Residential exposure to mold, dampness, and indoor air pollution and risk of respiratory tract infections: a study among children ages 11 and 12 in the Danish National Birth Cohort.

BACKGROUND: The burden of respiratory tract infections (RTIs) is high in childhood. Several residential exposures may affect relative rates. OBJECTIVES: To determine risk of RTIs in children ages 11 and 12 by residential exposures. METHODS: We included children in the Danish National Birth Cohort (DNBC) at ages 11 and 12. We estimated incidence risk ratios (IRR) and 95% confidence intervals (CI) for counts of RTIs within the last year by exposure to mold/dampness, gas stove usage, summer and winter candle-burning, fireplace usage, cats and dogs indoors, and farmhouse living. We also estimated IRR and 95% CI for RTIs for predicted scores of four extracted factors ('owned house', 'mold and dampness', 'candles', and 'density') from exploratory factor analyses (EFA). RESULTS: We included 42 720 children with complete data. Mold/dampness was associated with all RTIs (common cold: IRRadj 1.09[1.07, 1.12]; influenza: IRRadj 1.10 [1.05, 1.15]; tonsillitis: IRRadj 1.19 [1.10, 1.28]; conjunctivitis: IRRadj 1.16 [1.02, 1.32]; and doctor-diagnosed pneumonia: IRRadj 1.05 [0.90, 1.21]), as was the EFA factor 'mold/dampness' for several outcomes. Gas stove usage was associated with conjunctivitis (IRRadj 1.25 [1.05, 1.49]) and with doctor-diagnosed pneumonia (IRRadj 1.14 [0.93, 1.39]). Candle-burning during summer, but not winter, was associated with several RTIs, for tonsillitis in a dose-dependent fashion (increasing weekly frequencies vs. none: [IRRadj 1.06 [0.98, 1.14], IRRadj 1.16 [1.04, 1.30], IRRadj 1.23 [1.06, 1.43], IRRadj 1.29 [1.00, 1.67], and IRRadj 1.41 [1.12, 1.78]). CONCLUSION: Residential exposures, in particular to mold and dampness and to a lesser degree to indoor combustion sources, are related to the occurrence of RTIs in children.

Exposure to different residential indoor characteristics during childhood and asthma in adolescence: a latent class analysis of the Danish National Birth Cohort.

BACKGROUND: Many residential indoor environments may have an impact on children's respiratory health. OBJECTIVES: The aims of this study were to identify latent classes of children from the Danish National Birth Cohort (DNBC) who share similar patterns of exposure to indoor home characteristics, and to examine the association between membership in the latent classes and asthma in adolescence. METHODS: We included data on residential indoor characteristics of offspring from the DNBC whose mothers had responded to the child's 11-year follow-up and who had data on asthma from the 18-year follow-up. Number of classes and associations were estimated using latent class analysis. To account for sample selection, we applied inverse probability weighting. RESULTS: Our final model included five latent classes. The probability of current asthma at 18 years was highest among individuals in class one with higher clustering on household dampness (9, 95%CI 0.06-0.13). Individuals in class four (with higher clustering on pets ownership and living in a farm) had a lower risk of current asthma at age 18 compared to individuals in class one (with higher clustering on household dampness) (OR 0.53 (95%CI 0.32-0.88), p = .01). CONCLUSION: Our findings suggest that, in a high-income country such as Denmark, groups of adolescents growing up in homes with mold and moisture during mid-childhood might be at increased risk of current asthma at age 18. Adolescents who grew-up in a farmhouse and who were exposed to pets seem less likely to suffer from asthma by age 18.

Exposure to residential mold and dampness and the associations with respiratory tract infections and symptoms thereof in children in high income countries: A systematic review and meta-analyses of epidemiological studies.

BACKGROUND: Multiple reviews have been conducted on the associations between residential mold and dampness and respiratory outcomes in children, with few specifically investigating respiratory tract infections (RTIs). OBJECTIVE: We aimed to review and synthesize the available epidemiological literature on mold and dampness and risk of RTIs and respiratory symptoms compatible with RTIs in children living in high-income countries. METHOD: We performed a systematic search of literature available from MEDLINE, Embase, and Web of Science for observational studies. We conducted meta-analyses using two-level random effects (RE) and multi-level random effects (ML) models for contrasts of three exposure and three outcome categories, including multiple estimates reported by single studies. We report central estimates for pooled odds ratios (OR) and 95 % confidence intervals (CI).We conducted a risk of bias assessment using the Joanna Briggs Initiative (JBI) checklists for cross-sectional, case-control, and cohort studies. We additionally report on cumulative meta-analyses, leave-one-out analyses of single estimates, subgroup analyses by study quality and study design and inclusion of all effect estimates. RESULTS: Of the 932 studies initially screened by title and abstract, we included 30 studies with 267 effect estimates that met the inclusion criteria. Most were cross-sectional (n = 22), with fewer cohort (n = 5) and case-control (n = 3) studies. Most of the studies were according to the bias assessment of poor or fair quality (n = 24). The main meta-analyses generally provided similar results regardless of statistical model and central estimates ranged from OR 1.28 (95 % CI; 1.08, 1.53) for dampness and RTIs to OR 1.76 (95 % CI; 1.64, 1.88) for mold and respiratory symptoms. Most analyses were of moderate heterogeneity. Funnel plots did not indicate strong publication bias. CONCLUSION: Our results are compatible with a weak to moderate effect of residential mold and or dampness on risk of RTIs in children in high-income countries. However, these results are based primarily on cross-sectional studies.

Vitamin D concentrations from neonatal dried blood spots and the risk of early-onset type 2 diabetes in the Danish D-tect case-cohort study.

AIMS/HYPOTHESIS: The aim of this study was to examine the influence of neonatal vitamin D concentration on the development of early-onset type 2 diabetes in a large population sample. METHODS: We conducted a case-cohort study utilising data from the Danish biobank and registers. Neonatal vitamin D was assessed measuring 25-hydroxyvitamin D3 [25(OH)D3] concentrations on the dried blood spot samples from the Biological Specimen Bank for Neonatal Screening. Cases of type 2 diabetes (n = 731) were retrieved from the Danish National Patient Register for all individuals born in Denmark between 1 May 1981 and 31 December 1992. The sub-cohort (n = 1765) was randomly selected from all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first type 2 diabetes diagnoses by quintiles of 25(OH)D3 and restricted cubic spline. RESULTS: The median 25(OH)D3 concentration (IQR) among cases was 21.3 nmol/l (13.3-34.1) and 23.9 nmol/l (13.7-35.7) in the sub-cohort. There was no indication of a potential lower risk of early-onset type 2 diabetes among individuals in the higher quintile of vitamin D concentration compared with the lowest (HRcrude 0.97 [95% CI 0.71, 1.33] p = 0.85; HRadjusted 1.29 [95% CI 0.92, 1.83] p = 0.14). CONCLUSIONS/INTERPRETATION: The results of this study do not support the hypothesis that higher neonatal vitamin D concentrations are associated with a lower risk of early-onset type 2 diabetes in adulthood.

'Standing together - at a distance': Documenting changes in mental-health indicators in Denmark during the COVID-19 pandemic.

Aims: There is a need to document the mental-health effects of the COVID-19 pandemic and its associated societal lockdowns. We initiated a large mixed-methods data collection, focusing on crisis-specific worries and mental-health indicators during the lockdown in Denmark. Methods: The study incorporated five data sources, including quantitative surveys and qualitative interviews. The surveys included a time series of cross-sectional online questionnaires starting on 20 March 2020, in which 300 (3×100) Danish residents were drawn every three days from three population groups: the general population (N=1046), families with children (N=1032) and older people (N=1059). These data were analysed by trend analysis. Semi-structured interviews were conducted with 32 people aged 24-83 throughout Denmark to provide context to the survey results and to gain insight into people's experiences of the lockdown. Results: Absolute level of worries, quality of life and social isolation were relatively stable across all population groups during the lockdown, although there was a slight deterioration in older people's overall mental health. Many respondents were worried about their loved ones' health (74-76%) and the potential long-term economic consequences of the pandemic (61-66%). The qualitative interviews documented significant variation in people's experiences, suggesting that the lockdown's effect on everyday life had not been altogether negative. Conclusions: People in Denmark seem to have managed the lockdown without alarming changes in their mental health. However, it is important to continue investigating the effects of the pandemic and various public-health measures on mental health over time and across national contexts.

Substitution of sugar-sweetened beverages for other beverages and the risk of developing coronary heart disease: Results from the Harvard Pooling Project of Diet and Coronary Disease.

Sugar-sweetened beverage (SSB) intake is associated with metabolic disorders. The reduction of SSB intake has been promoted to prevent death and disability from chronic diseases. We investigated the association between SSB intake and the risk of coronary events and death, and assessed if substitution of coffee, tea, milk, fruit juice and artificially-sweetened beverages (ASB) for SSBs was associated with a reduced risk of coronary events and death. This was a follow-up study in which data from six studies were pooled and standard observational analyses were performed. Diet intake was assessed at baseline by food-frequency questionnaires. Hazard ratios (HRs) with 95% confidence intervals for the incidence of coronary events and deaths were calculated by Cox proportional hazards regression. The effect of substituting another beverage for SSBs was calculated by taking the difference in the individual effect estimates. During the median 8.2-year follow-up, 4248 coronary events and 1630 coronary deaths were documented among 284,345 individuals. 355 ml daily increase of SSB intake was associated with an increased risk of coronary events (HR: 1.08; 95%CI: 1.02, 1.14) and possibly coronary death (HR: 1.05; 95%CI: 0.96, 1.16). Substitution analyses suggested that replacing SSBs with coffee (HR: 0.93; 95%CI: 0.87, 1.00) or ASB (HR: 0.89; 95%CI: 0.83, 0.97), might be associated with a lower risk of developing coronary events. We found that SSB intake was associated with an increased risk of coronary events and possibly coronary death. Our findings also suggest that replacing SSB's with ASBs or coffee may lower the risk of developing CHD.

Environmental and individual predictors of 25-hydroxyvitamin D concentrations in Denmark measured from neonatal dried blood spots: the D-tect study.

Environmental factors such as sunshine hours, temperature and UV radiation (UVR) are known to influence seasonal fluctuations in vitamin D concentrations. However, currently there is poor understanding regarding the environmental factors or individual characteristics that best predict neonatal 25-hydroxyvitamin D (25(OH)D) concentrations. The aims of this study were to (1) identify environmental and individual determinants of 25(OH)D concentrations in newborns and (2) investigate whether environmental factors and individual characteristics could be used as proxy measures for neonatal 25(OH)D concentrations. 25-Hydroxyvitamin D3 (25(OH)D3) was measured from neonatal dried blood spots (DBS) of 1182 individuals born between 1993 and 2002. Monthly aggregated data on daily number of sunshine hours, temperature and UVR, available from 1993, were retrieved from the Danish Meteorological Institute. The individual predictors were obtained from the Danish National Birth register, and Statistics Denmark. The optimal model to predict 25(OH)D3 concentrations from neonatal DBS was the one including the following variables: UVR, temperature, maternal education, maternal smoking during pregnancy, gestational age at birth and parity. This model explained 30 % of the variation of 25(OH)D3 in the neonatal DBS. Ambient UVR in the month before the birth month was the best single-item predictor of neonatal 25(OH)D3, accounting for 24 % of its variance. Although this prediction model cannot substitute for actual blood measurements, it might prove useful in cohort studies ranking individuals in groups according to 25(OH)D3 status.

The Importance of the World Health Organization Sugar Guidelines for Dental Health and Obesity Prevention.

The World Health Organization (WHO) recommends a reduced intake of free sugars throughout the life course (strong recommendation) with a reduction of free sugars intake to less than 10% of the total energy intake (strong recommendation) and preferably below 5% of the total energy intake (conditional recommendation) in both adults and children. Available data clearly show that people already consume significantly more sugar than they should, increasing the risk for dental caries, overweight and obesity. The WHO recommendations are intended for use by the policy makers as a benchmark for assessing intake of sugars by populations and as a driving force for policy change. To create a favorable environment, enabling the overall amount of free sugar intake to be as low as possible and to reduce the frequency of consumption of sugar-rich foods, a range of public health interventions is advised.

Concentration of 25-hydroxyvitamin D from neonatal dried blood spots and the relation to gestational age, birth weight and Ponderal Index: the D-tect study.

Studies have suggested that vitamin D status at birth may be associated with a range of neonatal outcomes. The aim of this study was to assess the association between neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentration and gestational age, birth weight, Ponderal Index and size for gestational age. Neonatal capillary blood stored as dried blood spots was used to assess 25(OH)D3 concentrations among 2686 subjects selected from a random population sub-sample of individuals, born in Denmark from 1 May 1981 to 31 December 2002. There was an inverse association between 25(OH)D3 concentration and gestational age at birth of -0·006 (95 % CI -0·009, -0·003, P<0·001) weeks of gestation per 1 nmol/l increase in 25(OH)D3 concentration. An inverted U-shaped association between 25(OH)D3 and birth weight and Ponderal Index (P=0·04) was found, but no association with size for gestational age was shown. This study suggests that neonatal 25(OH)D3 concentration is associated with anthropometric measures at birth known to be correlated with many subsequent health outcomes such as obesity and type 2 diabetes.

In utero exposure to extra vitamin D from food fortification and the risk of subsequent development of gestational diabetes: the D-tect study.

BACKGROUND: The primary aim of this study was to assess whether exposure during fetal life to extra vitamin D from food fortification was associated with a reduction in the risk of subsequently developing gestational diabetes mellitus (GDM). Furthermore, we examined whether the effect of the vitamin D from fortification differed by women's season of birth. METHODS: This semi-ecological study is based on the cancellation in 1985 of the mandatory policy to fortify margarine with vitamin D in Denmark, with inclusion of entire national adjacent birth cohorts either exposed or unexposed to extra vitamin D in utero. The identification of GDM cases later in life among both exposure groups was based on the Danish national health registers. Logistic regression analyses generating odds ratios (ORs) and 95% confidence intervals (95% CIs) were performed. RESULTS: Women who were prenatally exposed to the extra vitamin D from fortification tended to have a lower risk of subsequently developing GDM than unexposed women (OR 0.87, 95%CI 0.74,1.02, P = 0.08). When analyses were stratified by women's season of birth, exposed women born in spring had a lower risk of developing GDM compared to unexposed subjects (OR 0.68, 95%CI 0.50,0.94, p = 0.02). CONCLUSION: This study suggests that prenatal exposure to extra vitamin D from mandatory fortification may lower the risk of developing gestational diabetes among spring-born women. TRIAL REGISTRATION: This study is part of the D-tect project, which is registered on clinicaltrials.gov: NCT03330301 .

Changes in job strain and subsequent weight gain: a longitudinal study, based on the Danish Nurse Cohort.

OBJECTIVE: Obesity as well as job strain is increasing, and job strain might contribute to weight gain. The objective of the current study was to examine associations between longitudinal alterations in the components of job strain and subsequent weight gain. DESIGN: The study was designed as a prospective cohort study with three questionnaire surveys enabling measurement of job-strain alterations over 6 years and subsequent measurements of weight gain after further 10 years of follow-up. ANCOVA and trend analyses were conducted. Job demands were measured as job busyness and speed, and control as amount of influence. SETTING: Employed nurses in Denmark. SUBJECTS: We included a sub-sample of 6188 female nurses from the Danish Nurse Cohort, which consisted of the nurses who participated in surveys in 1993, 1999 and 2009. RESULTS: A linear trend in weight gain was seen in nurses who were often busy in 1999 between those who were rarely v. sometimes v. often busy in 1993 (P=0·03), with the largest weight gain in individuals with sustained high busyness in both years. Loss of influence between 1993 and 1999 was associated with larger subsequent weight gain than sustained high influence (P=0·003) or sustained low influence (P=0·02). For speed, no associations were found. CONCLUSIONS: Busyness, speed and influence differed in their relationship to subsequent weight gain. A decrease in job influence and a sustained burden of busyness were most strongly related to subsequent weight gain. Focus on job strain reduction and healthy diet is essential for public health.

A retrospective analysis of a societal experiment among the Danish population suggests that exposure to extra doses of vitamin A during fetal development may lower type 2 diabetes mellitus (T2DM) risk later in life.

Vitamin A deficiency has been associated with impaired fetal pancreatic development and increased risk of developing type 2 diabetes mellitus (T2DM). In 1962, mandatory margarine fortification with vitamin A was increased by 25 % in Denmark. We aimed to determine whether offspring of mothers who had been exposed to the extra vitamin A from fortification during pregnancy had a lower risk of developing T2DM in adult life, compared with offspring of mothers exposed to less vitamin A. Individuals from birth cohorts with the higher prenatal vitamin A exposure (born 1 December 1962-31 March 1964) and those with lower prenatal exposure (born 1 September 1959-31 December 1960) were followed up with regard to development of T2DM before 31 December 2012 in the Danish National Diabetes Registry and National Patient Register. Logistic and Cox regression analyses were performed to determine the risk of T2DM by vitamin A exposure level. A total of 193 803 individuals were followed up until midlife. Our results showed that individuals exposed prenatally to extra vitamin A from fortified margarine had a lower risk of developing T2DM than those exposed to lower levels: OR 0·88; 95 % CI 0·81, 0·95, P=0·001, after adjustment for sex. Fetal exposure to small, extra amounts of vitamin A from food fortification may reduce the risk of T2DM. These results may have public health relevance, as they demonstrate that one of the most costly chronic diseases may be prevented by food fortification - a simple and affordable public health nutrition intervention.

Sugar-sweetened beverages, vascular risk factors and events: a systematic literature review.

OBJECTIVE: A high intake of sugar-sweetened beverages (SSB) has been linked to weight gain, obesity and type 2 diabetes; however, the influence on CVD risk remains unclear. Therefore, our objective was to summarize current evidence for an association between SSB consumption and cardiovascular risk factors and events. DESIGN: The article search was performed in August 2013. Two independent researchers performed the article search and selection, data extraction and quality assessment. Eligible studies reported the intake of SSB and one of the following outcomes: change in blood pressure, blood lipid or blood sugar, or CVD events such as stroke or myocardial infarction. Only intervention and longitudinal studies were included. SUBJECTS: Only studies in adults (aged 18+ years old) were considered. RESULTS: Two of four prospective studies found clear direct associations between SSB consumption and CHD, while two of three studies, including both men and women, found direct associations between SSB consumption and stroke; however, the association was significant among women only. All included studies examining vascular risk factors found direct associations between SSB consumption and change in blood pressure, blood lipid or blood sugar. CONCLUSIONS: The reviewed studies generally showed that SSB intake was related to vascular risk factors, whereas associations with vascular events were less consistent. Due to a limited number of published papers, especially regarding vascular events, the strength of the evidence is still limited and hence more studies are needed before firm conclusions can be made.

Indoor home environments of Danish children and the socioeconomic position and health of their parents: A descriptive study.

BACKGROUND: Housing and indoor home environments are associated with the risk of infections and asthma in children. To better understand the determinants and characteristics of these environments, we aimed to describe the associations between parental health and socioeconomic position and housing and indoor home environments of children in Denmark, and the clustering of the factors within these environments. METHODS: Offspring in the Danish National Birth Cohort (DNBC) whose parents responded to the 11-year follow-up were eligible for inclusion. We included complete cases only. Data on the indoor and housing environments (i.e. variables on housing, sources of gaseous and particle pollution, mould and moisture, and pets) were collected through an online questionnaire responded to by a parent. Data on socioeconomic position were obtained through linkage with registry data on maternal education at offspring birth and household equivalized income at offspring birth. Data on parental health were obtained by linking self-reported data from the 11-year follow-up for mother and father with administrative registry data for the mother. We present descriptive statistics and exploratory factor analyses. RESULTS: A total of 42 723 offspring were included for analyses. The distributions of nearly all indoor and housing environments differed according to educational and income strata, with patterns similar for both education and income. Generally, higher parental educational and income strata had more favorable indoor and housing environments (less secondhand smoking, gas stove use, mould and condensation and higher house ownership, detached house dwellings and newer building age). However, candle use was approximately similar between strata, fireplace use among lower educational and income strata tended towards the extremes (none or daily), and water damage was more common among higher educational and income strata. Parental health was strongly associated with housing and indoor home environment factors - especially parental affective disorders was strongly associated with mould. Four factors were extracted from the exploratory factor analyses, relating primarily in order of extraction to: housing ownership, mould and moisture, candle use and household density. CONCLUSION: Parental health and socioeconomic position are strongly related to housing and indoor home environments. Additionally, several factors in these environments correlate strongly and cluster together. Observational studies on associations and causal effects of factors in the indoor and housing environments of children on their morbidity, must consider both of these conclusions to arrive at valid estimates and effects.

Impact of housing conditions on changes in youth's mental health following the initial national COVID-19 lockdown: a cohort study.

We aimed to investigate if declines in youth's mental health during lockdown were dependent on housing condition among 7445 youth (median age ~ 20 years) from the Danish National Birth Cohort (DNBC), with data collected at 18 years of age and again three weeks into the first national lockdown (April 2020). We examined associations between housing conditions (access to outdoor spaces, urbanicity, household density, and household composition) and changes in mental health (mental well-being, Quality of Life (QoL) and loneliness). We report results from multivariate linear and logistic regression models. Youth without access to outdoor spaces experienced greater declines in mental well-being (vs. garden; mean difference: - 0·75 (95% CI - 1·14, - 0·36)), and correspondingly greater odds of onset of low mental well-being (vs. garden; OR: 1·72 (95% CI 1·20, 2·48)). Youth in higher density households vs. below median or living alone vs. with parents only also had greater odds of onset of low mental well-being (OR: 1·26 (95% CI 1·08, 1·46) and OR: 1·62 (95% CI 1·17, 2·23), respectively). Living in denser households (vs. below median; OR: 1·18 (95% CI 1·06, 1·33), as well as living alone (vs. with parents; OR: 1·38 (95% CI 1·04, 1·82) was associated with onset of low QoL. Living alone more than doubled odds of onset of loneliness compared to living with parents, OR: 2·12 (95% CI 1·59, 2·82). Youth living alone, in denser households, and without direct access to outdoor spaces may be especially vulnerable to mental health declines.

Housing environment and mental health of Europeans during the COVID-19 pandemic: a cross-country comparison.

Many studies have investigated the impact of the COVID-19 pandemic on mental health. Throughout the pandemic, time spent at home increased to a great extent due to restrictive measures. Here we set out to investigate the relationship between housing conditions and the mental health of populations across European countries. We analyzed survey data collected during spring 2020 from 69,136 individuals from four cohorts from Denmark, France, and the UK. The investigated housing conditions included household density, composition, and crowding, access to outdoor facilities, dwelling type, and urbanicity. The outcomes were loneliness, anxiety, and life satisfaction. Logistic regression models were used, and results were pooled using random-effects meta-analysis. In the meta-analysis, living alone was associated with higher levels of loneliness (OR = 3.08, 95% CI 1.87-5.07), and lower life satisfaction (OR = 1.27, 95% CI 1.05-0.55), compared to living with others. Not having access to an outdoor space and household crowding were suggestively associated with worse outcomes. Living in crowded households, living alone, or lacking access to outdoor facilities may be particularly important in contributing to poor mental health during a lockdown. Addressing the observed fundamental issues related to housing conditions within society will likely have positive effects in reducing social inequalities, as well as improving preparedness for future pandemics.

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.

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.

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.