The development of coronary artery disease (CAD) is significantly affected by impaired endocrine and metabolic status. Under this circumstance, improved prevention and treatment of CAD may result from knowing the connection between metabolites and CAD. This study aims to delve into the causal relationship between human metabolic biomarkers and CAD by using two-sample Mendelian randomization (MR). Utilizing two-sample bidirectional MR analysis, we assessed the correlation between 1400 blood metabolites and CAD, and the metabolites data from the CLSA, encompassing 8299 participants. Metabolite analysis identified 1091 plasma metabolites and 309 ratios as instrumental variables. To evaluate the causal link between metabolites and CAD, we analyzed three datasets: ebi-a-GCST005195 (547,261 European & East Asian samples), bbj-a-159 (29,319 East Asian CAD cases & 183,134 East Asian controls), and ebi-a-GCST005194 (296,525 European & East Asian samples). To estimate causal links, we utilized the IVW method. To conduct sensitivity analysis, we used MR-Egger, Weighted Median, and MR-PRESSO. Additionally, we employed MR-Egger interception and Cochran\'s Q statistic to assess potential heterogeneity and pleiotropy. What\'s more, replication and reverse analyses were performed to verify the reliability of the results and the causal order between metabolites and disease. Furthermore, we conducted a pathway analysis to identify potential metabolic pathways. 59 blood metabolites and 27 metabolite ratios nominally associated with CAD (P < 0.05) were identified by IVW analysis method. A total of four known blood metabolites, namely beta-hydroxyisovaleroylcarnitine (OR 1.06, 95% CI 1.027-1.094, FDR 0.07), 1-palmitoyl-2-arachidonoyl (OR 1.07, 95% CI 1.029-1.110, FDR 0.09), 1-stearoyl-2- docosahexaenoyl (OR 1.07, 95% CI 1.034-1.113, FDR 0.07) and Linoleoyl-arachidonoyl-glycerol, (OR 1.07, 95% CI 1.036-1.105, FDR 0.05), and two metabolite ratios, namely spermidine to N-acetylputrescine ratio (OR 0.94, 95% CI 0.903-0.972, FDR 0.09) and benzoate to linoleoyl-arachidonoyl-glycerol ratio (OR 0.87, 95% CI 0.879-0.962, FDR 0.07), were confirmed as having a significant causal relationship with CAD, after correcting for the FDR method (p < 0. 1). A causal relationship was found to be established between beta -hydroxyisovalerylcarnitine and CAD with the validation in other two datasets. Moreover, multiple metabolic pathways were discovered to be associated with CAD. Our study supports the hypothesis that metabolites have an impact on CAD by demonstrating a causal relationship between human metabolites and CAD. This study is important for new strategies for the prevention and treatment of CAD.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.
METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.
RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10-39; OR = 4.73, p = 2 × 10-10; OR = 2.3, p = 7.49 × 10-9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10-7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10-16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10-6).
CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.

UNASSIGNED: In the context of emerging SARS-CoV-2 variants or lineages and new vaccines, it is key to accurately monitor COVID-19 vaccine effectiveness (CVE) to inform vaccination campaigns.
UNASSIGNED: To estimate the effectiveness of COVID-19 vaccines administered in autumn and winter 2022 to 2023 against symptomatic SARS-CoV-2 infection (with all circulating viruses and XBB lineage in particular) among people aged 60 years or older in Europe, and to compare different CVE approaches across the exposed and reference groups used.
UNASSIGNED: This case-control study obtained data from VEBIS (Vaccine Effectiveness, Burden and Impact Studies), a multicenter study that collects COVID-19 and influenza data from 11 European sites: Croatia; France; Germany; Hungary; Ireland; Portugal; the Netherlands; Romania; Spain, national; Spain, Navarre region; and Sweden. Participants were primary care patients aged 60 years or older with acute respiratory infection symptoms who were recruited at the 11 sites after the start of the COVID-19 vaccination campaign from September 2022 to August 2023. Cases and controls were defined as patients with positive and negative, respectively, reverse transcription-polymerase chain reaction (RT-PCR) test results.
UNASSIGNED: The exposure was COVID-19 vaccination. The exposure group consisted of patients who received a COVID-19 vaccine during the autumn and winter 2022 to 2023 vaccination campaign and 14 days or more before symptom onset. Reference group included patients who were not vaccinated during or in the 6 months before the 2022 to 2023 campaign (seasonal CVE), those who were never vaccinated (absolute CVE), and those who were vaccinated with at least the primary series 6 months or more before the campaign (relative CVE). For relative CVE of second boosters, patients receiving their second booster during the campaign were compared with those receiving 1 booster 6 months or more before the campaign.
UNASSIGNED: The outcome was RT-PCR-confirmed, medically attended, symptomatic SARS-CoV-2 infection. Four CVE estimates were generated: seasonal, absolute, relative, and relative of second boosters. CVE was estimated using logistic regression, adjusting for study site, symptom onset date, age, chronic condition, and sex.
UNASSIGNED: A total of 9308 primary care patients were included, with 1687 cases (1035 females; median [IQR] age, 71 [65-79] years) and 7621 controls (4619 females [61%]; median [IQR] age, 71 [65-78] years). Within 14 to 89 days after vaccination, seasonal CVE was 29% (95% CI, 14%-42%), absolute CVE was 39% (95% CI, 6%-60%), relative CVE was 31% (95% CI, 15% to 44%), and relative CVE of second boosters was 34% (95% CI, 18%-47%) against all SARS-CoV-2 variants. In the same interval, seasonal CVE was 44% (95% CI, -10% to 75%), absolute CVE was 52% (95% CI, -23% to 82%), relative CVE was 47% (95% CI, -8% to 77%), and relative CVE of second boosters was 46% (95% CI, -13% to 77%) during a period of high XBB circulation. Estimates decreased with time since vaccination, with no protection from 180 days after vaccination.
UNASSIGNED: In this case-control study among older Europeans, all CVE approaches suggested that COVID-19 vaccines administered in autumn and winter 2022 to 2023 offered at least 3 months of protection against symptomatic, medically attended, laboratory-confirmed SARS-CoV-2 infection. The effectiveness of new COVID-19 vaccines against emerging SARS-CoV-2 variants should be continually monitored using CVE seasonal approaches.

Despite the inclusion of both individual interventions and population-based measures in the Aotearoa New Zealand (Aotearoa NZ) Tobacco Control Programme, the gap between Māori, Pacific peoples and European/Asian/Other (EAO) populations in tobacco use has not decreased significantly. Tobacco control interventions that focus on individual behaviour change have produced little impact towards reducing tobacco smoking inequities for Māori and Pacific peoples in Aotearoa NZ. Using data from the New Zealand Health Survey (NZHS), this research investigates the impact of the wider determinants of health and individual-level factors on inequities in tobacco use between Māori, Pacific peoples and EAO. A conceptual framework was developed to support the theoretical positioning of this research and to inform data categorization, framing, discourse, analyses and interpretation. We conducted hierarchical regression to examine the effect of factors from each domain on ethnic inequities in tobacco use. We found that socioeconomic factors accounted for a significant amount of the disparity in adults currently smoking between Māori and Pacific peoples and EAO. Our results suggest that socioeconomic factors may be a more effective target of intervention than individual behaviours for reducing tobacco-related inequities. Addressing the broader determinants of health through comprehensive cross-agency cooperation to reduce ethnic inequities in tobacco use in Aotearoa NZ is likely to be more effective than individual behaviour change approaches.

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms.

BACKGROUND: Fibromyalgia is characterized by chronic widespread pain accompanied by reduced levels of physical activity and associated comorbidities such as overweight and obesity which have been associated to sarcopenia development. The aim of this systematic review is to ascertain whether Europeans with fibromyalgia show a reduction in sarcopenia determinants compared to apparently-healthy controls and to determine the risk of sarcopenia and its possible risk factors (PROSPERO: CRD42023439839).
METHODS: Systematic searches were conducted on six databases (Academic-Search-Ultimate, CENTRAL, PubMed, SciELO, WOS-Core Collection, and ClinicalTrials.gov last-search February-2024) looking for original studies developed in European countries which assessed any of the sarcopenia determinants proposed by the EWGSOP2-guidelines (handgrip strength, five sit-to-stand, appendicular skeletal mass [ASM], skeletal muscle index [SMI]) and included fibromyalgia and healthy-control individuals. Studies mixing fibromyalgia with other diagnoses were excluded. Random-effects meta-analyses and meta-regressions were used to analyze possible differences and associated risk factors. The risk of bias was assessed using the Cochrane-Rob tool and the Quality Assessment Tool for Observational Studies, and the certainty of the evidence using GRADE-approach.
RESULTS: A total of 25 studies (6393 individuals; 97% women; 20-65 years) were included. Fibromyalgia individuals showed reduced muscle strength ([handgrip] SMD: -1.16 [-1.29, -1.03]; high-certainty; [five sit-to-stand] not-assessed) and muscle quantity ([ASM] mean-difference: -0.83 kg [-1.41, -0.37]; [SMI] mean-difference: -0.26 kg/m2 [-0.41, -0.10]; both low-certainty) compared to healthy-controls. Fibromyalgia individuals had nine-times greater risk for probable sarcopenia (OR: 9.23 [6.85, 12.45]; high-certainty), but not for confirmed sarcopenia ([ASM] OR: 0.91 [0.49, 1.67]; [SMI] OR: 0.67 [0.19, 2.33]; both low-certainty) according to the EWGSOP2 cut-off points. Reduced muscle strength was strongly associated to fibromyalgia-severity (β=-0.953 [-0.069, -0.038]). Studies were rated as high-risk of bias overall because did not account for some potential confounders (physical activity, sedentary time, Body Mass Index) which could influence the estimated effect.
CONCLUSIONS: Europeans with fibromyalgia have a large reduction in muscle strength and may have a reduction in muscle quantity. The risk of probable sarcopenia according to the EWGSOP2 cut-off points was nine-times higher, but may have no difference in risk of reduced muscle quantity relative to healthy-controls. Muscle strength was strongly associated to disease severity.

OBJECTIVE: The aims of this study were to measure the prevalence of polypharmacy and describe the prescribing of selected medications known for overuse in older people with polypharmacy in primary care.
METHODS: This was a multinational retrospective cohort study across six countries: Belgium, France, Germany, Italy, Spain and the UK. We used anonymized longitudinal patient-level information from general practice databases hosted by IQVIA. Patients ≥65 years were included. Polypharmacy was defined as having 5-9 and ≥10 distinct drug classes (ATC Level 3) prescribed during a 6-month period. Selected medications were: opioids, antipsychotics, proton pump inhibitors (PPI), benzodiazepines (ATC Level 5). We included country experts on the healthcare context to interpret findings.
RESULTS: Age and gender distribution was similar across the six countries (mean age 75-76 years; 54-56% female). The prevalence of polypharmacy of 5-9 drugs was 22.8% (UK) to 58.3% (Germany); ≥10 drugs from 11.3% (UK) to 28.5% (Germany). In the polypharmacy population prescribed ≥5 drugs, opioid prescribing ranged from 11.5% (France) to 27.5% (Spain). Prescribing of PPI was highest with almost half of patients receiving a PPI, 42.3% (Germany) to 65.5% (Spain). Benzodiazepine prescribing showed a marked variation between countries, 2.7% (UK) to 34.9% (Spain). The healthcare context information explained possible underreporting for selected medications.
CONCLUSIONS: We have found a high prevalence of polypharmacy with more than half of the older population being prescribed ≥5 drugs in four of the six countries. Whilst polypharmacy may be appropriate in many patients, worryingly high usage of PPIs and benzodiazepines supports current efforts to improve polypharmacy management across Europe.

Disease prevalence and mean phenotype values differ between many populations, including Inuit and Europeans. Whether these differences are partly explained by genetic differences or solely due to differences in environmental exposures is still unknown, because estimates of the genetic contribution to these means, which we will here refer to as mean genotypic values, are easily confounded, and because studies across genetically diverse populations are lacking.
Leveraging the unique genetic properties of the small, admixed and historically isolated Greenlandic population, we estimated the differences in mean genotypic value between Inuit and European genetic ancestry using an admixed sibling design. Analyses were performed across 26 metabolic phenotypes, in 1474 admixed sibling pairs present in a cohort of 5996 Greenlanders.
After FDR correction for multiple testing, we found significantly lower mean genotypic values in Inuit genetic ancestry compared to European genetic ancestry for body weight (effect size per percentage of Inuit genetic ancestry (se), -0.51 (0.16) kg/%), body mass index (-0.20 (0.06) kg/m2/%), fat percentage (-0.38 (0.13) %/%), waist circumference (-0.42 (0.16) cm/%), hip circumference (-0.38 (0.11) cm/%) and fasting serum insulin levels (-1.07 (0.51) pmol/l/%). The direction of the effects was consistent with the observed mean phenotype differences between Inuit and European genetic ancestry. No difference in mean genotypic value was observed for height, markers of glucose homeostasis, or circulating lipid levels.
We show that mean genotypic values for some metabolic phenotypes differ between two human populations using a method not easily confounded by possible differences in environmental exposures. Our study illustrates the importance of performing genetic studies in diverse populations.

Observational studies have linked selenium and metabolic syndrome (MetS), but the causality remains unclear. Therefore, this study intends to determine the causal relationship between selenium and the risk of MetS and its component features [body mass index (BMI), waist circumference adjusted for BMI (WCadjBMI), triglycerides (TC), HDL-cholesterol (HDL-C), fasting blood glucose (FBG), fasting blood insulin (FBI), systolic blood pressure (SBP), and diastolic blood pressure (DBP)]. This study was designed as the two-sample Mendelian randomization (MR), and genetic variants were obtained from the genome-wide association studies. The inverse variance weighted (IVW) was applied as the primary method, and the MR-Egger, weighted median, and MR-PRESSO were supplemented to assess its robustness. The Bonferroni method was used to correct p-values for multiple tests. Genetically incremented selenium level was related to higher odds ratios of developing the MetS (OR = 1.054, 95% CI = 1.016-1.094, p = 0.0049). As for components, significant causal links were identified between selenium and BMI (β = 0.015, p = 1.321 × 10-5), WCadjBMI (β = 0.033, p = 2.352 × 10-4), HDL-C (β = -0.036, p = 1.352 × 10-8), FBG (β = 0.028, p = 0.001), and FBI (β = 0.028, p = 0.002). No significant association was discovered for SBP (β = -0.076, p = 0.218) and DBP (β = 0.054, p = 0.227). These results were generally supported by the weighted median and MR-PRESSO methods. Our study provided evidence of the causal effect of selenium on MetS risk from the genetic perspective in the European population, and further investigation across diverse populations was warranted.

OBJECTIVE: Sports participation is lower in people of Turkish and Moroccan origin in the Netherlands than in native Dutch people. Addressing this inequality calls for better insights into antecedents of sports participation in different ethnic groups. Theorists suggested that loneliness may hamper sports participation, and levels of loneliness are high among people of Turkish and Moroccan origin. This study assessed the longitudinal association between loneliness and regular sports participation among Turkish origin, Moroccan origin and native Dutch people.
METHODS: Data are from Turkish origin (n = 394), Moroccan origin (n = 387) and native Dutch (n = 1663) people who participated in Wave 1 (2008-2010) and Wave 2 (2013) of the Netherlands Longitudinal Lifecourse Study. Regular sports participation at follow-up was regressed on loneliness at baseline in logistic regression models adjusted for baseline sports participation and a range of confounders. Models were stratified by ethnic group.
RESULTS: Turkish and Moroccan origin people had lower rates of regular sports participation and higher levels of loneliness than native Dutch people. Loneliness at baseline was negatively associated with sports participation at follow-up for people of Turkish and Moroccan origin. No evidence of a longitudinal association between loneliness and sports participation among native Dutch people was found.
CONCLUSIONS: The demonstrated positive longitudinal association between loneliness and regular sports participation in people of Turkish and Moroccan origin potentially opens new ways to encourage physical activity in these groups. An integrated approach to addressing loneliness and physical inactivity among people with a non-western migration background may benefit the realization of both goals.