International time trends in sudden unexpected infant death, 1969–2012

Background: Sudden unexpected infant death (SUID) - including sudden infant death syndrome (SIDS) - continues to be a major contributor to infant mortality worldwide. Our objective was to analyse time trends and to identify country-clusters. Methods: The National Statistical Offices of 52 countries provided the number of deaths and live births (1969-2012). We calculated infant mortality rates per 1000 live births for SUID, SIDS, and all-cause mortality. Overall, 29 countries provided sufficient data for time course analyses of SUID. To sensitively model change over time, we smoothed the curves of mortality rates (1980-2010). We performed a hierarchical cluster analysis to identify clusters of time trends for SUID and SIDS, including all-cause infant mortality. Results: All-cause infant mortality declined from 28.5 to 4.8 per 1000 live births (mean 12.4; 95% confidence interval 12.0-12.9) between 1969 and 2012. The cluster analysis revealed four country-clusters. Clusters 1 and 2 mostly contained countries showing the typical peak of SUID mortality during the 1980s. Cluster 1 had higher SUID mortality compared to cluster 2. All-cause infant mortality was low in both clusters but higher in cluster 1 compared to cluster 2. Clusters 3 and 4 had low rates of SUID without a peak during the 1980s. Cluster 3 had the highest all-cause infant mortality of all clusters. Cluster 4 had an intermediate all-cause infant mortality. The time trends of SUID and SIDS mortality were similar. Conclusions: The country-specific time trends in SUID varied considerably. The identification of country-clusters may promote research into how changes in sleep position, smoking, immunisation, or other factors are related to our findings

Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG(+)) NMOSD. METHODS: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG(+) patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG(+)) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG(+) patients over a median observation period of 4.25 years. RESULTS: In patients with AQP4-IgG(+) NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG(+) patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG(+), but not MOG-IgG(+) patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG(+), but not MOG-IgG(+) patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG(+) NMOSD. Patients with AQP4-IgG(+) NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG(+) NMOSD. CONCLUSION: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG(+) NMOSD in phases of clinical remission

Life course trajectories of alcohol consumption in the United Kingdom using longitudinal data from nine cohort studies.

Background Alcohol consumption patterns change across life and this is not fully captured in cross-sectional series data. Analysis of longitudinal data, with repeat alcohol measures, is necessary to reveal changes within the same individuals as they age. Such data are scarce and few studies are able to capture multiple decades of the life course. Therefore, we examined alcohol consumption trajectories, reporting both average weekly volume and frequency, using data from cohorts with repeated measures that cover different and overlapping periods of life. Methods Data were from nine UK-based prospective cohorts with at least three repeated alcohol consumption measures on individuals (combined sample size of 59,397 with 174,666 alcohol observations), with data spanning from adolescence to very old age (90 years plus). Information on volume and frequency of drinking were harmonised across the cohorts. Predicted volume of alcohol by age was estimated using random effect multilevel models fitted to each cohort. Quadratic and cubic polynomial terms were used to describe non-linear age trajectories. Changes in drinking frequency by age were calculated from observed data within each cohort and then smoothed using locally weighted scatterplot smoothing. Models were fitted for men and women separately. Results We found that, for men, mean consumption rose sharply during adolescence, peaked at around 25 years at 20 units per week, and then declined and plateaued during mid-life, before declining from around 60 years. A similar trajectory was seen for women, but with lower overall consumption (peak of around 7 to 8 units per week). Frequent drinking (daily or most days of the week) became more common during mid to older age, most notably among men, reaching above 50% of men. Conclusions This is the first attempt to synthesise longitudinal data on alcohol consumption from several overlapping cohorts to represent the entire life course and illustrates the importance of recognising that this behaviour is dynamic. The aetiological findings from epidemiological studies using just one exposure measure of alcohol, as is typically done, should be treated with caution. Having a better understanding of how drinking changes with age may help design intervention strategies

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021

Causal mechanisms proposed for the Alcohol Harm Paradox - a systematic review

Background and Aims The Alcohol Harm Paradox (AHP) posits that disadvantaged groups suffer from higher rates of alcohol-related harm compared with advantaged groups, despite reporting similar or lower levels of consumption on average. The causes of this relationship remain unclear. This study aimed to identify explanations proposed for the AHP. Secondary aims were to review the existing evidence for those explanations and investigate whether authors linked explanations to one another. Methods Systematic review. We searched MEDLINE (1946-January 2021), EMBASE (1974 – January 2021) and PsycINFO (1967 – January 2021), supplemented via manual searching of grey literature. Included papers either explored the causes of the AHP or investigated the relationship between alcohol consumption, alcohol-related harm, and socioeconomic position. Papers were set in Organisation for Economic Co-operation and Development high income countries. Explanations extracted for analysis could be evidenced in the empirical results or suggested by researchers in their narrative. Inductive thematic analysis was applied to group explanations. Results Seventy-nine papers met the inclusion criteria and initial coding revealed these papers contained 41 distinct explanations for the AHP. Following inductive thematic analysis, these explanations were grouped into 16 themes within six broad domains: Individual, Lifestyle, Contextual, Disadvantage, Upstream and Artefactual. Explanations related to risk behaviours, which fit within the Lifestyle domain, were the most frequently proposed (n=51) and analysed (n=21). Conclusions While there are many potential explanations for the Alcohol Harm Paradox, most research focuses on risk behaviours while other explanations lack empirical testing

Impact of omega-3 fatty acid supplementation on memory functions in healthy older adults

As the process of Alzheimer’s disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50–75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age