European Cohort Studies Research Articles

Long-term effects of air temperature on cardiopulmonary outcomes in prospective European cohort studies

BACKGROUND AND AIM: Short-term health effects of air temperature have been well recognized. However, little is known about the effects of prolonged exposure to non-optimal air temperatures, particularly at the individual level. This study assessed long-term temperature effects on cardiopulmonary (CPD) outcomes using data collected in four prospective European cohorts. METHODS: Participants of the KORA (Augsburg, Germany), RoLS (Rome, Italy), CONOR (Norway), and UK Biobank (UK) cohorts were included in the current analysis. Their vital status and incident diseases were identified through death and disease registries as well as follow-up surveys. Annual mean and standard deviation (SD) of air temperature were calculated for each participant and follow-up year based on the daily mean air temperature at residences estimated by spatial-temporal models. We applied cohort-specific Cox proportional hazard models with adjustment for individual characteristics and time trends, using the distributed lag non-linear model approach, to assess the associations of long-term air temperature with CPD mortality and morbidity. Random-effects meta-analysis was used to pool the cohort-specific estimates. RESULTS: In the RoLS cohort, we observed a monotonically increasing risk for cardiovascular mortality associated with increasing annual mean and SD of temperature. For an increment from the 75th to the 95th percentile in the annual mean and SD, the hazard ratios for cardiovascular mortality were 1.055 (95% CI: 1.029, 1.081) and 1.151 (95% CI: 1.060, 1.251), respectively. Besides, increasing annual SD showed an indication of being associated with increased respiratory mortality risk. In the KORA cohort, no effects were observed for annual mean temperature or SD on CPD mortality and morbidity. Cohort-specific analyses in Norway and UK and the meta-analysis are ongoing. CONCLUSIONS: This study provides evidence for long-term air temperature effects on CPD outcomes but also indicates heterogeneity in such effects among four European cohorts. KEYWORDS: Air temperature, long-term, cardiopulmonary mortality, cohorts

Comparison of the safety and efficacy of YEARS, PEGeD, 4PEPS or the sole item "PE is the most likely diagnosis" strategies for the diagnosis of pulmonary embolism in the emergency department: post-hoc analysis of two European cohort studies.

The optimal strategy for the diagnosis of pulmonary embolism (PE) in the emergency department (ED) remains debated. To reduce the need of imaging testing, several rules have been recently validated using an elevated D-dimer threshold. To validate the safety of different diagnostic strategies and compare the efficacy in terms of chest imaging testing. Post-hoc analysis of individual data of 3330 adult patients without a high clinical probability of PE in the ED followed-up at 3 months in France and Spain (1916 from the PROPER cohort, 1414 from the MODIGLIANI cohort). Four diagnostic strategies with an elevated D-dimer threshold if PE is unlikely. The YEARS combined with Pulmonary Embolism Rule-out Criteria (PERC) the pulmonary embolism graduated D-dimer (PEGeD) combined with PERC and the 4-level pulmonary embolism probability score (4PEPS) rules were assessed. A modified simplified (MODS) rule with a simplified YEARS reduced to the sole item of "Is PE the most likely diagnosis" combined with PERC was also tested. The primary outcome was the proportion of diagnosed PE or deep venous thrombosis at 3 months in patients in whom PE could have been excluded without chest imaging according to the tested strategy. The safety of a strategy was confirmed if the failure rate was less than 1.85%. The secondary outcome was the use of imaging testing according to each rule. Among 3330 analyzed patients, 150 (4.5%) had a PE. The number of missed PEs were 25, 29, 30 and 26 for the PERC+YEARS, PERC+PEGeD, 4PEPS and MODS rules respectively, with a failure rate of 0.75% (95% CI 0.51% to 1.10%), 0.87% (0.61% to 1.25%), 0.90% (0.63% to 1.28%) and 0.78% (0.53% to 1.14%) respectively. There was no significant difference in the failure rate between rules. Except for a significant lower use of chest imaging for 4PEPS compared to YEARS (14.9% vs 16.3%, difference -1.4% [95%CI -2.1% to -0.8%]), there was no difference in the proportion of imaging testing. In this post-hoc analysis of patients with suspicion of PE, YEARS and PEGeD combined with PERC, and 4PEPS were safe to exclude PE. The safety of the modified simplified MODS strategy was also confirmed. There was no significant difference of the failure rate between strategies.

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood

People conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). The main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. Up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units). These findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

P-662 Association between polymorphisms in FSHR and reproductive outcomes following IVF. Secondary analysis of a prospective cohort study in Europe and Asia

Abstract Study question Does the presence of FSHR variants influence the clinical pregnancy rate (CPR), live birth rate (LBR) and cumulative live birth rate (CLBR) in predicted normoresponders? Summary answer The presence of at least one G allele in FSHR variant rs6165 is associated with higher CPR and LBR when compared to genotype AA. What is known already FSHR protein expression has been found in the placenta, umbilical cord, amnion and decidua, suggesting a role in the promotion of a healthy pregnancy. Previous reports have analysed the impact of FSHR SNP rs6166 in pregnancy outcomes with conflicting results, mainly due to the heterogeneity in the inclusion criteria and limited sample size. Moreover, the literature is scarce regarding the association between FSHR SNPs rs6165 and rs1394205 and reproductive outcomes. Our aim is to determine whether FSHR SNPs rs6166, rs6166 and rs1394205 influence the reproductive prognosis following IVF. Study design, size, duration We performed a secondary analysis of a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium and Spain (168 from Europe and 200 from Asia) from 11/2016-06/2019. All patients underwent ovarian stimulation with fixed-dose 150IU rFSH in an antagonist protocol. Participants/materials, setting, methods Patients aged <38 years, undergoing their first or second IVF cycle with a predicted normal response (antral follicle count >9 and/or antimullerian hormone >1.1ng/ml) were included. CPR, LBR and miscarriage rate (MR) in the first embryo transfer, as well as CLBR, were compared between the different genotypes of FSHR SNPs rs6166, rs6165 and rs1394205. Main results and the role of chance A total of 351 patients performed at least one embryo transfer (ET). Enrolled patients had a mean age of 30.5 ± 3.63 years. Mean CPR and LBR in the first ET were 56.1% and 48.4%, respectively. Univariate genetic model analysis revealed a significantly higher CPR in the dominant model for variant rs6165 (46.3% (38/82) for genotype AA vs 59.1% (159/269) for genotypes AG/GG, p = 0.04). No statistically significant difference was found regarding the CPR for variants rs6166 nor rs1394205. Also, no statistically significant difference was found in univariate analysis regarding LBR nor MR for the different FSHR variants. However, multivariable logistic regression analysis adjusted for patient age, BMI, ethnicity, type of embryo transfer, embryo stage and number of top quality embryos transferred revealed a statistically significant higher CPR and LBR for FSHR variant rs6165 genotype GG (adjOR 2.50, 95% CI 1.30-4.81, and adjOR 1.96, 95%CI 1.02-3.78, respectively). No statistically significant differences were found regarding CLBR for FSHR variants rs6166, rs6165 nor rs1394205. Limitations, reasons for caution The young age of the included patients precludes the generalization of the results to older patients. Also, the results should be confirmed in larger cohorts before being extrapolated to the general population. Wider implications of the findings Our results demonstrate a previously unreported association between variant FSHR SNPs rs6165 genotype GG and higher CPR and LBR and reinforce a potential role for the genetic background in the prediction of a favorable prognosis following IVF. Trial registration number not-applicable

May 2022 Stroke Highlights

May 2022 <i>Stroke</i> Highlights

Decompressive Craniectomy Practice following Traumatic Brain Injury in Comparison with Randomized Trials: Harmonized, Multi-Center Cohort Studies in Europe, the United Kingdom, and Australia

High quality evidence shows decompressive craniectomy (DC) following traumatic brain injury (TBI) may improve survival but increase the number of severely disabled survivors. Contemporary international practice is unknown. We sought to describe international use of DC, and the alignment with evidence and clinical practice guidelines, by analyzing the harmonized Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) and Australia-Europe NeuroTrauma Effectiveness Research in Traumatic Brain Injury (OzENTER-TBI) core study datasets, which include patients admitted to intensive care units (ICUs) in Europe, the United Kingdom, and Australia between 2015 and 2017. Outcomes of interest were treatment with DC relative to clinical trial evidence and the Brain Trauma Foundation guidelines. Of 2336 people admitted to ICUs following TBI, DC was performed in 320 (13.7%): in 64/1422 (4.5%) patients with diffuse TBI and 195/640 (30.5%) patients with traumatic mass lesions. Secondary DC (for treatment of intracranial hypertension) was used infrequently in patients who met enrollment criteria of the two randomized clinical trials informing the guidelines-specifically, in 11/124 (8.9%) of those matching Decompressive Craniectomy in Diffuse Traumatic Brain Injury trial (DECRA) enrollment, and in 30/224 (13.4%) of those matching Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp). Of patients who underwent DC, 258/320 (80.6%) were ineligible for either trial: 149/320 (46.6%) underwent primary DC, 62/320 (19.4%) were outside the trials' age criteria, and 126/320 (39.4%) did not develop intracranial hypertension refractory to non-operative therapies prior to DC. Secondary DC was used infrequently in patients in whom it had been shown to increase survival with severe disability, indicating alignment between contemporaneous evidence and practice. However, most patients who underwent DC were ineligible for the key trials; whether they benefited from DC remains unknown.

Predictors of resilience in older adults with lower limb osteoarthritis and persistent severe pain

BackgroundResilience refers to the process in which people function well despite adversity. Persistent severe pain may be considered an adversity in people with lower limb osteoarthritis (LLOA). The objectives of this study are: (1) to identify what proportion of older adults with LLOA and persistent severe pain show good functioning; and (2) to explore predictors of resilience.MethodsData from the European Project on OSteoArthritis (EPOSA) were used involving standardized data from six European population-based cohort studies. LLOA is defined as clinical knee and/or hip osteoarthritis. Persistent severe pain is defined as the highest tertile of the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index both at baseline and follow-up. Resilience is defined as good physical, mental or social functioning at follow-up despite having LLOA with persistent severe pain.ResultsIn total, 95 (14.9%) out of 638 individuals with LLOA had persistent severe pain. Among these, 10 (11.0%), 54 (57.4%) and 49 (53.8%) had good physical, mental and social functioning, respectively. Only 4 individuals (4.5%) were resilient in all three domains of functioning. Younger age, male sex, higher education, higher mastery, smoking and alcohol use, higher physical activity levels, absence of chronic diseases, and more contacts with friends predicted resilience in one or more domains of functioning.ConclusionsFew people with LLOA and persistent severe pain showed good physical functioning and about half showed good mental or social functioning. Predictors of resilience differed between domains, and might provide new insights for treatment.

Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis.

To identify groups of people with RA with different disability trajectories over 10 years, despite comparable levels of inflammation. Data for this analysis came from three European prospective cohort studies of people with RA [Norfolk Arthritis Register (NOAR), Early RA Network (ERAN), Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR)]. Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1 January 2000, <24 months baseline symptom duration, and disability (HAQ) and inflammation [two-component DAS28 (DAS28-2C)] recorded at baseline and at one other follow-up. People in each cohort also completed patient-reported outcome measures at each assessment (pain, fatigue, depressive symptoms). Group-based trajectory models were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up. This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). ESPOIR included more women and the participants were younger [mean (standard deviation) age: NOAR: 57.1 (14.6), ESPOIR: 47.6 (12.5), ERAN: 56.8 (13.8); women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories following the hypothesized pattern (comparable DAS28-2Cs but different HAQs) were identified. Higher pain, fatigue and depressive symptoms were associated with increased odds of being in the high HAQ trajectories. Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function.

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1-2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0-8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35-4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08-6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche.

Impact of the pre-examination phase on multicenter metabolomic studies

The development of metabolomics in clinical applications has been limited by the lack of validation in large multicenter studies. Large population cohorts and their biobanks are a valuable resource for acquiring insights into molecular disease mechanisms. Nevertheless, most of their collections are not tailored for metabolomics and have been created without specific attention to the pre-analytical requirements for high-quality metabolome assessment. Thus, comparing samples obtained by different pre-analytical procedures remains a major challenge. Here, 1H NMR-based analyses are used to demonstrate how human serum and plasma samples collected with different operating procedures within several large European cohort studies from the Biobanking and Biomolecular Resources Infrastructure – Large Prospective Cohorts (BBMRI-LPC) consortium can be easily revealed by supervised multivariate statistical analyses at the initial stages of the process, to avoid biases in the downstream analysis. The inter-biobank differences are discussed in terms of deviations from the validated CEN/TS 16945:2016 / ISO 23118:2021 norms. It clearly emerges that biobanks must adhere to the evidence-based guidelines in order to support wider-scale application of metabolomics in biomedicine, and that NMR spectroscopy is informative in comparing the quality of different sample sources in multi cohort/center studies.

Prone positioning during venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a pooled individual patient data analysis

BackgroundProne positioning (PP) reduces mortality of patients with acute respiratory distress syndrome (ARDS). The potential benefit of prone positioning maneuvers during venovenous extracorporeal membrane oxygenation (ECMO) is unknown. The aim of this study was to evaluate the association between the use of prone positioning during extracorporeal support and ICU mortality in a pooled population of patients from previous European cohort studies.MethodsWe performed a pooled individual patient data analysis of European cohort studies which compared patients treated with prone positioning during ECMO (Prone group) to “conventional” ECMO management (Supine group) in patients with severe ARDS.Results889 patients from five studies were included. Unadjusted ICU mortality was 52.8% in the Supine Group and 40.8% in the Prone group. At a Cox multiple regression analysis PP during ECMO was not significantly associated with a reduction of ICU mortality (HR 0.67 95% CI: 0.42–1.06). Propensity score matching identified 227 patients in each group. ICU mortality of the matched samples was 48.0% and 39.6% for patients in the Supine and Prone group, respectively (p = 0.072).ConclusionsIn a large population of ARDS patients receiving venovenous extracorporeal support, the use of prone positioning during ECMO was not significantly associated with reduced ICU mortality. The impact of this procedure will have to be definitively assessed by prospective randomized controlled trials.

Graves' disease and the risk of Parkinson's disease: a Korean population-based study.

Two European cohort studies have suggested that Graves’ disease is associated with the development of Parkinson’s disease, although the results were limited and controversial. We evaluated whether patients with Graves’ disease had an increased risk of developing Parkinson’s disease according to treatment modality. We included 65 380 Graves’ disease patients and 326 900 healthy controls matched according to age and sex, using the Korean National Health Insurance database. The primary outcome was the incidences of Parkinson’s disease amongst Graves’ disease patients and controls. Subgroup analyses of Graves’ disease patients were performed according to anti-thyroid drug treatment, radioactive iodine therapy and surgery. The cumulative dose and duration values of anti-thyroid drug were calculated for each patient and categorized into highest, middle and lowest tertiles. Amongst 65 380 Graves’ disease patients, 301 Parkinson’s disease cases were diagnosed during 453 654 person-years of follow-up. Relative to the controls, and regardless of age, sex or comorbidities, the Graves’ disease patients had a 33% higher risk of developing Parkinson’s disease (hazard ratio: 1.33, 95% confidence interval: 1.17–1.51). Most Graves’ disease patients (96%) had received medical therapy, and increased risks of Parkinson’s disease were observed in the various subgroups for cumulative dose and treatment duration. This study revealed that Graves’ disease was an independent risk factor for developing Parkinson’s disease, and that the risk remained elevated regardless of demographic factors or treatment duration/dosage of the anti-thyroid drug. Clinicians should be aware that Graves’ disease patients have an increased risk of developing Parkinson’s disease, even though Graves’ disease patients are often relatively young.

Gene-environment interactions related to maternal exposure to environmental and lifestyle-related chemicals during pregnancy and the resulting adverse fetal growth: a review.

BackgroundThere are only limited numbers of reviews on the association of maternal-child genetic polymorphisms and environmental and lifestyle-related chemical exposure during pregnancy with adverse fetal growth. Thus, this article aims to review: (1) the effect of associations between the above highlighted factors on adverse fetal growth and (2) recent birth cohort studies regarding environmental health risks.MethodsBased on a search of the PubMed database through August 2021, 68 epidemiological studies on gene-environment interactions, focusing on the association between environmental and lifestyle-related chemical exposure and adverse fetal growth was identified. Moreover, we also reviewed recent worldwide birth cohort studies regarding environmental health risks.ResultsThirty studies examined gene-smoking associations with adverse fetal growth. Sixteen maternal genes significantly modified the association between maternal smoking and adverse fetal growth. Two genes significantly related with this association were detected in infants. Moreover, the maternal genes that significantly interacted with maternal smoking during pregnancy were cytochrome P450 1A1 (CYP1A1), X-ray repair cross-complementing protein 3 (XRCC3), interleukin 6 (IL6), interleukin 1 beta (IL1B), human leukocyte antigen (HLA) DQ alpha 1 (HLA-DQA1), HLA DQ beta 1 (HLA-DQB1), and nicotinic acetylcholine receptor. Fetal genes that had significant interactions with maternal smoking during pregnancy were glutathione S-transferase theta 1 (GSTT1) and fat mass and obesity-associated protein (FTO). Thirty-eight studies examined the association between chemical exposures and adverse fetal growth. In 62 of the 68 epidemiological studies (91.2%), a significant association was found with adverse fetal growth. Across the studies, there was a wide variation in the analytical methods used, especially with respect to the genetic polymorphisms of interest, environmental and lifestyle-related chemicals examined, and the study design used to estimate the gene-environment interactions. It was also found that a consistently increasing number of European and worldwide large-scale birth cohort studies on environmental health risks have been conducted since approximately 1996.ConclusionThere is some evidence to suggest the importance of gene-environment interactions on adverse fetal growth. The current knowledge on gene-environment interactions will help guide future studies on the combined effects of maternal-child genetic polymorphisms and exposure to environmental and lifestyle-related chemicals during pregnancy.Supplementary informationThe online version contains supplementary material available at https://doi.org/10.1265/ehpm.21-00033.

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis

ObjectiveThe optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of...

A prognostic model, including quantitative fetal fibronectin, to predict preterm labour: the QUIDS meta-analysis and prospective cohort study.

The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Pregnant women at 22+0-34+6 weeks' gestation with signs and symptoms of preterm labour. Quantitative fetal fibronectin. Spontaneous preterm birth within 7 days. The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.

Irritable bowel syndrome and risk of glaucoma: An analysis of two independent population-based cohort studies.

ObjectiveIrritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome–host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma.DesignTwo prospective cohort studies.SubjectsThe 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members).MethodsIn the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital‐based contacts and prescription data from the national prescription database.Main Outcome MeasureThe main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674).ResultsIn the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26–15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician‐diagnosed glaucoma (95% CI: 1.16–1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06–1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03–1.38).ConclusionsIn two large European cohort studies, IBS is a risk factor for glaucoma.

OMEGA-NET Inventory of Occupational Cohorts

BACKGROUND AND AIM: Existing cohort studies in Europe capturing some type of occupational information enrol tens of millions of persons. There are few large-scale analyses systematically combining cohorts from this extraordinary resource. To some extent this is due to the absence of systematic organization of data available. In the OMEGA-NET project we created an inventory of cohorts with occupational information in Europe and implemented an online interactive tool with detailed information on these cohorts. The inventory aims to collect information that facilitates collaboration across cohorts to explore occupation, work related exposures and health relationships. METHODS: The inventory includes cohorts, case-control studies nested within cohorts and intervention studies that: (i) are active or can substantiate that their data are potentially accessible; (ii) collect data on occupation and/or industry or at least one occupational exposure; and (iii) have at least one follow-up either already conducted or planned. Information is collected using a web-based OMEGA-NET Inventory Questionnaire. The published version of the inventory is stored in a searchable web database. RESULTS:To-date the inventory includes information on 120 cohorts in more than 20 countries. Information is collected on: (i) Identification and basic description; (ii) Follow-up; (iii) Occupational Exposures (methods and specific exposures); (iv) Outcomes evaluated; (v) Biological samples and analysis; (vi) Other information e.g. Sociodemographic. CONCLUSIONS:The OMEGA-NET inventory will continue to identify and invite cohorts both in Europe and worldwide ensuring the quality of submitted information. The inventory does not incorporate primary cohort data, rather only cohort meta-data, and seeks to capture the majority of available cohorts with information on occupational exposures, many of them being non-occupational in their primary aim. The development of an inventory of occupational cohorts is a first and important prerequisite for an exploitation of the extensive information that has been collected worldwide on occupation and health. KEYWORDS: Occupational epidemiology, Occupational exposures, International collaboration

Prenatal exposure to lipophilic endocrine-disrupting chemicals and liver injury in children using chemical mixture approaches

BACKGROUND AND AIM: Exposure to Endocrine Disrupting Chemicals (EDC) may increase liver injury, but few studies have examined these associations in children and most focused on a single chemical group. We evaluated the associations between a wide range of prenatal EDC exposures and child liver injury. METHODS: We studied 1108 healthy children from the Human Early-Life Exposome (HELIX) project, a collaborative network of six established longitudinal population-based birth cohort studies in Europe. Thirty lipophilic EDCs (including 3 organochlorine pesticides, 5 polychlorinated-biphenyl, 2 polybrominated-diphenyl-ethers [PBDEs], 5 high molecular weight phthalates (HMWP), 5 low molecular weight phthalates, 6 phenols and 4 organophosphate pesticides) were measured in maternal pregnancy blood or urine. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and cytokeratin 18 (CK18) were measured in child serum at follow-up between age 6-11 years. Liver injury was defined as having any liver enzyme (ALT, AST or GGT) above the 90th percentile. We used Bayesian generalized linear mixed regressions (Bglmr) to estimate associations of individual chemicals, Bayesian Weighted Quantile Sum (BWQS) and Bayesian Kernel Machine Regression (BKMR) to assess the overall association of each chemical group with liver injury and CK18, adjusting for confounders. RESULTS:BWQS results indicated that organochlorine pesticides and PBDEs were associated with increased odds of liver injury (OR[95%CI] by chemical mixture quartile increase=1.44[1.23, 1.72] and 1.59[1.37, 1.90], respectively); whereas HMWP were associated with decreased odds of liver injury (OR[95%CI]=0.71[0.59, 0.85]). A quartile increase of PBDEs was positively associated with CK18 (Estimate[95%CI]=5.33 Units/Liter [2.52,8.16]). Bglmr and BKMR showed associations in same direction as the BWQS results. There was evidence of effect heterogeneity by sex for organochlorine pesticides and HMWPs with liver injury status. CONCLUSIONS:Using multiple chemical mixture approaches we found that prenatal exposures to persistent pollutants, especially to organochlorine compounds, and PBDEs, may be associated with increased risk for liver injury in childhood. KEYWORDS: Chemical exposures, Endocrine disrupting chemicals, Mixtures analysis, Modeling, Environmental epidemiology

Intrauterine Exposures and Maternal Health Status during Pregnancy in Relation to Later Child Health: A Review of Pregnancy Cohort Studies in Europe.

We show a description of pregnancy cohorts in the European region. Our investigation identified 66 pregnancy cohorts, mostly hosted in Western Central Europe. Among these 66 cohorts, 24 began recruitment before the year 2000, while six cohorts are still enrolling. The most common topics were lifestyle, environment and nutrition with allergies and neurodevelopment being a minority. We observed a pattern of positive correlations between data collected using medical records, structured interviews, and the collection of biological samples. Objectively assessed data were negatively correlated with self-administered questionnaires. Eight cohorts addressed intrauterine exposure, focusing on environmental pollutants such as endocrine-disrupting chemicals. The effects of these compounds on the developing foetus have been studied greatly, but more research on their effects is still needed. Many cohorts investigated genetics through the collection of biological samples from the mothers and children, to improve knowledge on the mother-to-child transmission of genetic information, antibodies, microbiota, etc. Paediatric epidemiology represents an important field of research since preserving healthy lives from conception onwards is the most efficient way to improve population health. According to our report, it seems that this field of research is well developed in Europe, where numerous high profile studies are currently ongoing.

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysis

Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model's intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than "treat all" or "treat none" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).