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.

Positive pressure device treatment for Menière's disease: an overview of the current evidence and a meta-analysis.

OBJECTIVE: The objective was to critically assess the current evidence investigating the efficacy of using a positive pressure device in patients with definite or probable Menière's disease. METHODS: We performed a systematic literature search in MEDLINE, EMBASE and PsycINFO up to February 2018. We included both systematic reviews and primary literature [randomized controlled trials (RCTs)] investigating positive pressure treatment, in patients (≥ 18 years of age), with Menière's disease. We assessed the internal validity of systematic reviews using the AMSTAR tool and risk of bias of primary studies using the Cochrane Risk of bias tool. We performed a meta-analysis for each outcome based on the identified studies. The overall certainty of evidence for the outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS: The search for systematic reviews identified four relevant reviews. These all included the same four RCTs. An updated search identified one additional RCT. In total, five RCTs were included in the data synthesis. Our data synthesis showed no effect of positive pressure treatment on primary nor secondary outcomes. No serious adverse events were reported. The overall certainty of evidence ranged from very low to low, due to the serious risk of bias and imprecision. CONCLUSION: The current available evidence does not support positive pressure device treatment in patients with Menière's disease. However, the limitations of the current literature hinder the possibility of any solid conclusion. There remains a need for randomized controlled trials of high quality to fully access the utility of this treatment.

Prenatal exposure to vitamin D from fortified margarine and risk of fractures in late childhood: period and cohort results from 222 000 subjects in the D-tect observational study.

Prenatal low vitamin D may have consequences for bone health. By means of a nationwide mandatory vitamin D fortification programme, we examined the risk of fractures among 10-18-year-old children from proximate birth cohorts born around the date of the termination of the programme. For all subjects born in Denmark during 1983-1988, civil registration numbers were linked to the Danish National Patient Registry for incident and recurrent fractures occurring at ages 10-18 years. Multiplicative Poisson models were used to examine the association between birth cohort and fracture rates. The variation in fracture rates across birth cohorts was analysed by fitting an age-cohort model to the data. We addressed the potential modification of the effect of vitamin D availability by season of birth. The risk of fractures was increased among both girls and boys who were born before the vitamin D fortification terminated in 1985 (rate ratio (RR) exposed v. non-exposed girls: 1·15 (95 % CI 1·11, 1·20); RR exposed v. non-exposed boys: 1·11 (95 % CI 1·07, 1·14). However, these associations no longer persisted after including the period effects. There was no interaction between season of birth and vitamin D availability in relation to fracture risk. The study did not provide evidence that prenatal exposure to extra vitamin D from a mandatory fortification programme of 1·25 µg vitamin D/100 g margarine was sufficient to influence the risk of fractures in late childhood, regardless of season of birth. Replication studies are needed.

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.

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 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.

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 Healthy Start project: a randomized, controlled intervention to prevent overweight among normal weight, preschool children at high risk of future overweight.

BACKGROUND: Research shows that obesity prevention has to start early. Targeting interventions towards subgroups of individuals who are predisposed, but yet normal weight, may prove more effective in preventing overweight than interventions towards unselected normal weight subsets. Finally, interventions focused on other factors than diet and activity are lacking. The objectives were to perform a randomized, controlled intervention aiming at preventing overweight in children aged 2-6 years, who are yet normal weight, but have high predisposition for future overweight, and to intervene not only by improving diet and physical activity, but also reduce stress and improve sleep quality and quantity. METHODS/DESIGN: Based on information from the Danish National Birth Registry and administrative birth forms, children were selected based on having either a high birth weight, a mother who was overweight prior to pregnancy, or a familial low socioeconomic status. Selected children (n = 5,902) were randomized into three groups; an intervention group, a shadow control group followed in registers exclusively, and a control group examined at the beginning and at the end of the intervention. Approximately 21% agreed to participate. Children who presented as overweight prior to the intervention were excluded from this study (n = 92). In the intervention group, 271 children were included, and in the control group 272 were included. Information obtained from the shadow control group is on-going, but it is estimated that 394 children will be included. The intervention took place over on average 1½ year between 2009 and 2011, and consisted of optional individual guidance in optimizing diet and physical activity habits, reducing chronic stress and stressful events and improving sleep quality and quantity. The intervention also included participation in cooking classes and play arrangements. Information on dietary intake, meal habits, physical activity, sleep habits, and overall stress level was obtained by 4-7 day questionnaire diaries and objective measurements. DISCUSSION: If the Healthy Start project is effective in preventing excessive weight gain, it will provide valuable information on new determinants of obesity which should be considered in future interventions, and on new strategies to prevent development of overweight and obesity at an early age.

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.

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.

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.

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.

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.

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.

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.

The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) -0.31 (95% Cl. -0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl -5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl -6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

Associations between Parental Stress and Subsequent Changes in Dietary Intake and Quality among Preschool Children Susceptible to Obesity.

BACKGROUND: Cross-sectional studies indicate that parental stress may be a barrier for healthy dietary behaviours among children. However, there is a lack of evidence from longitudinal studies on the association between parental stress and changes in dietary intake among toddlers. The aim of this study was to examine the association between parental stress and changes in dietary intake and quality among preschool children susceptible to obesity. METHODS: In the Healthy Start study, parents to 250 preschool children had completed a modified version of the Parental Stress Index and assessed the dietary intake of their children at baseline and after 15 months of follow up. The association between parental stress and changes in dietary intake and quality was examined using multiple linear regression analyses with adjustment for potential confounders. We tested for potential effect modification by group allocation and sex. RESULTS: There were no significant associations between parental stress and subsequent changes in child total energy intake, intake of macronutrients or intake of fruit, vegetables, sugar sweetened beverages, fish or starch, or dietary quality. CONCLUSION: This study provides no evidence to support an association between parental stress and subsequent change in dietary intake and quality of their children. TRIAL REGISTRATION: ClinicalTrials.gov, Trial number: NCT01583335, Registered: 31 March 2012, retrospectively registered.

Associations between Child Mental Well-Being or Conflicts during Mealtime and Picky Eating Behaviour.

Pickiness is an eating behavior that many families with young children face. Having joint family meals may impact the child's pickiness, for instance by influencing their willingness to try novel foods. Moreover, picky children have been shown to display greater emotionality. The aim of this study was to investigate if children's mental well-being and parent-reported conflicts during mealtime were associated with pickiness among obesity-prone children. Data was obtained from the baseline examination of the Healthy Start intervention study, the Danish Medical Birth registry and the Danish Health Visitor's Child Health Database, and included 635 children aged 2-6 years that were all at high risk for becoming overweight later in life. Children's mental well-being was measured by the strengths and difficulties questionnaire. Crude and adjusted ordinal logistic regressions were used to investigate the cross-sectional associations. Children had a higher odds associated with changing from a category of less pickiness to a category of more pickiness for each one point higher SDQ score (ORadj. = 1.35, 95% CI = 1.14; 1.61) and lower odds (ORadj. = 0.57, 95% CI = 0.38; 0.86) associated with changing pickiness category towards more pickiness for each one point higher SDQ prosocial score. Moreover, children with conflicts during mealtime had higher odds of being in a worse pickiness category compared to children without conflicts (ORadj. = 3.37, 95% CI = 2.27; 5.01). This study showed that among obesity-prone children, behavioral problems, as well as conflicts during mealtime, were associated with more picky behaviors. Further longitudinal studies are needed to confirm the findings, as are studies including general child population subsets.