Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration.

RATIONALE: Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based. OBJECTIVES: To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD. OUTCOMES: Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs. RISK OF BIAS: We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool. SYNTHESIS METHODS: We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes. INCLUDED STUDIES: We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards. SYNTHESIS OF RESULTS: With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies. AUTHORS' CONCLUSIONS: In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development. FUNDING: Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239). REGISTRATION: Protocol available via doi.org/10.1002/14651858.CD015804.

Psychosocial and medication interventions to stop or reduce alcohol consumption during pregnancy.

BACKGROUND: Despite the known harms, alcohol consumption is common in pregnancy. Rates vary between countries, and are estimated to be 10% globally, with up to 25% in Europe. OBJECTIVES: To assess the efficacy of psychosocial interventions and medications to reduce or stop alcohol consumption during pregnancy. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register (via CRSLive), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO, from inception to 8 January 2024. We also searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). All searches included non-English language literature. We handsearched references of topic-related systematic reviews and included studies. SELECTION CRITERIA: We included randomised controlled trials that compared medications or psychosocial interventions, or both, to placebo, no intervention, usual care, or other medications or psychosocial interventions used to reduce or stop alcohol use during pregnancy. Our primary outcomes of interest were abstinence from alcohol, reduction in alcohol consumption, retention in treatment, and women with any adverse event. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included eight studies (1369 participants) in which pregnant women received an intervention to stop or reduce alcohol use during pregnancy. In one study, almost half of participants had a current diagnosis of alcohol use disorder (AUD); in another study, 40% of participants had a lifetime diagnosis of AUD. Six studies took place in the USA, one in Spain, and one in the Netherlands. All included studies evaluated the efficacy of psychosocial interventions; we did not find any study that evaluated the efficacy of medications for the treatment of AUD during pregnancy. Psychosocial interventions were mainly brief interventions ranging from a single session of 10 to 60 minutes to five sessions of 10 minutes each. Pregnant women received the psychosocial intervention approximately at the end of the first trimester of pregnancy, and the outcome of alcohol use was reassessed 8 to 24 weeks after the psychosocial intervention. Women in the control group received treatment as usual (TAU) or similar treatments such as comprehensive assessment of alcohol use and advice to stop drinking during pregnancy. Globally, we found that, compared to TAU, psychosocial interventions may increase the rate of continuously abstinent participants (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.14 to 1.57; I2 =0%; 3 studies; 378 women; low certainty evidence). Psychosocial interventions may have little to no effect on the number of drinks per day, but the evidence is very uncertain (mean difference -0.42, 95% CI -1.13 to 0.28; I2 = 86%; 2 studies; 157 women; very low certainty evidence). Psychosocial interventions probably have little to no effect on the number of women who completed treatment (RR 0.98, 95% CI 0.94 to 1.02; I2 = 0%; 7 studies; 1283 women; moderate certainty evidence). None of the included studies assessed adverse events of treatments. We downgraded the certainty of the evidence due to risk of bias and imprecision of the estimates. AUTHORS' CONCLUSIONS: Brief psychosocial interventions may increase the rate of continuous abstinence among pregnant women who report alcohol use during pregnancy. Further studies should be conducted to investigate the efficacy and safety of psychosocial interventions and other treatments (e.g. medications) for women with AUD. These studies should provide detailed information on alcohol use before and during pregnancy using consistent measures such as the number of drinks per drinking day. When heterogeneous populations are recruited, more detailed information on alcohol use during pregnancy should be provided to allow future systematic reviews to be conducted. Other important information that would enhance the usefulness of these studies would be the presence of other comorbid conditions such as anxiety, mood disorders, and the use of other psychoactive substances.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Psychosocial interventions for stimulant use disorder.

BACKGROUND: Stimulant use disorder is a continuously growing medical and social burden without approved medications available for its treatment. Psychosocial interventions could be a valid approach to help people reduce or cease stimulant consumption. This is an update of a Cochrane review first published in 2016. OBJECTIVES: To assess the efficacy and safety of psychosocial interventions for stimulant use disorder in adults. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, three other databases, and two trials registers in September 2023. All searches included non-English language literature. We handsearched the references of topic-related systematic reviews and the included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any psychosocial intervention with no intervention, treatment as usual (TAU), or a different intervention in adults with stimulant use disorder. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included a total of 64 RCTs (8241 participants). Seventy-three percent of studies included participants with cocaine or crack cocaine use disorder; 3.1% included participants with amphetamine use disorder; 10.9% included participants with methamphetamine use disorder; and 12.5% included participants with any stimulant use disorder. In 18 studies, all participants were in methadone maintenance treatment. In our primary comparison of any psychosocial treatment to no intervention, we included studies which compared a psychosocial intervention plus TAU to TAU alone. In this comparison, 12 studies evaluated cognitive behavioural therapy (CBT), 27 contingency management, three motivational interviewing, one study looked at psychodynamic therapy, and one study evaluated CBT plus contingency management. We also compared any psychosocial intervention to TAU. In this comparison, seven studies evaluated CBT, two contingency management, two motivational interviewing, and one evaluated a combination of CBT plus motivational interviewing. Seven studies compared contingency management reinforcement related to abstinence versus contingency management not related to abstinence. Finally, seven studies compared two different psychosocial approaches. We judged 65.6% of the studies to be at low risk of bias for random sequence generation and 19% at low risk for allocation concealment. Blinding of personnel and participants was not possible for the type of intervention, so we judged all the studies to be at high risk of performance bias for subjective outcomes but at low risk for objective outcomes. We judged 22% of the studies to be at low risk of detection bias for subjective outcomes. We judged most of the studies (69%) to be at low risk of attrition bias. When compared to no intervention, we found that psychosocial treatments: reduce the dropout rate (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.91; 30 studies, 4078 participants; high-certainty evidence); make little to no difference to point abstinence at the end of treatment (RR 1.15, 95% CI 0.94 to 1.41; 12 studies, 1293 participants; high-certainty evidence); make little to no difference to point abstinence at the longest follow-up (RR 1.22, 95% CI 0.91 to 1.62; 9 studies, 1187 participants; high-certainty evidence); probably increase continuous abstinence at the end of treatment (RR 1.89, 95% CI 1.20 to 2.97; 12 studies, 1770 participants; moderate-certainty evidence); may make little to no difference in continuous abstinence at the longest follow-up (RR 1.14, 95% CI 0.89 to 1.46; 4 studies, 295 participants; low-certainty evidence); reduce the frequency of drug intake at the end of treatment (standardised mean difference (SMD) -0.35, 95% CI -0.50 to -0.19; 10 studies, 1215 participants; high-certainty evidence); and increase the longest period of abstinence (SMD 0.54, 95% CI 0.41 to 0.68; 17 studies, 2118 participants; high-certainty evidence). When compared to TAU, we found that psychosocial treatments reduce the dropout rate (RR 0.79, 95% CI 0.65 to 0.97; 9 studies, 735 participants; high-certainty evidence) and may make little to no difference in point abstinence at the end of treatment (RR 1.67, 95% CI 0.64 to 4.31; 1 study, 128 participants; low-certainty evidence). We are uncertain whether they make any difference in point abstinence at the longest follow-up (RR 1.31, 95% CI 0.86 to 1.99; 2 studies, 124 participants; very low-certainty evidence). Compared to TAU, psychosocial treatments may make little to no difference in continuous abstinence at the end of treatment (RR 1.18, 95% CI 0.92 to 1.53; 1 study, 128 participants; low-certainty evidence); probably make little to no difference in the frequency of drug intake at the end of treatment (SMD -1.17, 95% CI -2.81 to 0.47, 4 studies, 479 participants, moderate-certainty evidence); and may make little to no difference in the longest period of abstinence (SMD -0.16, 95% CI -0.54 to 0.21; 1 study, 110 participants; low-certainty evidence). None of the studies for this comparison assessed continuous abstinence at the longest follow-up. Only five studies reported harms related to psychosocial interventions; four of them stated that no adverse events occurred. AUTHORS' CONCLUSIONS: This review's findings indicate that psychosocial treatments can help people with stimulant use disorder by reducing dropout rates. This conclusion is based on high-certainty evidence from comparisons of psychosocial interventions with both no treatment and TAU. This is an important finding because many people with stimulant use disorders leave treatment prematurely. Stimulant use disorders are chronic, lifelong, relapsing mental disorders, which require substantial therapeutic efforts to achieve abstinence. For those who are not yet able to achieve complete abstinence, retention in treatment may help to reduce the risks associated with stimulant use. In addition, psychosocial interventions reduce stimulant use compared to no treatment, but they may make little to no difference to stimulant use when compared to TAU. The most studied and promising psychosocial approach is contingency management. Relatively few studies explored the other approaches, so we cannot rule out the possibility that the results were imprecise due to small sample sizes.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

[School-based screening strategies to prevent the spread of COVID-19 in school: a systematic review of the literature]. / Strategie di screening per contenere la diffusione del COVID-19 nella scuola: una revisione sistematica della letteratura.

OBJECTIVES: to describe studies that evaluated the screening programmes implemented in the school during the COVID-19 pandemic. DESIGN: a systematic literature review was conducted according to the PRISMA 2020 Guidelines. Studies published until December 2021 were included. The methodological quality of the studies was assessed with validated scales. Study selection, data extraction, and quality assessment were carried out by two authors independently. SETTING AND PARTICIPANTS: teachers and students belonging to schools of all levels, including universities. MAIN OUTCOMES MEASURES: a. transmission-related outcomes (such as the number or proportion of cases, cumulative frequency, incidence); b. feasibility/acceptability of the screening strategies; c. socioeconomic outcomes (such as testing cost, number of days spent in school, quarantine). RESULTS: after having removed duplicate articles, 2,822 records were retrieved. Thirty-six studies were included (15 used an observational design and 21 modelling study). Regarding the former, the methodological quality has been rated as high in 2 studies, intermediate in 6 and low in 2; in the remaining ones, it was not evaluated because only descriptive. Screenings were quite different in terms of school study population, types of tests used, methods of submission and analysis, and level of incidence in the community at the time of implementation. Outcome indicators were also varied, a heterogeneity that, on the one hand, did not allow for meta-analysis of results and, on the other, allowed for testing the performance of the screenings in very different settings. All of the field studies claim that the screenings reduced SARS-CoV-2 exposure and infection among children, adolescents, and college students, curbing at-school transmission and helping to reduce the number of closing school days. Studies that evaluated the cost of the intervention emphasized its cost-effectiveness, while those that focused on the acceptability of the instrument showed a preference among children, adolescents, and parents for minimally invasive, self-administered tests with high sensitivity and lower frequency of repetition. Simulation-based studies are mostly based on compartmental and agent-based models. Their quality is quite high methodologically, although uncertainty quantification and external validation, aimed at verifying the model ability to reproduce observed data, are lacking in many cases. The contexts to which the simulations refer are all school-based, although 7 studies consider residential situations, which are poorly suited to the Italian context. All simulation-based models indicate the importance of planning repeated testing on asymptomatic individuals to limit contagion. However, the costs of these procedures can be high unless assessments are spaced out or pool testing procedures are used. Obtaining high student adherence to the screening programme is extremely important to maximize results. CONCLUSIONS: school-based screenings, especially when combined with other preventive measures, have been important public health tools to contain infections during COVID-19 waves and to ensure children's and adolescents' right to education and to prevent the fallout in physical and mental health (with strong equity consequences) associated with school closures.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Italian Guidelines for the Management of Non-Functioning Benign and Locally Symptomatic Thyroid Nodules.

AIM: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. METHODS: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence and only those classified as "critical" were considered in the formulation of recommendations. RESULTS: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. CONCLUSION: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Baclofen for alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is one of the most widespread psychiatric disorders leading to detrimental consequences to people with this disorder and others. Worldwide, the prevalence of heavy episodic drinking (30-day prevalence of at least one occasion of 60 g of pure alcohol intake among current drinkers) is estimated at 20% and the prevalence of AUD at 5% of the adult general population, with highest prevalence in Europe and North America. Therapeutic approaches, including pharmacotherapy, play an important role in treating people with AUD. This is an update of a Cochrane Review first published in 2018. OBJECTIVES: To evaluate the benefits and harms of baclofen on achieving and maintaining abstinence or reducing alcohol consumption in people with AUD compared to placebo, no treatment or any other pharmacological relapse prevention treatment. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 22 November 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for AUD treatment with placebo, no treatment or other treatments. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. relapse, 2. frequency of use, 3. amount of use, 4. adverse events, 5. dropouts from treatment and 6. dropouts from treatment due to adverse events. Our secondary outcomes were 7. craving, 8. anxiety, 9. depression and 10. frequency of most relevant adverse events. MAIN RESULTS: We included 17 RCTs (1818 participants) with a diagnosis of alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition or International Classification of Diseases 10th edition criteria. Mean age was 46.5 years and 70% were men. Ten studies compared baclofen to placebo or another medication; seven compared two baclofen doses to placebo or another medication. Globally, 15 studies compared baclofen to placebo, two baclofen to acamprosate and two baclofen to naltrexone. In 16 studies, participants received psychosocial treatments. We judged most studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias. Ten studies detoxified participants before treatment; in seven studies, participants were still drinking at the beginning of treatment. Treatment duration was 12 weeks for 15 RCTs and longer in two studies. Baclofen daily dose was 30 mg to 300 mg: 10 RCTs used low doses (30 mg or less); eight RCTs medium doses (above 30 and 100 mg or less) and four RCTs high doses (above 100 mg). Compared to placebo, moderate-certainty evidence found that baclofen probably decreases the risk to relapse (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.77 to 0.99; 12 studies, 1057 participants). This result was confirmed among detoxified participants but not among other subgroups of participants. High-certainty evidence found that baclofen increases the percentage of days abstinent (mean difference (MD) 9.07, 95% CI 3.30 to 14.85; 16 studies, 1273 participants). This result was confirmed among all subgroups of participants except non-detoxified or those who received medium doses. There was no difference between baclofen and placebo in the other primary outcomes: heavy drinking days (standardised mean difference (SMD) -0.18, 95% CI -0.48 to 0.11; 13 studies, 840 participants; moderate-certainty evidence); number of drinks per drinking days (MD -0.45, 95% CI -1.20 to 0.30; 9 studies, 392 participants; moderate-certainty evidence); number of participants with at least one adverse event (RR 1.05, 95% CI 0.99 to 1.11; 10 studies, 738 participants; high-certainty evidence); dropouts (RR 0.88, 95% CI 0.74 to 1.03; 17 studies, 1563 participants; high-certainty evidence); dropouts due to adverse events (RR 1.39, 95% CI 0.89 to 2.18; 16 studies, 1499 participants; high-certainty evidence). These results were confirmed by subgroup analyses except than for the dropouts that resulted lower among participants who received high doses of baclofen and studies longer than 12 weeks. Compared to placebo, there was no difference in craving (SMD -0.16, 95% CI -0.37 to 0.04; 17 studies, 1275 participants), anxiety (MD -0.01, 95% CI -0.14 to 0.11; 15 studies, 1123 participants) and depression (SMD 0.07, 95% CI -0.12 to 0.27; 11 studies, 1029 participants). Concerning the specific adverse events, baclofen increases fatigue, dizziness, somnolence/sedation, dry mouth, paraesthesia and muscle spasms/rigidity. There was no difference in the other adverse events. Compared to acamprosate, one study (60 participants) found no differences in any outcomes but the evidence was very uncertain: relapse (RR 1.25, 95% CI 0.71 to 2.20; very low-certainty evidence); number of participants with at least one adverse event (RR 0.63, 95% CI 0.23 to 1.69; very low-certainty evidence); dropouts (RR 0.56, 95% CI 0.21 to 1.46; very low-certainty evidence); dropouts due to adverse events (RR 0.33, 95% CI 0.01 to 7.87; very low-certainty evidence) and craving (MD 5.80, 95% CI -11.84 to 23.44); and all the adverse events evaluated. Compared to naltrexone, baclofen may increase the risk of relapse (RR 2.50, 95% CI 1.12 to 5.56; 1 study, 60 participants; very low-certainty evidence) and decrease the number of participants with at least one adverse event (RR 0.35, 95% CI 0.15 to 0.80; 2 studies, 80 participants; very low-certainty evidence) but the evidence is very uncertain. One study (60 participants) found no difference between baclofen and naltrexone in the dropouts at the end of treatment (RR 1.00, 95% CI 0.32 to 3.10; very low-certainty evidence), craving (MD 2.08, 95% CI -3.71 to 7.87), and all the adverse events evaluated. AUTHORS' CONCLUSIONS: Baclofen likely reduces the risk of relapse to any drinking and increases the percentage of abstinent days, mainly among detoxified participants. It does not increase the number of participants with at least one adverse event, those who dropout for any reason or due to adverse events. It probably does not reduce number of heavy drinking days and the number of drinks per drinking days. Current evidence suggests that baclofen may help people with AUD in maintaining abstinence. The results of comparisons of baclofen with acamprosate and naltrexone were mainly based on only one study.

School closures and mental health, wellbeing and health behaviours among children and adolescents during the second COVID-19 wave: a systematic review of the literature.

OBJECTIVES: to evaluate the impact of school closures, as a measure to contain the transmission of SARS-CoV-2 infection, on the psychological well-being of students of all levels starting from the 2020-2021 school year. DESIGN: a systematic literature review was conducted according to the PRISMA 2020 Guidelines. The literature search was conducted on 4 different databases: MedLine, Embase, PsycINFO, and L.OVE Platform. Quantitative observational studies published until 10.01.2022 were included. Studies conducted during the first pandemic wave, i.e., during the 2019-2020 school year and/or during the mandatory lockdown or confinement period, were excluded. The methodological quality of the studies was assessed with validated scales. Study selection, data extraction, and quality assessment were carried out independently by two authors. SETTING AND PARTICIPANTS: children, adolescents, and young people attending all levels of education (including universities) and, for reasons related to COVID-19, having a suspension of "in presence" school or attending classes remotely. MAIN OUTCOME MEASURES: a. outcomes directly related to mental health: suicides, emergency department visits, and hospitalizations for psychiatric problems; anxiety and depression, emotional difficulties, feelings of loneliness and isolation; b. well-being outcomes: sleep quality, perceived well-being (by child/adolescent/youth or referred by parents); c. health-related behaviours: tobacco smoking, alcohol, drug use. Outcomes related to school/academic performance, physical health, and those related to parents were not considered. RESULTS: after having removed duplicate articles, 2,830 records were retrieved with the bibliographic search. Twelve studies (2 uncontrolled before-after studies and 10 cross sectional surveys) were included, involving a total of 27,787 participants. Three studies involved university students, 2 involved high school students, and the remaining involved a mixed population of students attending primary and middle schools. The studies were conducted between September 2020 and April 2021. The methodological quality was rated as high in five studies and intermediate in the remaining studies. Due to the high heterogeneity of outcome measures and statistical analyses performed among the included studies, it was not possible to conduct a meta-analysis of the results of the considered publications. Nevertheless, the present review showed a clear signal of increase in mental health problems in relation to school closure or virtual instruction. In particular, results suggest evidence of association between school closure and risk of suicidal attempts or thoughts, mental health symptoms such as anxiety, depression, emotional disorders, psychological stress. Sleeping problems, drug and alcohol addiction were poorly studied. CONCLUSIONS: despite the limitations of the included studies and possible residual confounding and contamination due to restrictive measures and social isolation implemented during the pandemic, the available evidence confirms the negative impact on students' mental health associated with school closures and distance learning. Given the availability of vaccination also for young children, a long period of school closure should be avoided also in the case of the emergence of new pandemic waves.

Does letting adolescent and young adult inpatients share decisions in choosing the central-line insertion site reduce central-line-associated bloodstream infections? An empty systematic review.

To study whether allowing adolescents and young adults (AYA) with chronic or oncologic diseases admitted to tertiary or intensive care units to share decisions in choosing the insertion site for central-venous catheters (CVC) implanted for intravenous therapies or parenteral nutrition reduces central-line-associated and catheter-related bloodstream infections (CLABSI and CRBSI). Following the PRISMA guidelines, we systematically reviewed the literature by searching MEDLINE, Embase, CINAHL, CENTRAL, SCOPUS, Cochrane Library, and Web of Science up to December 2019. According to our aims, the review identified no study that could be included. This empty systematic review on healthcare teams allowing AYA with chronic or oncologic diseases admitted in tertiary or intensive care units to share decisions in choosing the site for implanting CVC prompts further research on clinical pathways on this hot-topic. By considering purportedly risk-taking behaviors in youngsters thus reducing CLABSI and CRBSI, healthcare teams should test specific strategies by engaging AYA empathetically in sharing decisions on the site for implanting CVC to improve quality in health care bundles.

School Closures During Social Lockdown and Mental Health, Health Behaviors, and Well-being Among Children and Adolescents During the First COVID-19 Wave: A Systematic Review.

IMPORTANCE: School closures as part of broader social lockdown measures during the COVID-19 pandemic may be associated with the health and well-being of children and adolescents. OBJECTIVE: To review published reports on the association of school closures during broader social lockdown with mental health, health behaviors, and well-being in children and adolescents aged 0 to 19 years, excluding associations with transmission of infection. EVIDENCE REVIEW: Eleven databases were searched from inception to September 2020, and machine learning was applied for screening articles. A total of 16 817 records were screened, 151 were reviewed in full text, and 36 studies were included. Quality assessment was tailored to study type. A narrative synthesis of results was undertaken because data did not allow meta-analysis. FINDINGS: A total of 36 studies from 11 countries were identified, involving a total of 79 781 children and adolescents and 18 028 parents, which occurred during the first wave of the COVID-19 pandemic (February to July 2020). All evaluated school closure as part of broader social lockdown during the first COVID-19 wave, and the duration of school closure ranged from 1 week to 3 months. Of those, 9 (25%) were longitudinal pre-post studies, 5 (14%) were cohort, 21 (58%) were cross-sectional, and 1 (3%) was a modeling study. Thirteen studies (36%) were high quality, 17 (47%) were medium quality, and 6 (17%) were low quality. Twenty-three studies (64%) were published, 8 (22%) were online reports, and 5 (14%) were preprints. Twenty-five studies (69%) concerning mental health identified associations across emotional, behavioral, and restlessness/inattention problems; 18% to 60% of children and adolescents scored above risk thresholds for distress, particularly anxiety and depressive symptoms, and 2 studies reported no significant association with suicide. Three studies reported that child protection referrals were lower than expected number of referrals originating in schools. Three studies suggested higher screen time usage, 2 studies reported greater social media use, and 6 studies reported lower physical activity. Studies on sleep (10 studies) and diet (5 studies) provided inconclusive evidence on harms. CONCLUSIONS AND RELEVANCE: In this narrative synthesis of reports from the first wave of the COVID-19 pandemic, studies of short-term school closures as part of social lockdown measures reported adverse mental health symptoms and health behaviors among children and adolescents. Associations between school closure and health outcomes and behaviors could not be separated from broader lockdown measures.

The Standard of Care Definitions on COVID-19 Pharmacological Clinical Trials: A Systematic Review.

Background: Standard of Care (SoC) has been used with different significance across Randomized Clinical Trials (RCTs) on the treatment of Covid-19. In the context of a living systematic review on pharmacological interventions for COVID-19, we assessed the characteristics of the SoC adopted in the published RCTs. Methods: We performed a systematic review searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to April 10, 2021. We included all RCTs comparing any pharmacological intervention for Covid-19 against any drugs, placebo, or SoC. All trials selected have been classified as studies with SoC including treatments under investigation for COVID-19 (SoC+); studies with SoC without specifications regarding the potential therapies allowed (SoC-); studies including as control groups Placebo (P) or active controls (A+). Results: We included in our analysis 144 RCTs, comprising 78,319 patients. Most of these trials included SoC (108; 75.0%); some in all arms of the study (69.7%) or just as independent comparators (30.3%). Treatments under investigation for COVID-19 in other trials were included in the SoC (SoC+) in 67 cases (62.0%), Thirty-one different therapeutic agents (alone or in combination) were counted within the studies with SoC+: mostly hydroxychloroquine or chloroquine (28), lopinavir/ritonavir (20) or azithromycin (16). No specification was given regarding treatment allowed in the control groups (SoC-) in 41 studies (38.0%). Conclusion: Our analysis shows that the findings emerging from several clinical trials regarding the efficacy and safety of pharmacological intervention for COVID-19 might be jeopardized by the quality of control arms.

Comparative Effectiveness of Pharmacological Interventions for Covid-19: A Systematic Review and Network Meta-Analysis.

Background: Several pharmacological interventions are now under investigation for the treatment of Covid-19, and the evidence is evolving rapidly. Our aim is to assess the comparative efficacy and safety of these drugs. Methods and Findings: We performed a systematic review and network meta-analysis searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to December 10, 2020. We included all randomised controlled trials (RCTs) comparing any pharmacological intervention for Covid-19 against any drugs, placebo or standard care (SC). Data extracted from published reports were assessed for risk of bias in accordance with the Cochrane tool, and using the GRADE framework. Primary outcomes were all-cause mortality, adverse events (AEs) and serious adverse events (SAEs). We estimated summary risk ratio (RR) using pairwise and network meta-analysis with random effects (Prospero, number CRD42020176914). We performed a systematic review and network meta-analysis searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to December 10, 2020. We included all randomised controlled trials (RCTs) comparing any pharmacological intervention for Covid-19 against any drugs, placebo or standard care (SC). Data extracted from published reports were assessed for risk of bias in accordance with the Cochrane tool, and using the GRADE framework. Primary outcomes were all-cause mortality, adverse events (AEs) and serious adverse events (SAEs). We estimated summary risk ratio (RR) using pairwise and network meta-analysis with random effects (Prospero, number CRD42020176914). We included 96 RCTs, comprising of 34,501 patients. The network meta-analysis showed in terms of all-cause mortality, when compared to SC or placebo, only corticosteroids significantly reduced the mortality rate (RR 0.90, 95%CI 0.83, 0.97; moderate certainty of evidence). Corticosteroids significantly reduced the mortality rate also when compared to hydroxychloroquine (RR 0.83, 95%CI 0.74, 0.94; moderate certainty of evidence). Remdesivir proved to be better in terms of SAEs when compared to SC or placebo (RR 0.75, 95%CI 0.63, 0.89; high certainty of evidence) and plasma (RR 0.57, 95%CI 0.34, 0.94; high certainty of evidence). The combination of lopinavir and ritonavir proved to reduce SAEs when compared to plasma (RR 0.49, 95%CI 0.25, 0.95; high certainty of evidence). Most of the RCTs were at unclear risk of bias (42 of 96), one third were at high risk of bias (34 of 96) and 20 were at low risk of bias. Certainty of evidence ranged from high to very low. Conclusion: At present, corticosteroids reduced all-cause mortality in patients with Covid-19, with a moderate certainty of evidence. Remdesivir appeared to be a safer option than SC or placebo, while plasma was associated with safety concerns. These preliminary evidence-based observations should guide clinical practice until more data are made public.

[Impact of social distancing for covid-19 on youths' physical health: a systematic review of the literature.] / Impatto del distanziamento sociale per covid-19 sulla salute fisica dei giovani: una revisione sistematica della letteratura.

BACKGROUND: Schools' closure during covid-19 pandemic implemented almost all over the world, together with social distances measures and lockdown to reduce transmission, could have had negative impact on youths' health. AIM: Summarize the most relevant data from a literature systematic review on the impact on youths' physical health of the 2020 school closure and social distances measures implemented in response to covid-19 pandemic. METHODS: Authors of the original review searched on 11 international databases up to 1st September 2020 to retrieve cohort studies, cross sectional surveys, uncontrolled pre-post studies and modelling studies. Methodological quality has been assessed with validated checklists. RESULTS: Forty-two studies reporting the impact on physical health have been finally included. They have been conducted in 14 countries, most of which in Italy (30.9%) and UK (30.9%). The majority were cohort studies (40.5%) and the overall methodological quality, irrespective of study designs, was high for the 71.4% of the studies. Twenty-seven studies assessed the impact on health services utilization, whose results showed a relevant reduction of Emergency Departments accesses (64%-89.3%) and hospital admissions (31%-85%); however, an increase of acute cases was observed together with delayed admission. An important reduction of vaccine services utilization was also noted during the first period of lockdown. Domestic accidents and head trauma for suspected domestic violence increased. Health related behaviours worsened, with a relevant increase of screen time (mean of 2.9 hours to 5.1 hours), an important reduction of physical activity (up to 64%). Finally, sleep problems and increase of food consumption, particularly the unhealthy food were reported. CONCLUSIONS: Relevant negative effects of school closure and social distances measures have observed. All the studies have been conducted during the first wave of pandemic and assessed the short-term effect of closures implemented for relatively short periods. If school closure and rigid social distances measures imposition will extend for a long time, an even more pronounced negative effect can be expected. In the context of health policies, in addition to the potential benefits of school closures and social distancing measures on the containment of infection, the potential damage on the physical health of young people should be taken into account by implementing policies to safeguard their health.

[Impact of social distancing for covid-19 on the psychological well-being of youths: a systematic review of the literature.] / Impatto del distanziamento sociale per covid-19 sul benessere psicologico dei giovani: una revisione sistematica della letteratura.

BACKGROUND: During the first semester 2020 almost all country implemented rigid measures of social distances, including schools closure, to limit the transmission of SARS-CoV-2 infection. Up to now, however, the efficacy of school closure to reduce the spread of the disease in the community still remains unclear and no much is known about the potential negative effects of such measures on physical health and psychological wellbeing of youths, mainly if protracted for long periods. OBJECTIVE: To summarize the data of a systematic review on the impact of the 2020 school closure and social distances measures implemented in response to covid-19 pandemic on youths' physical health and psychological wellbeing. In the present paper we describe the impact on psychological wellbeing. METHODS: We searched 11 international databases up to 1st September 2020 to retrieve cohort studies, cross sectional surveys, uncontrolled pre-post studies and modelling studies. Methodological quality of included studies has been assessed with validated checklists. RESULTS: Sixty-four studies have been included; 27 assessed the impact on psychological wellbeing. All the studies have been conducted during the first wave of pandemic and assessed the short-term effect of social distances measures implemented for relatively short periods. The majority of the studies were conducted in the UK (37,6%) and China (27%). The 42.3% has been judged of high methodological quality. Two studies reported an increase of suicides, while two studies reported a reduction of the access to Psychiatric Emergency Department, Maltreatment allegations decreased substantially, likely due to a reduction in reports rather than actual incidence. Prevalence of anxiety among adolescents ranged between 19% and 64%, depression between 22.3% and 43.7%. Among children 5-12 years old, prevalence of anxiety varied between 19% and 78%, while depression between 6.3% and 22.6%. Among pre-school children, some studies found worsening of behavioural and emotional problems while others did not. CONCLUSIONS: Most of the studies reported relevant worsening of the psychological wellbeing, mainly among adolescents. If school closure and rigid social distances measures will extend for a long time, an even more pronounced negative effect can be expected. Further studies are needed on the long-term effect of prolonged social distances measures, as well as a careful harm-benefit analysis of the impact of such measures.

[Impact of social distancing for covid-19 on young people: type and quality of the studies found through a systematic review of the literature.] / Impatto del distanziamento sociale per covid-19 sui giovani: tipologia e qualità degli studi reperiti attraversouna revisione sistematica della letteratura.

BACKGROUND: During the first semester 2020 almost all country implemented rigid measures of social distances, including schools closure, to limit the transmission of SARS-CoV-2 infection. Up to now, however, the efficacy of school closure to reduce the spread of the disease in the community still remain unclear and no much is known about the potential negative effects of such measures on physical health and psychological wellbeing of children and adolescents, mainly if protracted for long periods. OBJECTIVE: To summarize the most relevant data of a systematic review on the impact of the 2020 school closure and social distances measures implemented in response to covid-19 pandemic on youths physical health and psychological wellbeing. In the present paper we describe the review's methodology and the characteristics and methodological quality of the retrieved studies. METHODS: We searched on 11 international databases up to 1st September 2020 to retrieve cohort studies, cross sectional surveys, uncontrolled pre-post studies and modelling studies. Methodological quality of included studies has been assessed with validated checklists. RESULTS: Sixty-four studies have been included; 42 assessed the effect of social distances measure of physical health and 27 on psychological wellbeing. All the studies have been conducted during the first wave of pandemic and assessed the short-term effect of social distances measures implemented for relatively short periods. The 32.4% of the studies has been conducted in the UK, 20.3% in Italy, 12.5% in China, 10.9% in developing countries and 9.4% in the US. 37.5% of the studies were cohort studies, 40.6% cross sectional surveys, 19.7% uncontrolled studies and 1 was a modeling study. 59.6% of the studies has been rated as high quality. The most important weakness of the cross-sectional surveys and uncontrolled studies was the scarce representativeness of the sample while 96% of the cohort studies were judged as high quality. CONCLUSIONS: A large number of acceptable quality studies have been published during the first months of pandemic to assess the impact of school closure and social distances measures on physical health and psychological wellbeing of youths. This highlights the relevance of the topic and the need to assess carefully the balance between harms and benefits of such measures in terms of actual reduction of transmission and youths' psychological and physical harms. Further studies are needed on the long-term effect of social distances measures extended over long periods.

[The praise of uncertainty: a systematic living review to evaluate the efficacy and safety of drug treatments for patients with covid-19.] / L'elogio dell'incertezza: una revisione sistematica living per valutare l'efficacia e la sicurezza dei trattamenti farmacologici per pazienti affetti da covid-19.

BACKGROUND: SARS-CoV-2 is a coronavirus that causes a disease which can leads to a severe form of fatal pneumonia. At december 2020 in Italy, more than 2 million people have contracted the virus and 78,755 people have died. The scientific community is studying and testing numerous compounds that can be effective and safe for treating people with covid-19. AIM: To synthesize and evaluate the quality of evidence of efficacy and safety for the treatment. The available evidence is summarized in a living systematic review, a review that is constantly updated on the basis of the results of the new clinical studies. METHODS: A bibliographic search is launched weekly on the electronic databases and on the main clinical trial registers. Two researchers independently select the articles and assess the quality of the studies using the criteria developed by the Cochrane Collaboration, the certainty of the overall quality of the evidence is assessed using the GRADE criteria. RESULTS: At 31/12/2020, 101 randomized controlled studies were included that consider 72 different comparisons and include a total of 55,281 patients. 37 drugs are tested with respect to the standard treatment, 6 are evaluated against placebo and finally 29 compare different drugs with each other. By selecting studies that evaluate the efficacy and safety of a drug compared to standard treatment, which include at least 2 studies and which have low to high certainty of evidence, results show that corticosteroids, remdesivir, favipiravir, immunoglobulins, colchicine, and umbilical cord mesenchymal stem cell infusion could reduce overall mortality. No differences for the risk of any adverse events are observed between convalescent plasma and remdesivir compared to standard treatment. Remdesivir probably reduces the risk of serious adverse events; a similar effect, although less strong, is also noted for tocilizumab and the lopinavir-ritonavir combination. In contrast, hydroxychloroquine, corticosteroids and convalescent plasma transfusion are associated with safety concerns with respect to the risk of serious adverse events. CONCLUSIONS: The 101 studies included consider 72 comparisons and numerous outcomes, the results often coming from single studies and of small dimensions, and for 61% with a very low certainty of evidence, are difficult to summarize and the final result is to increase the uncertainty rather than providing useful information to the clinic and research. From all the work carried out it seems to us that the pandemic has highlighted the many shadows of scientific literature as tool to improve knowledge.

Mindful organizing as a healthcare strategy to decrease catheter-associated infections in neonatal and pediatric intensive care units. A systematic review and grading recommendations (GRADE) system.

PURPOSE: To explore the clinical evidence available on mindful organizing (MO) that will improve teamwork for positioning and managing central venous catheters in patients admitted to neonatal intensive care and other pediatric intensive care units to decrease central-line-associated and catheter-related bloodstream infections (CLABSI and CRBSI). METHODS: We searched several databases (PubMed, Embase, CINAHL, CENTRAL, SCOPUS, and Web of Science) up to June 2018. We included studies investigating the effectiveness of MO teamwork in reducing CLABSI and CRBSI. The systematic review followed the PRISMA guidelines. We used validated appraisal checklists to assess quality. RESULTS: Seven studies were included: only one was a non-randomized case-controlled trial (CCT). All the others had a pre-post intervention design, one a time-series design and one an interrupted time-series design. The methodological heterogeneity precluded a meta-analysis. Despite the low certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, three studies including thousands of participants provided numerical data for calculating risk ratios (RR) and 95% confidence intervals (CI) comparing MO with no intervention for decreasing the CLABSI rate in neonatal and pediatric ICUs. The one CCT disclosed no significant difference in the CLABSI rate decrease between groups (RR = 0.96; 95%CI 0.47-1.97). Nor did the pre- and post-intervention interrupted time-series design disclose a significant decrease (RR = 0.80; 95%CI 0.36 1.77). In the study using a before-after study design, the GRADE system found that the CLABSI rate decrease differed significantly in favor of post-intervention (RR = 0.13; 95%CI 0.03 0.57; p = 0.007). CONCLUSIONS: Despite the decreased CLABSI rate, the available evidence is low in quality. To reduce the unduly high CLABSI rates in neonatal and pediatric intensive care settings, custom-designed clinical trials should further define the clinical efficacy of MO to include it in care bundles as a new international standard.

Impact of antipsychotics in children and adolescents with autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: The net health benefit of using antipsychotics in children and adolescents with ASD is unclear. This review was performed to provide the evidence necessary to inform the Italian national guidelines for the management of ASD. METHODS: We performed a systematic review of randomized controlled trials (RCTs) comparing antipsychotics versus placebo for the treatment of ASD in children and adolescents. For efficacy, acceptability and safety we considered outcomes evaluated by the guideline panel critical and important for decision-making. Continuous outcomes were analyzed by using standardized mean difference (SMD), and dichotomous outcomes by calculating the risk ratio (RR), with their 95% confidence interval (95% CI). Data were analyzed using a random effects model. We used the Cochrane tool to assess risk of bias of included studies. Certainty in the evidence of effects was assessed according to the GRADE approach. RESULTS: We included 21 RCTs with 1,309 participants, comparing antipsychotics to placebo. Antipsychotics were found effective on "restricted and repetitive interests and behaviors" (SMD - 0.21, 95% CI - 0.35 to - 0.07, moderate certainty), "hyperactivity, inattention, oppositional, disruptive behavior" (SMD - 0.67, 95% CI - 0.92 to - 0.42, moderate certainty), "social communication, social interaction" (SMD - 0.38, 95% CI - 0.59 to - 0.16, moderate certainty), "emotional dysregulation/irritability" (SMD - 0.71, 95% CI - 0.98 to - 0.43, low certainty), "global functioning, global improvement" (SMD - 0.64, 95% CI - 0.96 to - 0.33, low certainty), "obsessions, compulsions" (SMD - 0.30, 95% CI - 0.55 to - 0.06, moderate certainty). Antipsychotics were not effective on "self-harm" (SMD - 0.14, 95% CI - 0.58 to 0.30, very low certainty), "anxiety" (SMD - 0.38, 95% CI - 0.82 to 0.07, very low certainty). Antipsychotics were more acceptable in terms of dropout due to any cause (RR 0.61, 95% CI 0.48 to 0.78, moderate certainty), but were less safe in terms of patients experiencing adverse events (RR 1.19, 95% CI 1.07 to 1.32, moderate certainty), and serious adverse events (RR 1.07, 95% CI 0.48 to 2.43, low certainty). CONCLUSIONS: Our systematic review and meta-analysis found antipsychotics for children and adolescents with ASD more efficacious than placebo in reducing stereotypies, hyperactivity, irritability and obsessions, compulsions, and in increasing social communication and global functioning. Antipsychotics were also found to be more acceptable, but less safe than placebo.