin A in liver-transplanted recipients, as revealed by polychromatic flow cytometry. [Articolo su rivista]
Roat, Erika; DE BIASI, Sara; Bertoncelli, Linda; Rompianesi, Gianluca; Nasi, Milena; Gibellini, Lara; Pinti, Marcello; DEL GIOVANE, Cinzia; A., Zanella; DI BENEDETTO, Fabrizio; Gerunda, Giorgio Enrico; Cossarizza, Andrea
abstract

Several immunosuppressive drugs with different mechanisms of action are available to inhibit organ rejection after transplant. We analyzed different phenotypic and functional immunological parameters in liver-transplanted patients who received cyclosporin A (CsA) or Everolimus (Evr). In peripheral blood mononuclear cells (PBMC) from 29 subjects receiving a liver transplant and treated with two different immunosuppressive regimens, we analyzed T cell activation and differentiation, regulatory T cells (Tregs) and Tregs expressing homing receptors such as the chemokine receptor CXCR3. T cell polyfunctionality was studied by stimulating cells with the superantigen staphylococcal enterotoxin B (SEB), and measuring the simultaneous production of interleukin (IL)-2 and interferon (IFN)-γ, along with the expression of a marker of cytotoxicity such as CD107a. The analyses were performed by polychromatic flow cytometry before transplantation, and at different time points, up to 220 days after transplant. Patients taking Evr had a higher percentage of total CD4⁺ and naïve CD4⁺ T cells than those treated with CsA; the percentage of CD8⁺ T cells was lower, but the frequency of naïve CD8⁺ T cells higher. Patients taking Evr showed a significantly higher percentage of Tregs, and Tregs expressing CXCR3. After stimulation with SEB, CD8⁺ T cells from Evr-treated patients displayed a lower total response, and less IFN-γ producing cells. The effects on the immune system, such as the preservation of the naïve T cell pool and the expansion of Tregs (that are extremely useful in inhibiting organ rejection), along with the higher tolerability of Evr, suggest that this drug can be safely used after liver transplantation, and likely offers immunological advantages.

2012 - Pre-induction of labour: comparing dinoprostone vaginal insert to repeated prostaglandin administration: a systematic review and meta-analysis. [Articolo su rivista]
Facchinetti, Fabio; F., Fontanesi; Giovane, C. D.
abstract

To assess the efficacy and safety of the dinoprostone vaginal insert compared to repeated prostaglandin administration (including dinoprostone and misoprostol) in women at term.Electronic databases and additional handsearching were used to identify randomized controlled trial (RCT). We included studies reporting data separately for nulliparous and/or multiparous in women with unfavourable cervix (Bishop <5) and intact membranes. The primary efficacy outcome was caesarean section (CS) rate. Primary safety outcome was uterine hyperstimulation requiring immediate delivery.Eighteen RCTs were eligible and seven studies were included (totally 911 patients). The dinoprostone vaginal insert reduces CS rate in nulliparous women of 24\% compared to the other ways of administration (RR = 0.76, 95\% CI = 0.59, 0.98). The risk of oxytocin use is reduced with the use of vaginal insert (RR = 0.64, 95\% CI = 0.42, 0.99). The risk of hyperstimulation is statistically higher in nulliparous women using vaginal insert than the other ways of administration with RR = 2.17, 95\% CI = 1.08,4.33.In nulliparous women with unprepared cervix and intact membranes vaginal insert perform better than repeated vaginal doses since it is associated with more vaginal deliveries and less oxytocin use. Although vaginal insert is associated with more uterine hyperstimulation, it shows a protective effect toward caesarean section.

2012 - Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: A retrospective Italian survey [Articolo su rivista]
Masini, C.; Sabbatini, R.; Porta, C.; Procopio, G.; Di Lorenzo, G.; Onofri, A.; Buti, S.; Iacovelli, R.; Invernizzi, R.; Moscetti, L.; Aste, M. G.; Pagano, M.; Grosso, F.; Lucia Manenti, A.; Ortega, C.; Cosmai, L.; Del Giovane, C.; Conte, P. F.
abstract

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not significantly alter plasma concentrations. In this retrospective study we define the safety and efficacy of tyrosine kinase inhibitors in patients with metastatic RCC (mRCC) and end-stage renal disease requiring haemodialysis. Even though the retrospective nature of this survey and the relatively small sample size represent major limitations, these data indicate that treatment with sunitinib and sorafenib in this cohort of patients is feasible with no unexpected toxicity and good efficacy, results similar to those in the general population of patients with mRCC. Objective To investigate the safety and efficacy of tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring haemodialysis (HD). Patients and methods Between July 2006 and December 2010, 24 patients undergoing HD were treated with sunitinib and/or sorafenib for mRCC in 14 Italian institutions. We retrospectively reviewed the medical records of these patients to evaluate the administered doses of TKIs, treatment-related toxicities and the clinical response to therapy. Results Sunitinib was administered at 50 mg daily for 4-6 weeks in six patients, 37.5 mg daily for 4-6 weeks in seven patients (one patient subsequently increased the dose to 50 mg daily), 25 mg daily for 4-6 weeks in two patients and 12.5 mg daily for 4-6 weeks in one patient. Among the eight patients treated with sorafenib, four patients received 800 mg daily (400 mg every 12 h), three patients 400 mg daily and one patient 200 mg daily with a continuous schedule. The estimated median progression-free and overall survival periods of this cohort of patients were 10.3 months and 22.6 months, respectively. With regard to tolerability and safety, no unexpected adverse events were registered and no grade 4 haematological or non-haematological toxicities were reported. Conclusions Sunitinib and sorafenib treatment is not contraindicated in patients with mRCC undergoing HD. The outcome of this patient population is similar to that observed in patients with normal renal function treated with TKIs. These results merit further confirmation by a larger prospective trial. © 2012 BJU INTERNATIONAL.

2011 - A multicenter, case-control study on risk factors for antepartum stillbirth. [Articolo su rivista]
Facchinetti, Fabio; S., Alberico; C., Benedetto; I., Cetin; S., Cozzolino; G. C., Di Renzo; Giovane, C. D.; F., Ferrari; F., Mecacci; G., Menato; A. L., Tranquilli; D., Baronciani; I. S., Study Group
abstract

As the influence of socio-demographic variables, lifestyle and medical conditions on the epidemiology of stillbirth (SB) is modified by population features, we aimed at investigating the role played by these factors on the incidence of SB in a developed country.Multivariate logistic regression analysis (OR with 95\% CI) was utilized in a prospective multicentre nested case-control study to compare in a 1:2 ratio stillborn of >22 weeks gestation with matched for gestational age live-born (LB) infants. Intrapartum SB were excluded.Two hundred fifty-four consecutive SBs and 497 LBs were enrolled. Socio-demographic variables were equally distributed. Fetal malformations (7.96, 2.69-23.55), severe intrauterine growth restriction (IUGR) (birthweight ≤ 5(th) \%ile) (4.32, 2.27?8.24), BMI > 25 (2.87, 1.90-4.33), and preeclampsia (PE, 0.40, 0.21-0.77) were recognized as independent predictors for SB. At term, only BMI > 25 was associated with SB (7.70, 2.9-20.5).Fetal malformations, severe IUGR and maternal BMI > 25 were associated with a significant increase in the risk of SB; PE presented instead a protective role. Maternal BMI > 25 was the only risk factor for SB identified in term pregnancies.

2011 - BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph(+) acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Quadrelli, Chiara; Barozzi, Patrizia; Basso, S; Vallerini, Daniela; Zanetti, E; Morselli, M; Forghieri, Fabio; Maccaferri, M; Paolini, Ambra; DEL GIOVANE, Cinzia; D'Amico, Roberto; Marasca, Roberto; Narni, Franco; Iacobucci, I; Martinelli, G; Baccarani, M; Comoli, P; Potenza, Leonardo
abstract

BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy

2011 - CD4+ T-cell differentiation, regulatory T cells and gag-specific T lymphocytes are unaffected by CD4-guided treatment interruption and therapy resumption. [Articolo su rivista]
Nemes, Elisa; Lugli, Enrico; Bertoncelli, Linda; Nasi, Milena; Pinti, Marcello; Manzini, S; Prati, Francesca; Manzini, Lisa; DEL GIOVANE, Cinzia; D'Amico, Roberto; Cossarizza, Andrea; Mussini, Cristina
abstract

OBJECTIVES:Despite limiting exposure to antiretroviral drugs, structured treatment interruptions can influence multiple aspects of T-cell immunity, particularly those regarding CD4(+) T lymphocytes. We evaluated the impact of CD4-guided treatment interruption (CD4-GTI) and treatment resumption on regulatory T cells (Tregs), T-lymphocyte activation, differentiation and polyfunctional gag-specific response.METHODS:Patients were analyzed just prior to treatment interruption, at 2 and 6 months after treatment interruption, just prior to treatment resumption and at 2 and 6 months after treatment resumption. Thawed peripheral blood mononuclear cells were stained immediately for phenotype analysis or stimulated with HIV-gag peptides and analyzed by polychromatic flow cytometry.RESULTS:Treatment interruption resulted in a CD4(+) cell count decrease and plasma viral load (pVL) increase, but did not preclude a good immune reconstitution and a complete suppression of pVL after treatment resumption. Treatment interruption did not influence CD4(+) T-cell differentiation and Treg subsets. During treatment interruption, gag-specific CD4(+) T cells were not lost, although the frequency of HIV-specific CD8(+) cells increased. Most gag-specific CD4(+) T cells were potentially cytotoxic (CD107a(+)) and were not influenced by pVL or by HAART. Most helper (CD154(+)) gag-specific CD4(+) T lymphocytes did not produce interferon-γ or interleukin-2.CONCLUSION:CD4-GTI did not cause depletion of memory cells, Tregs or HIV-specific CD4(+) cells and, on the contrary, could induce HIV-specific responses. If guided by CD4(+) T-cell count, treatment interruption does not provoke irreversible immune damages.

2011 - Decreased mitochondrial DNA content in subcutaneous fat from HIV-infected women taking antiretroviral therapy as measured at delivery. [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Chiesa, E; Fiore, S; Manzini, S; DEL GIOVANE, Cinzia; D'Amico, Roberto; Palai, N; Campatelli, C; Sabbatini, F; Roccio, M; Tibaldi, C; Masuelli, G; Mussini, Cristina; Ferrazzi, E; d'Arminio Monforte, A; Cossarizza, Andrea
abstract

BACKGROUND: Increasing numbers of pregnant HIV-positive women are receiving combination antiretroviral regimens for preventing mother-to-child virus transmission or for treating the infection itself. Several studies have demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by several mechanisms, including depletion of mitochondrial DNA (mtDNA). By the quantification of mtDNA levels, we studied mitochondrial toxicity in HIV-positive women at delivery and the possible correlations with antiretroviral regimens, viroimmunological and metabolic parameters.METHODS: We analysed 68 HIV-positive women enrolled in the Italian Prospective Cohort Study on Efficacy and Toxicity of Antiretroviral in Pregnancy (TARGET Study); all were taking ≥1 NRTI. We quantified mtDNA copies per cell in subcutaneous fat samples collected during delivery. At the 3rd, 6th and 9th month of pregnancy, we collected data concerning CD4(+) T-cell count, plasma HIV RNA, total and high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and triglycerides. As a control, we analysed mtDNA levels in abdominal subcutaneous fat samples from 23 HIV-seronegative women at delivery.RESULTS: mtDNA content was significantly lower in HIV-infected women when compared with HIV-negative controls. mtDNA content varied independently from viroimmunological, lipid and glucose parameters at the different months, with the exceptions of triglycerides at the 9th month and of HDL at the 6th month of pregnancy.CONCLUSIONS: In subcutaneous tissue from women taking NRTI-based antiretroviral regimens, we observed a significant decrease of mtDNA content, compared with uninfected women not on antiviral treatment. Moreover, a significant correlation was noted between mtDNA content and HDL cholesterol and triglycerides.

2011 - FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer [Articolo su rivista]
Bertolini, Federica; Malavasi, Norma; Scarabelli, Laura; Fiocchi, Federica; Bagni, Bruno; DEL GIOVANE, Cinzia; Colucci, G; Gerunda, Giorgio Enrico; Depenni, Roberta; Zironi, S; Fontana, A; Pettorelli, Elisa; Luppi, G; Conte, Pierfranco
abstract

BACKGROUND: In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS). METHODS: In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment. RESULTS: From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001). CONCLUSIONS: FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

2011 - Identification and characterization of Aspergillus-specific immune responses to diagnose invasive aspergillosis in high risk patients: a multicenter study [Abstract in Rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Maertens, J; Candoni, A; Beauvais, A; Zanetti, Eleonora; Quadrelli, C; Morselli, M; Forghieri, Fabio; Maccaferri, M; Paolini, Ambra; Marasca, Roberto; DEL GIOVANE, Cinzia; D'Amico, Roberto; Ciceri, F; Comoli, P; Cesaro, S; Caira, M; Pagano, L; Romani, L; Narni, Franco; Latgè, Jp; Luppi, Mario
abstract

Background. The mortality of Invasive Aspergillosis (IA) still affects from 27% to 55% of high risk hematologic patients. The reasons of such a poor outcome also rely on several drawbacks limiting the di- agnostic accuracy of non cultural based diagnostic methods (NCBDM) and hampering the opportunities for an early intervention. Studies in mice model of IA and in healthy subjects have shown that Aspergillus-specific T-cells producing interferon-gamma (IFN- gamma-T1) are protective, while Aspergillus-specific T-cells pro- ducing interleukin-10 (IL-10-T2) are non-protective to IA. Aims. We have investigated whether the identification of Aspergillus-specific IFN-gamma-T1 and/or IL-10-T2 through an ex-vivo enzyme linked immunospot (ELISPOT) assay may be effective in the diagnosis of IA in high risk patients. Furthermore, in the proven IA patients, we have functionally and phenotipically characterized such T cells through the cytokine secretion assay (CSA). Methods. 180 patients (168 hemato- logic and 12 solid organ transplant patients) have been enrolled. They were classified, according the revised EORTC/MSG criteria, as fol- lows: 18 proven, 35 probable, 17 possible IA cases and 110 controls. The control patients were divided in two groups: group 1 included 86 (78.2%) patients with hystological and/or cultural verified infec- tious/inflammatory/neoplastic diseases, but other than IA; group 2 in- cluded 24 (21.8%) patients without clinical and/or microbiological features of IA. ELISPOT has been performed, as described [Potenza et al. Leukemia 2007; 21: 578-81], by using as antigens Aspergillus either conidia or recombinant antigens, namely CRF1p, GEL1p, PEP1p, SOD1p, α1-3 glucan, β1-3 glucan and galactomannan (GM). Results. The patient and sample positivity rates were 94.4%/89.5% in proven, 45.7%/35.3% in probable, 35.3%/50% in possible IA cases and 1.8%/4.5% in the controls, respectively. The sensitivity and speci- ficity of ELISPOT for the diagnosis of IA resulted 94.4% (95% CI, 73%-99%) and 98.2% (95% CI, 93%-99%), respectively. The PPV of the test was 89.5% (95% CI, 67%-99%), the NPV was 99.1% (95% CI, 94%-100%) and the efficiency was 97.6% (95% CI, 92.3%- 99.4%). The positive likelihood ratio (LR) resulted 51.89, the negative LR was 0.06 (Table 1A,B). In proven IA patients, CSA demonstrated that Aspergillus-specific IL-10-T2 were predominantly central memory (CM) CD4+ T cells (median frequency 0.37%/0.22%), while Aspergillus-specific IFN-gamma-T1 were either CD4+ or CD8+ cells of either effector memory (EM) or CM phenotype (median frequen- cies 0.24%/0.20%). Also lower frequencies of Aspergillus-specific ei- ther CD4+ or CD8+ T cells producing IL-4 (0.11%/0.19%) of EM phenotype, and EM CD8+ cells producing IL-17 (0.18%), were de- tected. Moreover, although CRF1p, GEL1p, α1-3 glucan and SOD1p resulted the antigens eliciting the highest number of Aspergillus-spe- cific IFN-gamma-T1, only GEL1p and α1-3 glucan were those most constantly targeted by protective immune responses along the entire course of the IA. Conclusions. Our findings demonstrate the potential of ELISPOT in the diagnosis of IA, suggesting that it may comple- ment the other NCBDM, enabling a more consistent diagnosis of IA. Furthermore, this study describes for the first time the Aspergillus- specific immune responses in patients with proven IA, identifying also the antigens predominantly targeted by protective IFN-gamma- T1, with possible consequences in designing strategies of either adoptive cell infusion or vaccine therapies.

2011 - Mucorles-specific T cells emerge in the course of invasive mucormucosis and may be used as a surrogate diagnostic marker in high-risk patients [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Forghieri, Fabio; Zanetti, Eleonora; Quadrelli, Chiara; Candoni, A; Maertens, J; Rossi, Giulio; Morselli, M; Codeluppi, M; Paolini, Ambra; Maccaferri, Monica; DEL GIOVANE, Cinzia; D'Amico, Roberto; Rumpianesi, F; Pecorari, M; Cavalleri, F; Marasca, Roberto; Narni, Franco; Luppi, Mario
abstract

Mucorales-specific T cells have been investigated in 28 hematologic patients during the course of their treatment. Three developed proven invasive mucormycosis (IM), 17 infections of known etiologies but other than IM, and 8 never showed fever upon the period of observation. The Mucorales-specific T cells may be detected only in patients with IM, at diagnosis and along the entire course of the IM, but neither before nor long time after the resolution of the infection. Such T cells produced predominantly interleukin-4, interferon-gamma (IFN-γ), interleukin-10, and to a lesser extent also interleukin-17, and belonged to either CD4+ or CD8+ subsets. The specific T cells producing IFN-γ were able to directly induce damage of Mucorales hyphae. None of the 25 patients without IM showed Mucorales-specific T cells. Specific T cells contribute to human immune responses against fungi of the order Mucorales and could be evaluated as a surrogate diagnostic marker of IM.

2011 - Photodynamic therapy for basal cell carcinoma: Clinical and pathological determinants of response [Articolo su rivista]
Fantini, F.; Greco, A.; Del Giovane, C.; Cesinaro, A. M.; Venturini, M.; Zane, C.; Surrenti, T.; Peris, K.; Calzavara-Pinton, P. G.
abstract

Background Photodynamic therapy (PDT) is increasingly used in the treatment of basal cell carcinoma (BCC). However, scant information is available about the impact of both patient- and lesion-related characteristics on the effectiveness of therapy. Therefore, on the basis of the current data, it is difficult to draw clear-cut indications to use PDT for treatment of BCC in clinical practice. Objective To investigate the clinical and pathological determinants of response of BCC to PDT with methylaminolevulinate (MAL) and red light. Methods The clinical and pathological characteristics of 194 BCCs in 135 patients, treated with MAL-PDT, were evaluated. Lesions were treated with MAL-PDT according to established methods and the response was assessed by clinical follow-up of the patients. Results Complete response to PDT was 62%, with a better response for superficial BCC (95/116, 82%) than nodular BCC (26/78, 33%). When determinants of response were analysed, the nodular type and the location on the limbs emerged as significant clinical predictors of failure. Among the pathological characteristics, the nodular and infiltrative histotypes, as well as ulceration and tumour thickness were associated with a lower response to therapy. Patients' age and gender, as well as the size of the lesions, were not found to be significant predictors. Conclusions Optimization of PDT procedure for BCC requires a careful selection of the lesions. In particular, superficial BCCs, preferentially located on the trunk, show the best therapeutic response. © 2010 The Authors.

2011 - Role Of The QFT-IT Assay For The Diagnosis Of Latent Tuberculosis Infection Among Adult Immigrants [Abstract in Rivista]
Losi, Monica; Dal Monte, Paola; Cagarelli, Roberto; Meacci, Marisa; DEL GIOVANE, Cinzia; Luppi, Fabrizio; Lombardi, Giulia; Spagnolo, Paolo; D'Amico, Roberto; Roversi, Pietro; Cerri, Stefania; Rumpianesi, Fabio; Fabbri, Leonardo; Richeldi, Luca
abstract

Background. Accurate identification and treatment of contacts with latent tuberculosis infection (LTBI) is a desirable goal to achieve effective tuberculosis (TB) control in areas with low prevalence of disease. In immigrants from high prevalence countries, especially in those who are close contacts of active TB cases, the low specificity of the tuberculin skin test (TST) represents an obstacle to the identification of truly infected BCG-vaccinated individuals. The Interferon-Gamma (IFN-g) Release Assays (IGRAs), based on M. tuberculosis -specific antigens, might improve LTBI diagnosis in this population. Methods. In a retrospective study, we assess the performance of the QuantiFERON-TB Gold In-Tube (QFT-IT, Cellestis Ltd., Victoria, Australia) assay and the TST in 84 adult immigrants from high prevalence countries: 68 (80.9%) of those individuals were close contacts of active TB cases. Results. In 84 immigrants (mean age 37.7 ± 11.6 years, 46.3 % were males, 46.3% were BCG-vaccinated) TST was positive in 68 (80.9%) individuals: among these TST-positive individuals, 26 (38.2%) were negative with QFT-IT. QFT-IT assay tested positive in 44 (52.4%) subjects (TST vs QFT-IT: 80.9% vs 52.4%, p< 0.001). Two (2.4%) subjects tested QFT-IT-indeterminate and was TST-positive. Diagnostic overall agreement between TST and QFT-IT was 63.4% (k=0.23). Conclusions. These preliminary data suggest that the rate of LTBI among adult immigrants from TB endemic countries, in our study most of them also close contacts of active TB cases, is significantly lower when detected by QFT-IT, than by TST. Moreover, our findings suggest that using an IGRA test for LTBI screening in this high risk population might reduce the number of candidates to preventive treatment and can provide potential substantial benefits for TB control.

2011 - Role of the quantiferon-TB test in ruling out pleural tuberculosis: a multi-centre study. [Articolo su rivista]
M., Losi; M., Bocchino; A., Matarese; B., Bellofiore; P., Roversi; F., Rumpianesi; M. G., Alma; P., Chiaradonna; Giovane, C. D.; A. M., Altieri; Richeldi, Luca; A., Sanduzzi
abstract

Diagnosing pleural tuberculosis (plTB) might be difficult due to limited sensitivity of conventional microbiology tools. As M. tuberculosis (MTB)-specific T cells are recruited into pleural space in plTB, their detection may provide useful clinical information. To this aim, in addition to standard diagnostic tests, we used the QuantiFERON-TB Gold In-Tube (QFT-IT) test in blood and pleural effusion (PE) samples from 48 patients with clinical suspicion of plTB, 18 (37.5\%) of whom had confirmed plTB. Four of them (22.2\%) tested positive with a nucleic acid amplification test for MTB. The tuberculin skin test was positive in most confirmed plTB cases (88.9\%). Positive QFT-IT tests were significantly more frequent in patients with confirmed plTB, as compared to patients with an alternative diagnosis, both in blood (77.7 vs 36.6\%, p=0.006) and in PE samples (83.3\% vs 46.6\%, p=0.02). In addition, both blood and PE MTB-stimulated IFN-gamma levels were significantly higher in plTB patients (p=0.03 and p=0.0049 vs non-plTB, respectively). In blood samples, QFT-IT had 77.8\% sensitivity and 63.3\% specificity, resulting in 56.0\% positive (PPV) and 82.6\% negative (NPV) predictive values. On PE, QFT-IT sensitivity was 83.3\% and specificity 53.3\% (PPV 51.7\% and NPV 84.2\%). The optimal AUC-derived cut-off for MTB-stimulated pleural IFN-gamma level was 3.01 IU/mL (77.8\% sensitivity, 80\% specificity, PPV 68.4\% and NPV 82.8\%). These data suggest that QFT-IT might have a role in ruling out plTB in clinical practice.

2011 - Tuberculosis infection in foreign-born children: a screening survey based on skin and blood testing. [Articolo su rivista]
Losi, M.; Bergamini, Barbara Maria; Venturelli, C.; DEL GIOVANE, Cinzia; Sighinolfi, G.; Rumpianesi, F.; Richeldi, Luca
abstract

This study, carried out in a low tuberculosis (TB) prevalence country with high immigration rates from high TB prevalence countries, deals with the interferon-gamma release assay, QuantiFERON®-TB Gold In-Tube, for the diagnosis of latent TB infection (LTBI) in foreign-born children. The results of our study highlight the potential advantages and concerns of using a blood test for diagnosing LTBI in a 'two-step' strategy in foreign-born children.

2010 - Common vascular endothelial growth factor variants and risk for posttransplant Kaposi sarcoma. [Articolo su rivista]
Zanetti, E; Barozzi, Patrizia; Brown, Ee; Bosco, R; Vallerini, Daniela; Riva, Giovanni; Quadrelli, Chiara; Potenza, Leonardo; Forghieri, Fabio; Montagnani, G; D'Amico, Roberto; Del Giovane, Cinzia; Duraes, C; Whitby, D; Machado, Jc; Schulz, Tf; Torelli, G; Luppi, Mario
abstract

No abstract available

2010 - Emergence of BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term Imatinib mesylate treatment. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Barozzi, Patrizia; Quadrelli, Chiara; Basso, S; Vallerini, Daniela; Zanetti, Eleonora; Morselli, M; Forghieri, Fabio; Maccaferri, M; Volzone, F; DEL GIOVANE, Cinzia; D'Amico, Roberto; Locatelli, F; Torelli, Giuseppe; Comoli, P; Potenza, Leonardo
abstract

Imatinib mesylate (IM) has been demonstrated to be permissive for the emergence of T cells directed against chronic myeloid leukemia cells. Ten Philadelphia chromosome-positive acute lymphoblastic leukemia patients, receiving high dose IM maintenance, underwent a long-term immunological monitoring (range 2-65 months) of (p190)BCR-ABL-specific T cells in the bone marrow (BM) and peripheral blood (PB). (p190)BCR-ABL-specific T lymphocytes were detected in all patients, more frequently in BM than in PB samples (67% vs 25%, p<0.01), and resulted significantly associated with lower minimal residual disease values (p<0.001), while absent at leukemia relapse. Specific T cells were mainly effector memory CD8+ and CD4+ T cells, producing IFNgamma, TNFalpha and IL-2 (median % positive cells: 3.34, 3.04, 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL-positive leukemia blasts were also detectable. Whether these autologous (p190)BCR-ABL-specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo and exploited for immunotherapy remains to be addressed.

2010 - Non-steroid agents for idiopathic pulmonary fibrosis [Articolo su rivista]
Spagnolo, Paolo; Del Giovane, C.; Luppi, F.; Cerri, Stefania; Balduzzi, Sara; Walters, Eh; D'Amico, Roberto; Richeldi, Luca
abstract

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive lung disease with poor outcome and no effective treatment to date. This is an update of a Cochrane Review first published in 2003.OBJECTIVES: To assess the efficacy of non-steroid agents in adults with idiopathic pulmonary fibrosis.SEARCH STRATEGY: We searched the Cochrane Airways Group Register (30 March 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2010), Ovid MEDLINE to March week 5, 2010, EMBASE to week 13, 2010 and PubMed to April 2010, with additional handsearching, including abstracts of international conferences. We also contacted pharmaceutical companies and researchers in the field.SELECTION CRITERIA: Randomised studies comparing non-steroid drugs with placebo or steroids in adults with idiopathic pulmonary fibrosis.DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality, extracted data and assessed risk of bias. We contacted pharmaceutical companies to obtain missing information, if any. We combined survival outcomes using Peto odds ratios or hazard ratios (HR).MAIN RESULTS: Fifteen trials involving 10 different drugs were included. Two trials enrolling 1156 patients compared interferon gamma-1beta with placebo: interferon gamma-1beta did not significantly improve survival (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68). Four trials involving 1155 patients compared pirfenidone with placebo. Three trials, conducted in 1046 patients, provided data on progression-free survival: pirfenidone significantly reduced the risk of disease progression by 30% (HR 0.70, 95% CI 0.56 to 0.88, P = 0.002). Data on the effect of pirfenidone on pulmonary function could only be assessed for two studies analysing 314 patients. Forced vital capacity or vital capacity was significantly improved by pirfenidone (mean difference 0.08 L, 95% CI 0.03 to 0.13, P = 0.0006).AUTHORS' CONCLUSIONS: Based on available data, partly still unpublished, pirfenidone appears to improve progression-free survival and, to a lesser extent, pulmonary function in patients with idiopathic pulmonary fibrosis. More data are needed on overall survival and quality of life on treatment. From the studies in this review, interferon gamma-1beta has not been shown to affect survival. Other agents evaluated in single studies either failed to provide evidence for a benefit or need to be assessed in larger randomised controlled trials.

2010 - Predictive Value of Intracellular HIV-1 DNA Levels During CD4-Guided Treatment Interruption in HIV(+) Patients [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Manzini, S; Gibellini, Lara; Manzini, Lisa; Bisi, Luca; DE BIASI, Sara; DEL GIOVANE, Cinzia; D'Amico, Roberto; Borghi, V; Mussini, Cristina; Cossarizza, Andrea
abstract

The amount of HIV-1 DNA within peripheral blood mononuclear cells is an important marker of viral activity. We studied intracellular HIV-1 DNA content in purified CD4(+) T cells from 28 chronically HIV-1-infected adults with sustained CD4(+) T cell counts (>500 cells/microl) and undetectable plasma viral load (<50 copies/ml), who underwent CD4-guided treatment interruption (TI). Patients were followed up for 18 months during TI, and for 6 months after treatment resumption (TR). Six naïve HIV(+) patients starting therapy were also enrolled and followed up for 6 months. All patients were studied every 2 months; HIV-1 DNA copy number was quantified with real-time PCR. Considering all patients remaining off-treatment, in the first 18 months of TI, intracellular HIV-1 DNA levels (expressed as Log(10) copies/million cells) remained stable (mean, 3.82 and 3.77 at time 0 and after 18 months, respectively). Similarly, HIV-1 DNA values, either in patients who restarted treatment after TI (time 0, 4.90) or in naïve patients who started treatment for the first time (time 0, 4.37), did not change significantly in the first 6 months of therapy (4.42 and 3.67, respectively). Evaluating HIV-1 DNA variations during the first 2 months of TI, we found that patients with a stable level had a lower risk to reach a CD4(+) T cell count <350 cells/microl, and thus to restart therapy, whereas this risk was significantly higher in those with a marked increase of HIV-1 DNA. In conclusion, intracellular HIV-1 DNA is a predictive marker for the length of CD4-guided TI.

2010 - Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. [Articolo su rivista]
C., Bengala; Bettelli, Stefania Raffaella; F., Bertolini; G., Sartori; Fontana, Annalisa; N., Malavasi; R., Depenni; S., Zironi; DEL GIOVANE, Cinzia; G., Luppi; Conte, Pierfranco
abstract

Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear.We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak's tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed.Tumour regression grade 4 and TRG3-4 were achieved in 14.4 and 30.8\% of the patients respectively. Twenty-nine (19.9\%) and 33 patients (19.2\%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50\% respectively; 28 patients (19.2\%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5\%, respectively, and no significant relation with EGFR GCN or KRAS status was found.Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

2010 - Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial [Articolo su rivista]
Bengala, C; Bertolini, Federica; Malavasi, Norma; Boni, C; Aitini, E; Dealis, Cristina; Zironi, S; Depenni, R; Fontana, Annalisa; DEL GIOVANE, Cinzia; Luppi, G; Conte, Pierfranco
abstract

BACKGROUND: Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-beta, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma. METHODS: We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks. RESULTS: A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0-12 months), and the median overall survival was 4.4 months (range: 0-22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients. CONCLUSIONS: Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable.

2010 - Temperature changes in guttapercha using two different heat sources: a preliminary in vitro study. [Abstract in Rivista]
Generali, Luigi; Ambu, E.; DEL GIOVANE, Cinzia; Giannetti, Luca; Bertoldi, Carlo; Consolo, Ugo
abstract

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2006 - Health-related quality of life in recent and long standing chronic HCV infection. [Abstract in Atti di Convegno]
Tesini, E. M. C.; BARBANTI SILVA, V.; Pigozzi, F.; Ferrari, Silvia; DEL GIOVANE, C.; Marino, M.; Rigatelli, Marco; PONZ DE LEON, Maurizio; Vandelli, Carmen
abstract

Not available

Università degli studi di Modena e Reggio Emilia

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