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To investigate the causal relationship between sleep duration and heart failure (HF) in a European population. We focused on the continuous sleep duration of 460,099 European individuals as our primary exposure. Genome-wide significant single nucleotide polymorphisms (SNPs, n = 9851,867) linked to continuous sleep duration were adopted as instrumental variables. The outcome of interest was based on HF events in a European cohort (n = 977,323; with 930,014 controls and 47,309 cases). We employed a two-sample Mendelian randomization (MR) approach to infer causality between sleep duration and the incidence of HF. For validation purposes, an additional cohort of 336,965 European individuals diagnosed with insomnia was selected as a secondary exposure group. Using its SNPs, a subsequent two-sample MR analysis was conducted with the HF cohort to further corroborate our initial findings. Employing the MR methodology, we selected 57 SNPs that are associated with sleep duration, and 24 SNPs that are associated with insomnia as instrumental variables. We discerned a substantial association between genetically inferred sleep duration and HF risk (odds ratio: 0.61; 95% confidence interval: 0.47-0.78, P < .0001). Our subsequent analysis highlighted a pronounced increased HF risk associated with insomnia (odds ratio: 1.54; 95% confidence interval: 1.08-2.17, P < .02). These conclusions were further bolstered by consistent results from sensitivity analyses. Our study suggests a causal linkage between sleep duration and the onset risk of HF in the European population. Notably, shorter sleep durations were associated with a heightened risk of HF., Competing Interests: The authors declare no conflict of interest, financial or otherwise. We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest in any product, service, and/or company that could be construed as influencing the position presented in the manuscript entitled., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The relationship between selenium and renal function has always attracted widespread attention. Increased selenium level has been found to cause impaired renal function in our previous study, but the mechanism is not clear. In this study, we evaluate the potential mediating effects of plasma proteome in the association of selenium level and renal function to understand the mechanisms of selenium's effect on renal function., Methods: Utilizing two-sample two-step mediating mendelian randomization (MR) methodology to investigate the genetically causal relationship between selenium level and renal function as well as the role of the plasma proteome in mediating them. Additionally, the mediating proteins were enriched and analyzed through bioinformatics to understand the potential mechanisms of selenium effects on renal function., Results: In the MR analysis, an increase in selenium level was found to decrease estimated glomerular filtration rate (eGFR). Specifically, for each standard deviation (SD) increase in selenium levels, eGFR levels are reduced by 0.003 SD [Beta (95% CI): -0.003 (-0.004 ~ -0.001), P=0.001, with no observed heterogeneity and pleiotropy]. Through mediation analysis, 35 proteins have been determined mediating the genetically causal effects of selenium on the levels of eGFR, including Fibroblast growth factor receptor 4 (FGFR4), Fibulin-1, Cilia- and flagella-associated protein 45, Mothers against decapentaplegic homolog 2 (SMAD2), and E3 ubiquitin-protein ligase ZNRF3, and the mediation effect rates of these proteins ranged from 1.59% to 23.70%. In the enrichment analysis, 13 signal transduction pathways, including FGFR4 mutant receptor activation and Defective SLC5A5 causing thyroid dyshormonogenesis 1, were involved in the effect of selenium on eGFR levels., Conclusion: Our finding has revealed the underlying mechanism by which increased selenium level lead to deterioration of renal function, effectively guiding the prevention of chronic kidney disease and paving the way for future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fu, Qian, Yuan, Su, Ma, Li and Xu.)

Background: HCC is a major cause of cancer death worldwide. Serum biomarkers such as alpha-fetoprotein (AFP), protein induced by vitamin K absence-II, and the Gender, Age, AFP-L3, AFP, Des-gamma-carboxy prothrombin (GALAD) score have been recommended for HCC surveillance. However, inconsistent recommendations in international guidelines limit their clinical utility., Methods: In this multicenter study, over 2000 patient samples were collected in 6 Latin American and 2 European countries. The performance of the GALAD score was validated in cirrhotic cases, and optimized versions were tested for early-stage HCC and prediagnostic HCC detection., Results: The GALAD score could distinguish between HCC and cirrhosis in Latin American patients with an AUC of 0.76, sensitivity of 70%, and specificity of 83% at the conventional cutoff value of -0.63. In a European cohort, GALAD had an AUC of 0.69, sensitivity of 66%, and specificity of 72%. Optimizing the score in the 2 large multicenter cohorts revealed that AFP-L3 contributed minimally to early-stage HCC detection. Thus, we developed a modified GALAD score without AFP-L3, the ASAP (age, sex, AFP, and protein induced by vitamin K absence-II), which showed promise for early-stage HCC detection upon validation. The ASAP score also identified patients with cirrhosis at high risk for advanced-stage HCC up to 15 months before diagnosis (p < 0.0001) and differentiated HCC from hemangiomas, with a specificity of 100% at 71% sensitivity., Conclusion: Our comprehensive analysis of large sample cohorts validates the GALAD score's utility in Latin American, Spanish, and Dutch patients for early-stage HCC detection. The optimized GALAD without AFP-L3, the ASAP score, is a good alternative and shows greater promise for HCC prediction., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

With the global lockdown, meteorological factors are highly discussed for COVID-19 transmission. In this study, national-specific and region-specific data sets from Germany, Italy, Spain and the United Kingdom were used to explore the effect of temperature, absolute humidity and diurnal temperature range (DTR) on COVID-19 transmission. From February 1st to November 1st, a 7-day COVID-19 case doubling time (Td), meteorological factors with cumulative 14-day-lagged, government response index and other factors were fitted in the distributed lag nonlinear models. The overall relative risk (RR) of the 10th and the 25th percentiles temperature compared to the median were 0.0074 (95% CI: 0.0023, 0.0237) and 0.1220 (95% CI: 0.0667, 0.2232), respectively. The pooled RR of lower (10th, 25th) and extremely high (90th) absolute humidity were 0.3266 (95% CI: 0.1379, 0.7734), 0.6018 (95% CI: 0.4693, 0.7718) and 0.3438 (95% CI: 0.2254, 0.5242), respectively. While the DTR did not have a significant effect on Td. The total cumulative effect of temperature (10th) and absolute humidity (10th, 90th) on Td increased with the change of lag days. Similarly, a decline in temperature and absolute humidity at cumulative 14-day-lagged corresponded to the lower RR on Td in pooled region-specific effects. In summary, the government responses are important factors in alleviating the spread of COVID-19. After controlling that, our results indicate that both the cold and the dry environment also likely facilitate the COVID-19 transmission., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival., Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2)., Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study., Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles., Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug)., Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug., Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted., Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

The ixodid tick Haemaphysalis concinna Koch, 1844 is a proven vector of tick-borne encephalitis (TBE) virus and Francisella tularensis, the causative agent of tularaemia. In the present study, up-to-date maps depicting the geographical distribution and climate adaptation of H. concinna are presented. A dataset was compiled, resulting in 656 georeferenced locations in Eurasia. The distribution of H. concinna ranges from the Spanish Atlantic coast to Kamchatka, Russia, within the belt of 28-64° N latitude. H. concinna is the second most abundant tick species after Ixodes ricinus collected from birds, and third most abundant tick species flagged from vegetation in Central Europe. To investigate the climate adaptation of H. concinna, the georeferenced locations were superimposed on a high-resolution map of the Köppen-Geiger climate classification. A frequency distribution of the H. concinna occurrence under different climates shows three peaks related to the following climates: warm temperate with precipitation all year round, boreal with precipitation all year round and boreal, winter dry. Almost 87.3 % of all H. concinna locations collected are related to these climates. Thus, H. concinna prefers climates with a warm and moist summer. The remaining tick locations were characterized as cold steppes (6.2%), cold deserts (0.8%), Mediterranean climates (2.7%) or warm temperate climates with dry winter (2.9%). In those latter climates H. concinna occurs only sporadically, provided the microclimate is favourable. Beyond proven vector competence pathogen findings in questing H. concinna are compiled from the literature., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.