The short-term and long-term adverse effects of melatonin treatment in children and adolescents: a systematic review and GRADE assessment.

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I2 = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Vitamin D Supplementation and Vitamin D Status during Pregnancy and the Risk of Congenital Anomalies-A Systematic Review and Meta-Analysis.

Maternal dietary factors have been suggested as possible contributing influences for congenital anomalies (CAs). We aimed to assess the association between vitamin D supplementation or vitamin D status (s-25OHD) during pregnancy and CAs in the offspring. A comprehensive literature search was conducted in the three electronic databases: PubMed, Embase, and Cochrane Library. Included studies were critically appraised using appropriate tools (risk of bias 2, ROBINS-I). A protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019127131). A meta-analysis of four randomised controlled trials (RCTs) including 3931 participants showed no effect of vitamin D supplementation on CAs, a relative risk of 0.76 (95% CI 0.45; 1.30), with moderate certainty in the effect estimates by GRADE assessment. Of the nine identified observational studies, six were excluded due to a critical risk of bias in accordance with ROBINS-I. Among the included observational studies, two studies found no association, whereas one case-control study identified an association between s-25OHD < 20 nmol/L and neural tube defects, with an adjusted odds ratio of 2.34 (95% CI: 1.07; 5.07). Interpretation of the results should be cautious given the low prevalence of CAs, RCTs with onset of supplementation after organogenesis, and low-quality observational studies.

Use of melatonin for children and adolescents with chronic insomnia attributable to disorders beyond indication: a systematic review, meta-analysis and clinical recommendation.

Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2-20 years, with chronic insomnia due to disorders beyond indication. Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2-20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2-4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2-4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3-6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42-6.34, 9 studies, I2 = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I2 = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low. Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Use of melatonin in children and adolescents with idiopathic chronic insomnia: a systematic review, meta-analysis, and clinical recommendation.

Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5-20 years with idiopathic chronic insomnia. Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5-20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96-41.70, 4 studies, I2 = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I2 = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25-9.42, 4 studies, I2 = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning. Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised. Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation.

The Effects of Exercise during Pregnancy on Gestational Diabetes Mellitus, Preeclampsia, and Spontaneous Abortion among Healthy Women-A Systematic Review and Meta-Analysis.

The aim was to compare the effects of different exercise modalities (aerobic, resistance, aerobic and resistance combined, or mind-body exercise) on gestational diabetes mellitus (GDM), preeclampsia, spontaneous abortion, withdrawal from the study, and adverse events in healthy pregnant women. A systematic search was conducted in February 2022 using MEDLINE, EMBASE, Cochrane library, and SPORT Discus to identify eligible randomized trials. The meta-analysis of 18 studies that examined exercise compared to no exercise showed a reduced risk of GDM (RR: 0.66 (95% CI: 0.50 to 0.86)). No subgroup differences were found regarding modality, intensity, or supervision. Exercise did not reduce the risk of preeclampsia (nine studies, RR: 0.65 (95% CI: 0.42 to 1.03)); however, in subgroup analyses, mind-body exercise and low-intensity exercise seemed to be effective in reduction of preeclampsia. There was no effect of exercise on withdrawal or adverse events found. No studies reported on spontaneous abortion, therefore, exercise during pregnancy is beneficial and safe. In the prevention of GDM, any modality and intensity seem equally effective. Subgroup analyses support an association between mind-body exercise and physical activity with low intensity and reduced risk of preeclampsia, but more high-quality randomized studies are needed. PROSPERO: CRD42022307053.

Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.

OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; ß=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391.

The role of prenatal vitamin D on the development of childhood asthma and wheeze: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND & OBJECTIVE: It has been suggested that prenatal vitamin D plays a role in the development of childhood asthma and wheeze. Several systematic reviews have been conducted, but the results are inconsistent, and the methodological quality has not been studied. Therefore, the objective of this umbrella review was to assess the internal validity of the evidence base and the evidence for an association between prenatal vitamin D and asthma or wheezing in the offspring. METHODS: We searched the electronic databases Embase, PubMed, and Cochrane Library for studies on prenatal vitamin D using search words such as vitamin D, 25-hydroxyvitamin D, calcidiol, fetal, and neonatal. The search was conducted in June 2020, and the databases were searched from their date of establishment. We included systematic reviews and/or meta-analyses of experimental and observational studies assessing the association between prenatal vitamin D or asthma and wheeze. We excluded narrative reviews, commentaries, and other umbrella reviews. The methodological quality of systematic reviews was assessed using AMSTAR 2 tool. PROSPERO reg. no. CRD42020151329. RESULTS: We identified 22 eligible systematic reviews (17 on asthma and 20 on wheeze). Using the AMSTAR 2 quality assessment tool, the methodological quality was rated as critically low in 21 out of 22 systematic reviews, suggesting that previous reviews and meta-analyses did not provide accurate and comprehensive summaries of the included studies and that conclusions reached were potentially flawed. The majority of the included reviews reported that prenatal vitamin D reduces the risk of wheeze in the offspring. CONCLUSION: Prior to informing public guidelines, high-quality systematic reviews of the current evidence are greatly warranted.

A systematic review of blood eosinophils and continued treatment with inhaled corticosteroids in patients with COPD.

Inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD) has been debated for 20 years. In our systematic literature review and meta-analysis, we addressed the following: Should patients with COPD and a blood eosinophil count (EOS) of, respectively, a) < 150 cells/µl, b) 150-300 cells/µl, and c) > 300 cells/µl continue treatment with ICS? Protocol registered in PROSPERO (CRD42020178110) and funded by the Danish Health Authority. We searched Medline, Embase, CINAHL and Cochrane Central on 22nd July 2020 for randomized controlled trials (RCT) of ICS treatment in patients with COPD (≥40 years, no current asthma), which analyzed outcomes by EOS count and where >50% of patients used ICS prior. We used the GRADE method. Meta-analyzes for the outcomes were divided into EOS subgroups and analyzed for differences. We identified 11 RCTs with a total of 29,654 patients. A significant difference (p < 0.00001) between the three subgroups' reduction of risk of moderate to severe exacerbation was found. Rate ratios for EOS counts: <150 cells/µL was 0.88 (95%CI: 0.83, 0.94); 150-300 cells/µL was 0.80 (95%CI: 0.69, 0.94); >300 cells/µL was 0.57 (95%CI: 0.49, 0.66). Overall, the certainty of the effect estimates was low to very low due to risk of bias, unexplained heterogeneity, few RCTs, and wide confidence intervals. A clear correlation was demonstrated between effect of continued ICS treatment (number of exacerbations, lung function, and quality of life) and increasing EOS count. Our meta-analyses suggested that treatment with ICS seemed beneficial for everyone except patients with EOS count below 150 cells/µl.

Effects of the healthy start randomized intervention on psychological stress and sleep habits among obesity-susceptible healthy weight children and their parents.

Poor sleep and psychological stress are obesity determinants that are rarely included in obesity prevention programs. The aim was to report the effects of the Healthy Start randomized intervention on the secondary outcomes psychological stress and sleep duration and onset latency. Data was obtained from the Healthy Start randomized intervention conducted in 2009-2012 among Danish healthy weight children aged 2-6 years, who had either a high birth weight (>4,000 g), high maternal pre-pregnancy body mass index (>28 kg/m2), or low maternal educational level (≤10 years of schooling) and their parents. The intervention was designed to deliver improvements in diet and physical activity habits, optimization of sleep habits, and reduction of psychological family stress. The average intervention period was 15 months. Children with information on a 7-day sleep record, sleep onset latency, Strengths and Difficulties Questionnaire (SDQ), and a modified version of Parenting Stress Index (PSI) were included. The effects of the intervention on sleep habits, PSI scores, SDQ Total Difficulties (SDQ-TD) and Pro-social Behavior scores, and 95% Confidence Intervals (95% CI) were analyzed using linear regression intention-to-treat (n = 543 (intervention group n = 271, control group n = 272)) analyses. No statistically significant effects on sleep duration, sleep onset latency, PSI score, or SDQ Pro-social Behavior score were observed. Values both before and after the intervention were within the normal range both for children in the intervention and children in the control group. Mean change in SDQ-TD was 0.09 points (95% CI -0.57;0.59) in the intervention group, and -0.69 points (95% CI -1.16; -0.23) in the control group (p = 0.06). In conclusion, there were no intervention effects in relation to sleep duration, sleep onset latency, PSI score, or SDQ Pro-social behavior. There was an indication that children in the intervention group had slightly more behavioral problems than the control group after the intervention, but values were within normal range both before and after the intervention, and the difference is not considered to be clinically meaningful.

Vitamin D Concentrations at Birth and the Risk of Rheumatoid Arthritis in Early Adulthood: A Danish Population-Based Case-Cohort Study.

Background: Low vitamin D in pregnancy may impair the development of the fetal immune system and influence the risk of later development of rheumatoid arthritis (RA) in the offspring. The aim was to examine whether lower 25-hydroxyvitamin D3 (25(OH)D) concentrations at birth were associated with the risk of developing RA in early adulthood. Methods: This case-cohort study obtained data from Danish registers and biobanks. Cases included all individuals born during 1981−1996 and recorded in the Danish National Patient Register with a diagnosis of RA with age >18 years at first admission. The random comparison consisted of a subset of Danish children. Vitamin D concentrations were measured in newborn dried blood. In total, 805 RA cases and 2416 individuals from the subcohort were included in the final analysis. Weighted Cox regression was used to calculate hazard ratio (HR). Results: The median (interquartile rage (IQR)) 25(OH)D concentrations among cases were 24.9 nmol/L (IQR:15.4;36.9) and 23.9 nmol/L (IQR:13.6;36.4) among the subcohort. There was no indication of a lower risk of RA among individuals in the highest vitamin D quintile compared with the lowest (HRadj.:1.21 (0.90;1.63)). Conclusion: The risk of RA in early adulthood was not associated with vitamin D concentrations at birth.

Usefulness of Cochrane Reviews in Clinical Guideline Development-A Survey of 585 Recommendations.

The Danish Health Authority develops clinical practice guidelines to support clinical decision-making based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and prioritizes using Cochrane reviews. The objective of this study was to explore the usefulness of Cochrane reviews as a source of evidence in the development of clinical recommendations. Evidence-based recommendations in guidelines published by the Danish Health Authority between 2014 and 2021 were reviewed. For each recommendation, it was noted if and how Cochrane reviews were utilized. In total, 374 evidence-based recommendations and 211 expert consensus recommendations were published between 2014 and 2021. Of the 374 evidence-based recommendations, 106 included evidence from Cochrane reviews. In 28 recommendations, all critical and important outcomes included evidence from Cochrane reviews. In 36 recommendations, a minimum of all critical outcomes included evidence from Cochrane reviews, but not all important outcomes. In 33 recommendations, some but not all critical outcomes included evidence from Cochrane reviews. Finally, in nine recommendations, some of the important outcomes included evidence from Cochrane reviews. In almost one-third of the evidence-based recommendations, Cochrane reviews were used to inform clinical recommendations. This evaluation should inform future evaluations of Cochrane review uptake in clinical practice guidelines concerning outcomes important for clinical decision-making.

Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review.

Celiac disease (CD), a gluten-induced autoimmune disease, is associated with low bone mineral density (BMD) among children. Unfortunately, it is often diagnosed in adulthood, which may lead to an increased risk of fragile bones. The aim of this systematic review was to report on BMD status among young adults newly diagnosed with CD, and to examine the effect of a gluten-free diet (GFD), nutritional supplements, such as vitamin D, or antiresorptive medications on BMD recovery. Databases searched were Medline, Embase, and Cochrane Library up to July 2nd, 2020. Both observational studies and clinical trials were considered, if patients were newly diagnosed and between 20 and 35 years of age and reported on BMD. We critically appraised the identified studies using ROBINS-I and summarized the findings narratively. Out of 3991 references, we identified 3 eligible studies: one cross-sectional study and two longitudinal studies. In total, 188 patients were included, and the study population consisted primarily of women with an age range between 29 and 37 years old. Compared to healthy controls, our target population had lower BMD. Moreover, a strict GFD may increase BMD during a follow-up period of up to 5 years. Newly diagnosed CD patients aged 20-35 years are at risk of lower BMD. Therefore, it may be crucial to assess BMD at time of diagnosis in young women. Whether the results can be extrapolated to young men is unknown. While strict GFD may improve BMD over time, there is a lack of robust evidence to demonstrate that nutritional supplements or antiresorptive agents are beneficial in the prevention of fragile bones in this age group.

Parent-Mediated Interventions for Children and Adolescents With Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

There has been increasing interest in parent-mediated interventions (PMIs) for children with autism spectrum disorders (ASDs). The objective of this systematic review and meta-analysis was to examine the effect of PMIs compared to no PMI for children with ASD aged 2-17 years. The primary outcome was adaptive functioning rated by a parent or clinician. The secondary outcomes were long-term adaptive functioning rated by the parents, adverse events, core symptoms of ASD, disruptive behavior, parental well-being, quality of life of the child rated by the parents and anxiety. The MEDLINE, PsycInfo, Embase, and CINAHL databases were searched in March 2020. The Cochrane Risk of Bias Tool was used to rate the individual studies, and the certainty in the evidence was evaluated using GRADE. We identified 30 relevant randomized controlled trials (RCTs), including 1,934 participants. A clinically relevant effect of PMIs on parent-rated adaptive functioning was found with a low certainty of evidence [Standard mean difference (SMD): 0.28 (95% CI: -0.01, 0.57)] on Vineland Adaptive Behavior Scales (VABS), whereas no clinically relevant effect was seen for clinician-rated functional level, with a very low certainty of evidence [SMD on Clinical Global Impressions (CGI)-severity scale: SMD -0.45 [95% CI: -0.87, -0.03)]. PMIs may slightly improve clinician-rated autism core symptoms [SMD: -0.35 (95% CI: -0.71, 0.02)]. Additionally, no effect of PMIs on parent-rated core symptoms of ASD, parental well-being or adverse effects was identified, all with a low certainty of evidence. There was a moderate certainty of evidence for a clinically relevant effect on disruptive behavior [SMD: 0.55 (95% Cl: 0.36, 0.74)]. The certainty in the evidence was downgraded due to serious risk of bias, lack of blinding, and serious risk of imprecision due to few participants included in meta-analyses. The present findings suggest that clinicians may consider introducing PMIs to children with ASD, but more high-quality RCTs are needed because the effects are not well-established, and the results are likely to change with future studies. The protocol for the systematic review is registered at the Danish Health Authority website (www.sst.dk).

Processed Meat Consumption and the Risk of Cancer: A Critical Evaluation of the Constraints of Current Evidence from Epidemiological Studies.

Based on a large volume of observational scientific studies and many summary papers, a high consumption of meat and processed meat products has been suggested to have a harmful effect on human health. These results have led guideline panels worldwide to recommend to the general population a reduced consumption of processed meat and meat products, with the overarching aim of lowering disease risk, especially of cancer. We revisited and updated the evidence base, evaluating the methodological quality and the certainty of estimates in the published systematic reviews and meta-analyses that examined the association between processed meat consumption and the risk of cancer at different sites across the body, as well as the overall risk of cancer mortality. We further explored if discrepancies in study designs and risks of bias could explain the heterogeneity observed in meta-analyses. In summary, there are severe methodological limitations to the majority of the previously published systematic reviews and meta-analyses that examined the consumption of processed meat and the risk of cancer. Many lacked the proper assessment of the methodological quality of the primary studies they included, or the literature searches did not fulfill the methodological standards needed in order to be systematic and transparent. The primary studies included in the reviews had a potential risk for the misclassification of exposure, a serious risk of bias due to confounding, a moderate to serious risk of bias due to missing data, and/or a moderate to serious risk of selection of the reported results. All these factors may have potentially led to the overestimation of the risk related to processed meat intake across all cancer outcomes. Thus, with the aim of lowering the risk of cancer, the recommendation to reduce the consumption of processed meat and meat products in the general population seems to be based on evidence that is not methodologically strong.

Vertiginous Episodes in Menière Disease following Transmyringeal Ventilation Tube Insertion: A Systematic Review on the Current State of Evidence

Abstract Introduction Menière disease (MD) is a disorder characterized by episodes of vertigo, sensorineural hearing loss, tinnitus and aural fullness. Objectives To assess the effect of ventilation tube insertion (VTI) on vertiginous episodes in patients (≥ 18 years old) with MD. Data Synthesis A systematic literature search on randomized clinical trials (RCTs), nonrandomized trials and other systematic reviews was performed. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to assess the overall certainty of evidence. Two RCTs and four nonrandomized studies were identified. Data extraction was only possible for one RCT. Results showed that the number of patients with no vertigo attacks significantly increased following active treatment (relative risk 1.52; [95% confidence interval: 1.19-1.94]). The quality of evidence was rated as low. None of the nonrandomized trials included a proper control group, which hindered data extraction and quality assessment. Conclusion There are currently no RCTs that specifically assess the efficacy of VTI in patients with MD. Current limited data suggest a considerable positive effect on the number of vertiginous episodes in patients with MD. However, due to poor evidence, a fluctuating course and a substantial placebo-effect associated with MD-treatment, no solid conclusion(s) regarding the efficacy of VTI can be made. There is a need for high-quality RCTs.

Vertiginous Episodes in Menière Disease following Transmyringeal Ventilation Tube Insertion: A Systematic Review on the Current State of Evidence.

Introduction Menière disease (MD) is a disorder characterized by episodes of vertigo, sensorineural hearing loss, tinnitus and aural fullness. Objectives To assess the effect of ventilation tube insertion (VTI) on vertiginous episodes in patients (≥ 18 years old) with MD. Data Synthesis A systematic literature search on randomized clinical trials (RCTs), nonrandomized trials and other systematic reviews was performed. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to assess the overall certainty of evidence. Two RCTs and four nonrandomized studies were identified. Data extraction was only possible for one RCT. Results showed that the number of patients with no vertigo attacks significantly increased following active treatment (relative risk 1.52; [95% confidence interval: 1.19-1.94]). The quality of evidence was rated as low. None of the nonrandomized trials included a proper control group, which hindered data extraction and quality assessment. Conclusion There are currently no RCTs that specifically assess the efficacy of VTI in patients with MD. Current limited data suggest a considerable positive effect on the number of vertiginous episodes in patients with MD. However, due to poor evidence, a fluctuating course and a substantial placebo-effect associated with MD-treatment, no solid conclusion(s) regarding the efficacy of VTI can be made. There is a need for high-quality RCTs.

Assessing Health Consequences of Vitamin D Fortification Utilizing a Societal Experiment Design: Methodological Lessons Learned from the D-Tect Project.

By utilizing historical changes in Danish legislation related to mandatory vitamin D fortification of margarine, which was implemented in the mid 1930s and abruptly abandoned in June 1985, the studies in the D-tect project investigated the effects of vitamin D on health outcomes in individuals, who during gestation were exposed or unexposed to extra vitamin D from fortified margarine. This paper reviews and narratively summarizes the analytic approaches alongside the results of the societal fortification experiment studies from the D-tect project and addresses the challenges in designing societal experiment studies and evaluating their results. The latter are discussed as lessons learned that may be useful for designers of similar studies, expected to be extensively utilized while researching the health consequences of the COVID-19 pandemic by comparing individuals born before and after the epidemic. In the D-tect project, 16 articles based on the societal fortification experiment were published analyzing 10 different outcomes and using different statistical approaches. Lessons learned included the detail of the analysis of the historical information on the exposure, availability and validity of the outcome data, variety of analytical approaches, and specifics concerning vitamin D effect evaluation, such as consideration of the influence of sunshine or season. In conclusion, the D-tect project clearly demonstrated the cost-effectiveness and research potential of natural- or societal-experiment-based studies.

Age and Sex Specific Trends in Incidence of Juvenile Idiopathic Arthritis in Danish Birth Cohorts from 1992 to 2002: A Nationwide Register Linkage Study.

This study reports age- and sex-specific incidence rates of juvenile idiopathic arthritis (JIA) in complete Danish birth cohorts from 1992 through 2002. Data were obtained from the Danish registries. All persons born in Denmark, from 1992-2002, were followed from birth and until either the date of first diagnosis recording, death, emigration, 16th birthday or administrative censoring (17 May 2017), whichever came first. The number of incident JIA cases and its incidence rate (per 100,000 person-years) were calculated within sex and age group for each of the birth cohorts. A multiplicative Poisson regression model was used to analyze the variation in the incidence rates by age and year of birth for boys and girls separately. The overall incidence of JIA was 24.1 (23.6-24.5) per 100,000 person-years. The rate per 100,000 person-years was higher among girls (29.9 (29.2-30.7)) than among boys (18.5 (18.0-19.1)). There were no evident peaks for any age group at diagnosis for boys but for girls two small peaks appeared at ages 0-5 years and 12-15 years. This study showed that the incidence rates of JIA in Denmark were higher for girls than for boys and remained stable over the observed period for both sexes.

Longitudinal Associations between Intake of Fruit and Vegetables and Height Attainment from Preschool to School Entry.

To examine associations between fruit and vegetable intake in young childhood and height attainment during preschool and at school entry. Data for this study was based on "The Healthy Start" primary intervention study, which included 635 obesity-prone children, (58% boys), from the greater Copenhagen area, with a mean (SD) age of 4.0 (1.1) years (age range 2-6 years) at baseline. In the current study, 553 children (57% boys) were included with information on dietary intake at baseline and height measured at baseline (preschool age), and 511 children (56.8% boys) with the height measured at school entry (~6 years old). Height was measured by trained health professionals during the intervention and by school nurses at school entry. Information on intakes of fruit and vegetables, separately and combined, was gathered with four-day dietary records reported by parents. Participants were grouped into tertiles for their intakes at baseline. Compared to boys with low consumption, those with a moderate and high intakes of fruit and vegetables (F&V) had a greater attained height at preschool of 1.3 cm (95% confidence interval (CI): 0.3; 2.3) and at school entry of 2.4 cm (95% CI: 0.8; 3.9) and 1.8 cm (95% CI: 0.2; 3.4), respectively, also after adjustment for differences in age, body mass index (BMI), and total energy intake. Additional adjustment for mid-parental height and parents' education did not alter the significant associations between moderate consumption of F&V and attained height at preschool and school entry. There was no association among girls. Our results showed that a moderate consumption of F&V was directly associated with higher attainment in height at preschool and school entry in boys. From a public health perspective, it should be prioritized to continue developing intervention programs to improve fruit and vegetable intake.

Effect of real-time and post-event feedback in out-of-hospital cardiac arrest attended by EMS - A systematic review and meta-analysis.

OBJECTIVES: A systematic review to determine if cardiopulmonary resuscitation (CPR) guided by either real-time or post-event feedback could improve CPR quality or patient outcome compared to unguided CPR in out-of-hospital cardiac arrest (OHCA). METHODS: Four databases were searched; PubMed, Embase, CINAHL, and Cochrane Library in August 2020 for post 2010 literature on OHCA in adults. Critical outcomes were chest compression depth, rate and fraction. Important outcomes were any return of spontaneous circulation, survival to hospital and survival to discharge. RESULTS: A total of 9464 studies were identified with 61 eligibility for full text screening. A total of eight studies was included in the meta-analysis. Five studies investigated real-time feedback and three investigated post-event feedback. Meta-analysis revealed that real-time feedback statistically improves compression depth and rate while post-event feedback improved depth and fraction. Feedback did not statistically improve patient outcome but an improvement in absolute numbers revealed a clinical effect of feedback. Heterogenity varied from "might not be important" to "considerable". CONCLUSION: To significantly improve CPR quality real-time and post-event feedback should be combined. Neither real-time nor post event feedback could statistically be associated with patient outcome however, a clinical effect was detected. The conclusions reached were based on few studies of low to very low quality. PROSPERO REGISTRATION: CRD42019133881.