Aluminium adjuvants versus placebo or no intervention in vaccine randomised clinical trials: a systematic review with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development. DESIGN: Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SOURCES: We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021. ELIGIBILITY CRITERIA: Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias with Cochrane's RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I2 statistic. We GRADE assessed the certainty of the evidence. RESULTS: We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants' seroprotection. CONCLUSIONS: Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.

Occupational noise exposure and risk of incident stroke: a pooled study of five Scandinavian cohorts.

OBJECTIVES: To investigate the association between occupational noise exposure and stroke incidence in a pooled study of five Scandinavian cohorts (NordSOUND). METHODS: We pooled and harmonised data from five Scandinavian cohorts resulting in 78 389 participants. We obtained job data from national registries or questionnaires and recoded these to match a job-exposure matrix developed in Sweden, which specified the annual average daily noise exposure in five exposure classes (LAeq8h): <70, 70-74, 75-79, 80-84, ≥85 dB(A). We identified residential address history and estimated 1-year average road traffic noise at baseline. Using national patient and mortality registers, we identified 7777 stroke cases with a median follow-up of 20.2 years. Analyses were conducted using Cox proportional hazards models adjusting for individual and area-level potential confounders. RESULTS: Exposure to occupational noise at baseline was not associated with overall stroke in the fully adjusted models. For ischaemic stroke, occupational noise was associated with HRs (95% CI) of 1.08 (0.98 to 1.20), 1.09 (0.97 to 1.24) and 1.06 (0.92 to 1.21) in the 75-79, 80-84 and ≥85 dB(A) exposure groups, compared with <70 dB(A), respectively. In subanalyses using time-varying occupational noise exposure, we observed an indication of higher stroke risk among the most exposed (≥85 dB(A)), particularly when restricting analyses to people exposed to occupational noise within the last year (HR: 1.27; 95% CI: 0.99 to 1.63). CONCLUSIONS: We found no association between occupational noise and risk of overall stroke after adjustment for confounders. However, the non-significantly increased risk of ischaemic stroke warrants further investigation.

Early Occupational Intervention for People with Low Back Pain in Physically Demanding Jobs: 1-year Follow-up Results of the Randomized Controlled GOBACK Trial.

STUDY DESIGN: Randomized controlled trial with 1-year follow up. OBJECTIVE: The aim of this study was to assess whether people with low back pain (LBP) and self-reported physically demanding jobs, benefit from an occupational medicine intervention, in addition to a single hospital consultation and a magnetic resonance imaging, at 1 year of follow-up. Secondly, to examine whether the positive health effects, found in both groups at 6 months, persist at 1-year follow-up. SUMMARY OF BACKGROUND DATA: The prevalence of LBP is high in the working population, resulting in a substantial social and economic burden. Although there are many guidelines available on the management of LBP, including multidisciplinary biopsychosocial rehabilitation, they provide limited guidance on the occupational medicine aspects. METHODS: As reported previously, 305 participants with LBP and self-reported physically demanding jobs were enrolled in the randomized controlled study and randomly allocated to clinical care with additional occupational medicine intervention or clinical care alone. Data were collected at baseline, 6 months, and 1 year. Outcomes included in the present 1-year follow-up study are changes in neuropathic pain (painDETECT questionnaire), severity of pain (0-10 numerical rating scale), disability (Roland Morris Disability Questionnaire), fear-avoidance beliefs (FABQ), physical, and mental quality of life (short-form 36). RESULTS: The study showed no effect of an occupational intervention on neuropathic pain, fear-avoidance beliefs, physical and mental quality of life nor disability measured after 1 year. The positive effects found at 6 months in both groups, remained at 1-year follow-up. CONCLUSION: The results suggest that a thorough clinical consultation, with focus on explaining the cause of pain and instructions to stay active, can promote long-lasting physical and mental health in individuals with LBP. Therefore, additional occupational interventions could focus on altering occupational obstacles on a structural level.Level of Evidence: 2.

Risk of work-related hand eczema in relation to wet work exposure.

Objective Albeit a pivotal risk for the development of hand eczema (HE), the exposure-response relationship between wet work and HE remains to be further investigated. Knowledge on exposure-response is important regarding preventive measures, medico-legal regulations and job-counseling. Recently, a job-exposure matrix (JEM) for wet work was developed, providing information on the likelihood of wet work. By combining the JEM with data on HE we aimed to investigate the relationship between extent of wet work and HE. Methods This study is a case-referent study including patients registered in the National Database of Contact Allergy, Denmark, and comprises data on sex, age, atopic dermatitis, HE, face eczema and patch testing results. Patients with HE served as cases and patients with facial eczema served as referents. Information on profession was retrieved from the DOC*X database in accordance with the DISCO-88 classification system. A wet-work-specific JEM provides - for each profession - an estimate for (i) the likelihood of wet work lasting ≥2 hours/day and (ii) the average number of hours of wet work per day. Results After two hours of wet hands and glove wear, the odds ratio (OR) was 3.49 and 3.19, respectively, for females and 2.41 and 1.82, respectively, for males. Females had a higher risk of HE than males with probability of wet hands <75% (OR 2.34, 95% CI 2.12-2.58 compared to males 1.68, 95% CI 1.22-2.31) and regarding glove wear at all exposure levels. Conclusion Our data confirms a close association between wet work and HE. Exposure lasting less than the current definition of wet work (having wet hands for ≥2 hours per day) may be of importance.

Influence of errors in job codes on job exposure matrix-based exposure assessment in the register-based occupational cohort DOC*X.

Objective Job-exposure matrices (JEM) may be efficient for exposure assessment in occupational epidemiological studies, but they rely on valid job information. We evaluated the agreement between JEM-based exposure estimates according to self-reported job titles converted to DISCO-88 codes and according to register-based DISCO-88 codes in the Danish Occupational Cohort with eXposure data (DOC*X). Furthermore, we evaluated the agreement between these two sets of DISCO-88 codes. Methods We used JEM regarding wood dust, lifting, standing/walking, arm elevation >90°, and noise from DOC*X. Participants from previous questionnaire studies were assigned JEM-based exposure estimates using (i) self-reported job titles converted to DISCO-88 codes and (ii) DISCO-88 codes registered in DOC*X, in four time periods (1976-78: N=7707; 1981-83: N=2193; 1991-94: N=2664; 2004: N=11 782). Agreement between the exposure estimates and between the DISCO-88 codes (four-digit levels, 1-4) was evaluated by kappa (κ) statistics. Sensitivities were calculated using the self-reported observation as the gold standard. Results We found substantial agreement (κ>0.60) between exposure estimates for all types of job-exposures and all time periods except for one κ. Low sensitivity (30-65%) was found for the period 1981-83, but for the other time periods the sensitivities varied between 60-91%. For individual 4-digit DISCO-88 codes, the sensitivities varied substantially and overall the sensitivities increased by lower digit level of DISCO-88. Conclusion The validity of the DISCO-88 codes in DOC*X was generally high. Substantial agreement was found for the JEM-based exposure estimates and the DISCO-88 codes per se, although the DISCO-88 code-specific agreement varied across digit levels and time periods.

Acute myocardial infarction in relation to physical activities at work: a nationwide follow-up study based on job-exposure matrices.

Objective This study aimed to evaluate sex-specific risks of acute myocardial infarction (AMI) according to lifting and standing/walking at work. Methods The study population included 1.15 million Danish wage earners. Annual job codes from 1976 onwards were linked to specific exposures using job-exposure matrices (JEM). Cases of AMI during follow-up 1996-2016 were retrieved from national registers. Incidence rate ratios (IRR) were computed by Poisson regression adjusting for demographic and JEM-assessed lifestyle factors. Models addressed physical activities at work the previous 0-2 years (short-term risk) and cumulative physical activities (long-term risk). Results During 21.4 million person-years of follow-up, 22 037 AMI occurred in men and 6942 in women. Exposure-response relationships between recent physical activities at work and AMI were not evident. In men, the fully adjusted long-term IRR for the highest of five exposure categories compared to the lowest were 1.09 [95% confidence interval (CI) 1.03-1.15] for lifting and 1.01 (95% CI 0.96-1.07) for standing/walking. In women, the corresponding figures were 1.27 (95% CI 1.15-1.40) and 1.18 (95% CI 1.07-1.30). The latter risk estimate was strongly attenuated, and the trend became insignificant when adjusted for lifting. Findings were only partially supported by sensitivity analyses. Conclusion The study provides limited support to the hypothesis that long-term lifting and standing/walking at work is related to increased risk of AMI. Possible effects of acute physical exertion are not addressed and bias towards the null because of crude exposure assignment cannot be ruled out.

Physical work demands and psychosocial working conditions as predictors of musculoskeletal pain: a cohort study comparing self-reported and job exposure matrix measurements.

OBJECTIVES: Determining exposure to occupational factors by workers' job titles is extensively used in epidemiological research. However, the correspondence of findings regarding associations to health between job exposure matrices (JEMs) and individual-level exposure data is largely unknown. We set out to examine the prospective associations of physical work demands and psychosocial working conditions with musculoskeletal pain, comparing JEMs with individual-level self-reported exposures. METHODS: We analysed data of 8132 participants from the Work Environment and Health in Denmark cohort study. Using random intercept multilevel modelling, we constructed age-specific and sex-specific JEMs estimating predicted exposures in job groups. We analysed associations between working conditions (individual and JEM level) at baseline and musculoskeletal pain at follow-up using multilevel modelling stratified by sex, adjusting for age, education and baseline pain. RESULTS: Any consistent associations present in the individual-level analysis were also found in the JEM-level analysis. Higher pain levels at follow-up was seen for employees with higher baseline physical work demands, women exposed to violence and men with lower decision authority, whether measured at the individual or JEM level. Higher JEM-level quantitative demands were associated with less pain, but no association was seen at the individual level. CONCLUSIONS: We found predominately comparable prospective associations between working conditions and pain, whether using JEMs or individual level exposures, with the exception of quantitative demands. The results suggest that, with few notable exceptions, findings obtained using JEMs may be comparable with those obtained when using self-reported exposures.

Physically strenuous work during pregnancy and risk of preterm birth.

The aim of the study was to examine the risk of preterm birth following physically strenuous work during pregnancy. We included 343 pregnant women referred to an occupational medical clinic. Data on preterm birth and covariates were retrieved from the Danish Birth Registry. Risk estimates were computed by logistic regression using a population sample of gainfully employed women as reference (n = 345,915). The risk of preterm birth was increased in women lifting heavy loads during pregnancy (OR 1.40, 95% CI [0.88, 2.23]) but not in women with physically strenuous work (OR 0.98, 95% CI [0.66, 1.46]). The mean gestational age in the heavy-lifting group compared to the reference group was 2.4 days shorter (95% CI [0.36, 4.41]). The study challenges earlier reassuring findings as heavy-lifting pregnant women had a reduced gestational age, indicating a possibility of increased risk of preterm birth.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

BACKGROUND: More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE: The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS: A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES: The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS: The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.

Maternal vitamin D status and offspring bone fractures: prospective study over two decades in Aarhus City, Denmark.

BACKGROUND: Studies investigating the association between maternal vitamin D status and offspring bone mass measured by dual-energy X-ray absorptiometry (DXA) during childhood have shown conflicting results. PURPOSE: We used occurrence of bone fractures up to the age of 18 as a measure reflecting offspring bone mass and related that to maternal vitamin D status. METHODS: The Danish Fetal Origins 1988 Cohort recruited 965 pregnant women during 1988-89 at their 30th gestation week antenatal midwife visit. A blood sample was drawn and serum was stored, which later was analyzed for the concentration of 25-hydroxyvitamin D (25(OH)D) by the liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS). Outcome was diagnosis of first time bone fractures extracted from the Danish National Patient Register. RESULTS: Vitamin D status was available for 850 women. The median (5th-95th percentile) 25(OH)D was 76.2 (23.0-152.1) nmol/l. During follow up 294 children were registered with at least one bone fracture diagnosis. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between maternal vitamin D status and first time bone fractures. However, there was a significantly increased hazard ratio (HR) during childhood for those who had maternal blood drawn in Dec/Jan/Feb compared with Jun/Jul/Aug (HR: 1.75, 95%CI: 1.11-2.74). Adjustment for vitamin D status strengthened this association (1.82, 1.12-2.97), which indicated a potential seasonal impact on offspring fractures independent of maternal vitamin D status. In a sensitivity analysis we found a borderline significant inverse association between continuous concentrations of 25(OH)D and offspring forearm fractures (P = 0.054). CONCLUSION: Overall, our results did not substantiate an association between maternal vitamin D status and offspring bone fractures. Further studies on this subject are needed, but the study populations must be large enough to allow for subdivision of fractures.

Vitamin D measured in maternal serum and offspring neurodevelopmental outcomes: a prospective study with long-term follow-up.

BACKGROUND: Vitamin D is obtained from dietary sources and synthesized in the skin during exposure to ultraviolet B radiation in sunlight. During pregnancy, vitamin D is transported from mother to fetus through the placenta in the form of 25-hydroxyvitamin D [25(OH)D]. There is evidence that vitamin D influences neuronal differentiation, endocrine functions, and fetal brain growth. Animal studies indicate alterations in the offspring brain as a consequence of vitamin D deficiency during pregnancy. In humans, maternal vitamin D insufficiency has been linked to impaired child language development. Using data from a prebirth cohort with up to 22 years of follow-up, we examined the association of vitamin D status with proxies of offspring neurodevelopmental outcomes. During 1988-1989, pregnant women were recruited for the DaFO88 cohort (n = 965) in Aarhus, Denmark. Maternal concentrations of 25(OH)D were quantified in serum from week 30 of gestation via the LC-MS/MS method (n = 850). Offspring were followed up through national registries until the age of 22 years. We evaluated the association of the maternal concentration of 25(OH)D with offspring neurodevelopmental outcomes defined as first admission diagnosis or prescription of medication for (1) ADHD, (2) depression, and (3) scholastic achievement based on the mean grade on standardized written examinations in the 9th grade (final exams after 10 years of compulsory school in Denmark). KEY MESSAGES: Maternal concentrations of 25(OH)D were higher compared to current levels (median 76 nmol/l; 5th to 95th percentiles 23-152). There was a direct association between maternal vitamin D status and offspring depression (p(trend) = 0.01); for ADHD there was no association. Scholastic achievement was slightly higher for offspring of mothers with a vitamin D status in the range of >50-125 nmol/l, but this nonlinear association was not statistically significant. CONCLUSIONS: Our analyses based on biomarker measurement of 25(OH)D from a cohort of 850 pregnant women combined with long-term follow-up showed no support for a beneficial fetal programming effect of vitamin D status with regard to behavioral and affective disorders and scholastic achievement.