Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Real-World Use of Carvedilol in Children With Dilated Cardiomyopathy: Long-Term Effect on Survival and Ventricular Function.

Background: Carvedilol is recommended for chronic heart failure (HF) treatment in children. However, the ideal dosage and administration are not standardized, and data on its long-term effects are lacking. This study aimed to assess the effect of a high dosage regimen of carvedilol on cardiac outcomes in children with HF. Methods: We conducted a retrospective cohort study including all children with HF and dilated cardiomyopathy. We analyzed medical records before starting treatment, at 1 and 3 years after reaching the maximum therapeutic dosage. All data were compared with a historical control group. Kaplan-Meier analysis and Cox proportional hazard regression have been used to evaluate the effect of high dosage carvedilol therapy. The main outcome was a composite of all-cause mortality and heart transplant. Results: One hundred thirty-five were included in the study and 65 treated with a high dosage of carvedilol regimen (up to 1 mg/kg/day). Heart rate reduction (mean reduction 30%, p < 0.0001) and ejection fraction improvement (32 ± 9.4 vs. 45. ± 10.1%, p < 0.0001) were statistically significant in those. Long-term survival and freedom from heart transplant were significantly improved in those treated with high dosage carvedilol therapy (p = 0.00001). Conclusions: Treatment with the high dosage of carvedilol, in addition to standard HF therapy, significantly improves ventricular function and survival in children with dilated cardiomyopathy and chronic HF.

The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric trial center in Italy.

Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians' participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure.However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children's Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present 10 years' experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.

Systematic review and meta-analysis of recent high-quality studies on exposure to particulate matter and risk of lung cancer.

BACKGROUND: Several aspects of the association between exposure to air pollution and risk of lung cancer remain unclear. OBJECTIVE: We aimed at performing a meta-analysis of high-quality cohort studies on exposure to particulate matter (PM) 10 and PM2.5 and risk of lung cancer. METHODS: We identified cohort studies published since 2004, that reported risk estimates of lung cancer for exposure to PM2.5 and PM10 adjusted for tobacco smoking and socioeconomic status, and conducted a meta-analysis based on random-effects models, including stratification by outcome, sex, country, tobacco smoking, and age. RESULTS: Results on PM2.5 exposure were available from 15 studies; the summary relative risk (RR) for an increase of 10 µg/m3 was 1.16 (95% confidence interval [CI] 1.09, 1.23). The corresponding RR for PM10 exposure was 1.23 (95 CI 1.05, 1.40; seven studies). A higher risk was suggested in studies based on lung cancer mortality and in studies conducted in East Asia, while no difference was shown according to sex, smoking status or age. There was no suggestion of publication bias. CONCLUSIONS: Our meta-analysis supported the hypothesis of an association between exposure to PM2.5 or PM10 and risk of lung cancer, and provided evidence that the magnitude of the risk might be higher than previously estimated, and might be modified by outcome and geographic region.

Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis.

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.

Psychosocial interventions in stimulant use disorders: a systematic review and qualitative synthesis of randomized controlled trials.

Stimulant use disorders are highly prevalent with a large burden of disease. Most clinical guidelines recommend psychosocial interventions, but there are no clear hierarchies or indications. Moreover, these interventions have been reported unevenly in the literature. Identifying the most suitable treatment for each patient therefore represents a major challenge. In this review, we describe all psychosocial interventions for stimulant use disorders investigated in randomized controlled trials - including contingency management, cognitive behavioral interventions, community reinforcement approach, 12-step program, meditation-based interventions and physical exercise, supportive expressive psychodynamic therapy, interpersonal psychotherapy, family therapy, motivational interviewing, drug counseling -, and we synthesize the main findings of these studies. Similarities and differences between treatments are highlighted, suggesting that distinct psychosocial interventions can be relevant for certain patients' groups but not for others. Conversely, several interventions can be equally effective in similar clinical contexts, suggesting that a shared element such as therapeutic alliance is key. Finally, combined approaches emerge as a viable option for people with complex needs. Future studies will need to benchmark psychosocial interventions in stimulant use disorders and ascertain markers of response with a view to individualized treatment.

[Prevention of vector-borne diseases in Italy]. / Prevenzione delle Infezioni trasmesse da vettori in Italia.

In recent years, a constant increase of vector-borne diseases has been seen in Italy, due to various conditions including climate change, trade and international travel. These factors contribute to the diffusion on the Italian territory of newly introduced carriers and pathogens. These new pathogens can be an emerging cause of epidemics, as in the case of the Chikungunya virus in 2007 and in 2017, or can establish a true endemic disease, as in the case of the West Nile virus. It is even possible that diseases that had been endemic in the past, which were subsequently eliminated in Italy, could be reintroduced, as in the case of malaria. This review aims to illustrate the recent evolution of the diffusion of vectors and of the pathogens they convey, and to investigate which emerging pathogens could be responsible in the immediate future for new epidemics / endemics in Italy. Nowadays it is necessary to keep those neglected emerging diseases in mind, in order to establish a correct diagnostic-therapeutic approach at the individual level, and to identify the measures to avoid their diffusion at the community level. Preventive interventions, such as available vaccines or individual protection from vectors, are also discussed.

[The Italian Immunization Plan 2017: analysis and starting point for the Regional Plans]. / Il nuovo Piano Nazionale Prevenzione Vaccinale 2017-2019: analisi e punto di partenza per i piani regionali.

The National Immunization Plan 2017-2019 has been approved on January 2017. This official document contains the new Italian guidelines to improve vaccination coverage in the country. We conducted an accurate and critical analysis of the document, highlighting its key points and critical issues, in order to offer an practical tool for writing the Regional Plans. The new immunization schedule and the establishment of a restricted panel for the vaccine vigilance are the most significant innovations of the Plan. The Plan addresses also the issues of mandatory vaccination and of penalties for physicians who advise against vaccinations. Together with the presence of qualifying aspects as information about the ethical value and the benefits of vaccination, the Plan contains other interesting proposals, such as the introduction of a computerized vaccination register and the targeted use of new technologies to reach the population extensively. The Plan is set up as a conceptually rich tool, suitable for the development of regional operational plans.

Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis.

BACKGROUND: A number of biomarkers have been studied for the diagnosis of sepsis in paediatrics, but no gold standard has been identified. Procalcitonin (PCT) was demonstrated to be an accurate biomarker for the diagnosis of sepsis in adults and showed to be promising in paediatrics. Our study reviewed the diagnostic accuracy of PCT as an early biomarker of sepsis in neonates and children with suspected sepsis. METHODS: A comprehensive literature search was carried out in Medline/Pubmed, Embase, ISI Web of Science, CINAHL and Cochrane Library, for studies assessing PCT accuracy in the diagnosis of sepsis in children and neonates with suspected sepsis. Studies in which the presence of infection had been confirmed microbiologically or classified as "probable" by chart review were included. Studies comparing patients to healthy subjects were excluded. We analysed data on neonates and children separately. Our primary outcome was the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml, while as secondary outcomes we analysed PCT cut-offs <2 ng/ml and >2.5 ng/ml. Pooled sensitivities and specificities were calculated by a bivariate meta-analysis and heterogeneity was graphically evaluated. RESULTS: We included 17 studies, with a total of 1408 patients (1086 neonates and 322 children). Studies on neonates with early onset sepsis (EOS) and late onset sepsis (LOS) were grouped together. In the neonatal group, we calculated a sensitivity of 0.85, confidence interval (CI) (0.76; 0.90) and specificity of 0.54, CI (0.38; 0.70) at the PCT cut-off of 2.0-2.5 ng/ml. In the paediatric group it was not possible to undertake a pooled analysis at the PCT cut-off of 2.0-2.5 ng/ml, due to the paucity of the studies. CONCLUSIONS: PCT shows a moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml. More studies with high methodological quality are warranted, particularly in neonates, studies considering EOS and LOS separately are needed to improve specificity. TRIAL REGISTRATION: PROSPERO Identifier: CRD42016033809 . Registered 30 Jan 2016.

[Zika virus: a public health overview on epidemiology, clinical practice and prevention]. / Virus Zika: una panoramica di sanità pubblica su epidemiologia, clinica e prevenzione.

Zika virus is an arbovirus mainly transmitted by mosquitoes bites. During the last months, the attention of Public Health Institutions has been drawn by a significant increase of microcephaly cases in Brasil and analyses highlighted a connection between Zika virus infection in pregnant women and fetal microcephaly. Since 2015, many Zika virus outbreaks have been identified in South America and there is concern about the spread of the virus in areas where competent vectors are present. Nowadays, vaccination is not available and prevention is based on individual measures and on vectors control. This review of the most recent studies give an overview on the Zika problem.

The use of actigraphy in the monitoring of sleep and activity in ADHD: A meta-analysis.

Attention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. There is an increasing need to find objective measures and markers of the disorder in order to assess the efficacy of the therapies and to improve follow-up strategies. Actigraphy is an objective method for recording motor activity and sleep parameters that has been used in many studies in ADHD. Our meta-analysis aimed to assess the current evidence on the role of actigraphy in both the detection of changes in motor activity and in sleep patterns in ADHD. A systematic review was carried out to find studies comparing children with unmedicated ADHD versus controls, using actigraphic measures as an outcome. The primary outcome measures were "sleep duration" and daytime "activity mean". As secondary outcome measures we analyzed "sleep onset latency", "sleep efficiency" and "wake after sleep onset". Twenty-four studies comprising 2179 children were included in this review. We show evidence that ADHD compared to typically developing children present a higher mean activity during structured sessions, a similar sleep duration, and a moderately altered sleep pattern. This study highlights the role of actigraphy as an objective tool for the ambulatory monitoring of sleep and activity in ADHD.