Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative analysis of 136,401 Admixed Americans and 419,228 Europeans reveals ancestry-specific genetic determinants of clonal haematopoiesis

The development of clonal haematopoiesis (CH), the age-related expansion of mutated haematopoietic stem cell (HSC) clones, is influenced by genetic and non-genetic factors. To date, large-scale studies of CH have focused on individuals of European descent, such that the impact of genetic ancestry on CH development remains incompletely understood. Here, we investigate this by studying CH in 136,401 admixed participants from the Mexico City Prospective Study (MCPS) and 419,228 European participants from the UK Biobank (UKB). We observe that CH was significantly less common in MCPS compared to UKB (adjusted odds ratio (OR) = 0.56 [95% Cl = 0.55-0.59], P = 1.60 x 10-206), a difference that persisted when comparing MCPS participants whose genomes were >50% ancestrally Indigenous American to those whose genomes were >50% ancestrally European (adjusted OR = 0.76 [0.70-0.83], P = 1.78 x 10-10). Genome- and exome-wide association analyses in MCPS participants identified two novel loci associated with CH (CSGALNACT1 and DIAPH3), and ancestry-specific variants in the TCL1B locus with opposing effect on DNMT3A- versus non-DNMT3A-CH. Meta-analysis of the MCPS and UKB cohorts identified another five novel loci associated with overall or gene specific CH, including polymorphisms at PAPR11/CCND2, MEIS1 and UBE2G1/SPNS3. Our CH study, the largest in a non-European population to date, demonstrates the profound impact of ancestry on CH development and reveals the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis and advance health equity amongst different human populations.
Glucose control and outcomes in diabetic and nondiabetic patients treated with targeted temperature management after cardiac arrest

Hyperglycemia is commonly observed in critically ill patients and postcardiac arrest patients, with higher glucose levels and variability associated with poorer outcomes. In this study, we aim to compare glucose control in diabetic and nondiabetic patients using glycated hemoglobin (HbA1c) levels, providing insights for better glucose management strategies. This retrospective observational study was conducted at Seoul St. Mary’s Hospital from February 2009 to May 2022. Blood glucose levels were measured hourly for 48 h after return of spontaneous circulation (ROSC), and a glucose management protocol was followed to maintain arterial blood glucose levels between 140 and 180 mg/dL using short-acting insulin infusion. Patients were categorized into four groups based on diabetes status and glycemic control. The primary outcomes assessed were neurological outcome and mortality at 6 months after cardiac arrest. Among the 332 included patients, 83 (25.0%) had a previous diabetes diagnosis, and 114 (34.3%) had an HbA1c of 6.0% or higher. At least one hyperglycemic episode was observed in 314 patients (94.6%) and hypoglycemia was found in 63 patients (19.0%) during 48 h. After the categorization, unrecognized diabetes was noticed in 51 patients with median HbA1c of 6.3% (interquartile range [IQR] 6.1–6.6). Patients with inadequate diabetes control had the highest initial HbA1c level (7.0%, IQR 6.5–7.8) and admission glucose (314 mg/dL, IQR 257–424). Median time to target glucose in controlled diabetes was significantly shorter with the slowest glucose reducing rate. The total insulin dose required to reach the target glucose level and cumulative insulin requirement during 48 h were different among the categories (p <0.001). Poor neurological outcomes and mortality were more frequently observed in patients with diagnosed diabetes. Occurrence of a hypoglycemic episode during the 48 h after ROSC was independently associated with poor neurologic outcomes (odds ratio [OR] 3.505; 95% confidence interval [CI], 2.382–9.663). Surviving patients following cardiac arrest exhibited variations in glucose hemodynamics and outcomes according to the categories based on their preexisting diabetes status and glycemic condition. Specifically, even experiencing a single episode of hypoglycemia during the acute phase could have an influence on unfavorable neurological outcomes. While the classification did not directly affect neurological outcomes, the present results indicate the need for a customized approach to glucose control based on these categories.
Is there a shift from cardiovascular to cancer death in lipid-lowering trials? A systematic review and meta-analysis

Background Lipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk. Methods We performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs. Results We included 27 trials with 188’259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97–1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00–1.23), while the RR for CV death was 0.96 (0.91–1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99–1.47). Conclusion LLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations. PROSPERO registration CRD42021271658
Activation of testosterone‐androgen receptor mediates cerebrovascular protection by photobiomodulation treatment in photothrombosis‐induced stroke rats

Abstract Rationale Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)‐induced stroke rats remain largely unknown. Methods We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular‐associated and apoptotic proteins in PT‐induced stroke rats treated with flutamide and seven consecutive days of PBM treatment (350 mW, 808 nM, 2 min/day). To gain further insights into the mechanism of PBM on testosterone synthesis, we used testosterone synthesis inhibitors to study their effects on bEND.3 cells. Results We showed that PT stroke caused a decrease in cerebrovascular testosterone concentration, which was significantly increased by 7‐day PBMT (808 nm, 350 mW/cm2, 42 J/cm2). Furthermore, PBMT significantly increased cerebral blood flow (CBF) and the expression of vascular‐associated proteins, while inhibiting vascular permeability and reducing endothelial cell apoptosis. This ultimately mitigated behavioral deficits in PT stroke rats. Notably, treatment with the androgen receptor antagonist flutamide reversed the beneficial effects of PBMT. Cellular experiments confirmed that PBMT inhibited cell apoptosis and increased vascular‐associated protein expression in brain endothelial cell line (bEnd.3) subjected to oxygen‐glucose deprivation (OGD). However, these effects were inhibited by flutamide. Moreover, mechanistic studies revealed that PBMT‐induced testosterone synthesis in bEnd.3 cells was partly mediated by 17β‐hydroxysteroid dehydrogenase 5 (17β‐HSD5). Conclusions Our study provides evidence that PBMT attenuates cerebrovascular injury and behavioral deficits associated with testosterone/AR following ischemic stroke. Our findings suggest that PBMT may be a promising alternative approach for managing cerebrovascular diseases.
Experimental evidence for adaptive divergence in response to a warmed habitat reveals roles for morphology, allometry and parasite resistance

Abstract Ectotherms are expected to be particularly vulnerable to climate change–driven increases in temperature. Understanding how populations adapt to novel thermal environments will be key for informing mitigation plans. We took advantage of threespine stickleback (Gasterosteus aculeatus) populations inhabiting adjacent geothermal (warm) and ambient (cold) habitats to test for adaptive evolutionary divergence using a field reciprocal transplant experiment. We found evidence for adaptive morphological divergence, as growth (length change) in non‐native habitats related to head, posterior and total body shape. Higher growth in fish transplanted to a non‐native habitat was associated with morphological shape closer to native fish. The consequences of transplantation were asymmetric with cold sourced fish transplanted to the warm habitat suffering from lower survival rates and greater parasite prevalence than warm sourced fish transplanted to the cold habitat. We also found divergent shape allometries that related to growth. Our findings suggest that wild populations can adapt quickly to thermal conditions, but immediate transitions to warmer conditions may be particularly difficult.
The impact of breast‐conserving surgery and modified radical mastectomy on postoperative wound complications in patients with early breast cancer

Abstract In recent years, breast conservation surgery (BCS) and modified radical mastectomy (MRM) have been widely used in the treatment of early‐stage breast cancer. However, the effects of complications from these two surgical methods are still unclear. The purpose of this study was to evaluate the effects of BCS and MRM on postoperative wound complications in patients with early breast cancer. Eighty‐eight patients with early breast cancer were randomly divided into BCS group (n = 46) and MRM group (n = 42). The occurrence of postoperative wound complications was compared between the two groups. The results showed that BCS patients had significantly lower intraoperative surgical times, blood losses, incision lengths, drainage volumes, drainage times and lengths of hospital stays than their MRM counterparts (p < 0.05). The overall incidence of postoperative wound complications in the BCS group was significantly lower than that in the MRM group at 1 month after surgery, but the difference was not statistically significant (p < 0.001). The rate of excellent breast cosmetic outcome was significantly higher in the BCS group than in the MRM group (p < 0.001). Compared to MRM, BCS has a lower incidence of intraoperative and postoperative wound complications, better cosmetic outcomes and higher clinical value in the treatment of early‐stage breast cancer.
Evolving Spectrum of Dengue: A Two-Year Experience From a Tertiary Care Hospital in Pakistan

Objective: This study focused on examining the clinical manifestations, disease severity, and outcomes among cases of dengue fever (DF) confirmed through serological testing. The study specifically targeted individuals admitted to a tertiary care hospital in Islamabad, Pakistan. Methodology: This prospective observational study at the Pakistan Institute of Medical Sciences, Islamabad, Pakistan, tracked 1,003 patients from admission to discharge or death between August 2022 and November 2023. Patients were monitored, and admission criteria were established based on the identification of warning signs. The data collection process encompassed gathering demographic information, documenting clinical symptoms, and utilizing a severity classification system for the disease. Outcome measures comprised the duration of critical illness, length of hospital stay, overall outcomes (discharge or mortality), and the assessment of complications. The collected data were analyzed using IBM Statistical Package for the Social Sciences (SPSS) software version 22.0 (IBM Corp., Armonk, NY). Results: Baseline characteristics revealed a male predominance (67.8%), with an average age of 35.77 years, and common comorbidities such as hypertension (9.3%) and diabetes mellitus (7.3%). Dengue fever was most prevalent among patients whose blood group was B+ (15.0%). Nonstructural protein 1 (NS1) was positive in 73.4% of the cases. Fever was the predominant complaint in 98.0% of instances. Common bleeding manifestations included epistaxis, gum bleeding, and hematemesis. About 52.20% of cases were observed to have severe thrombocytopenia at admission. Hospital-related aspects demonstrated a mean stay of 3.35 days, a critical phase lasting 1.68 days, and rare complications like expanded dengue syndrome (2.2%). Encouragingly, 98.9% of patients were discharged, 0.4% were shifted, and 0.7% succumbed to the disease. Conclusion: This study comprehensively analyzes the demographic and clinical aspects of DF, emphasizing a male predominance and the fact that fever was the most common presenting complaint. The duration of hospitalization revealed a brief mean stay, a short critical phase, and low complication rates, with a high discharge rate suggesting positive outcomes.
Attitudes and perceptions of Irish health care professionals regarding functional neurological disorder: A national survey

Abstract Background Functional neurological disorder (FND) is a common and often disabling condition. Limited access to services for FND poses challenges both for patients and their health care providers. This survey explored the attitudes, experiences, support needs and training needs of health care professionals (HCPs) who provide care to individuals with FND in Ireland. Methods A broad range of HCPs working with patients with FND in Ireland partook in an anonymous online 12‐item survey. Participants were recruited via professional bodies and snowball convenience sampling utilising social media and email invitation. Descriptive and inferential statistics were employed to analyze data. Results A total of 314 HCPs working in Ireland completed the survey. 80% were female and over half worked in their current role for more than 10 years. 75% of the sample encountered three or less individuals with FND per month. Identified service‐related challenges to effective patient care included insufficient clinic time, lack of confidence explaining the diagnosis, and the need for greater access to specialist support. Data revealed persisting negative attitudes toward FND patients among a proportion of respondents. The majority of respondents did not feel they received adequate education on FND, with the exception of neurologists, of whom 65% felt adequately trained. The majority of respondents (85%) also felt that people with FND did not have access to appropriate FND services in Ireland. Conclusion This study indicates that there is a significant need to improve FND education among HCPs in Ireland, in addition to developing appropriately resourced, integrated, multidisciplinary care pathways for the FND patient group.
Machine perfusion of the liver and in vivo animal models: A systematic review of the preclinical research landscape

Machine perfusion (MP) is often referred to as one of the most promising advancements in liver transplantation research of the last few decades, with various techniques and modalities being evaluated in preclinical studies using animal models. However, low scientific rigor and subpar reporting standards lead to limited reproducibility and translational potential, hindering progress. This pre-registered systematic review (PROSPERO: CRD42021234667) aimed to provide a thematic overview of the preclinical research landscape on MP in liver transplantation using in vivo transplantation models and to explore methodological and reporting standards, using the ARRIVE (Animal Research: Reporting of In Vivo Experiments) score. In total 56 articles were included. Studies were evenly distributed across Asia, Europe, and the Americas. Porcine models were used in 57.1% of the studies, followed by rats (39.3%) and dogs (3.6%). In terms of graft type, 55.4% of the studies used donation after cardiac death grafts, while donation after brain death grafts accounted for 37.5%. Regarding MP modalities, the distribution was as follows: 41.5% of articles utilized hypothermic MP, 21.5% normothermic MP, 13.8% subnormothermic MP, and 16.9% utilized hypothermic oxygenated MP. The stringent documentation of ARRIVE elements concerning precise experimental execution, group size and selection, the choice of statistical methods, as well as adherence to the principles of the 3Rs, was notably lacking in the majority of publications, with less than 30% providing comprehensive details. Postoperative analgesia and antibiotics treatment were not documented in 82.1% of all included studies. None of the analyzed studies fully adhered to the ARRIVE Guidelines. In conclusion, the present study emphasizes the importance of adhering to reporting standards to promote reproducibility and adequate animal welfare in preclinical studies in machine perfusion. At the same time, it highlights a clear deficiency in this field, underscoring the need for further investigations into animal welfare-related topics.
Distinguishing characteristics of Staphylococcus schleiferi and Staphylococcus coagulans of human and canine origin

Staphylococcus schleiferi and Staphylococcus coagulans are opportunistic pathogens of animals and humans. They were previously classified as Staphylococcus schleiferi subs. schleiferi and Staphylococcus schleiferi subs. coagulans, respectively, and recently reclassified as separate species. S. coagulans, is frequently associated with dogs, whereas S. schleiferi is more commonly isolated from humans. Coagulase activity status is a defining characteristic of the otherwise closely related species. However, the use of coagulase tests originally developed to distinguish S. aureus from non-coagulase-producing staphylococci, for this purpose is questionable and the basis for their host preference has not been elucidated. In the current study, a putative coa gene was identified and correlated with coagulase activity measured using a chromogenic assay with human and bovine prothrombin (closely related to canine prothrombin). The results of the tests performed with human prothrombin showed greater reactivity of S. coagulans isolates from humans than isolates obtained from dogs with the same substrate. Our data suggest that unlike S. coagulans isolates from humans, isolates from dogs have more coagulase activity with bovine prothrombin (similar to canine prothrombin) than human prothrombin. Differences in nuc and 16s rRNA genes suggest a divergence in S. coagulans and S. schleiferi. Phenotypic and genotypic variation based on the number of IgG binding domains, and the numbers of tandem repeats in C-terminal fibronectin binding motifs was also found in protein A, and fibronectin-binding protein B respectively. This study identified a coa gene and associated phenotypic activity that differentiates S. coagulans and S. schleiferi and identified key phylogenetic and phenotypic differences between the species.
Effects of stream temperature and climate change on fluvial arctic grayling and non-native salmonids in the upper Big Hole River, Montana

The upper Big Hole River basin in southwestern Montana supports one of the last naturally-reproducing populations of fluvial Arctic grayling Thymallus arcticus in the coterminous United States. Warm summer water temperatures and negative interactions with non-native fish (brook trout Salvelinus fontinalis, rainbow trout Oncorhynchus mykiss, and brown trout Salmo trutta) have been identified as critical factors constraining this grayling population. Arctic grayling and these non-native fishes are all cold-water species with similar temperature requirements. Understanding when, where, and to what extent water temperatures are suitable for these fishes provides a physical basis for conservation planning. In chapter 2, I used a combination of thermal infrared (TIR) imagery and stationary temperature recorders to estimate water temperatures at a relatively fine spatial (every ~ 100 m of stream length) and temporal (continuous) resolution over a large extent of the Big Hole River (~ 100 km) during the warmest part of the summer in 2008. This modeling revealed considerable spatial and temporal heterogeneity in water temperature and highlighted the value of assessing thermal regimes at relatively fine spatial and temporal scales. In chapter 3, I assessed the potential effects of climate change on thermal suitability of summer water temperatures for these salmonids. Water temperature simulations projected significant warming from the 1980s through the 2060s. Despite this warming, water temperatures in some sections of stream remained below thermal tolerance thresholds through the 2060s. These stream temperature data provide a critical foundation for understanding the dynamic, multiscale habitat needs of these mobile stream fish and can aid in developing conservation strategies for fluvial Arctic grayling.
Sleep and APOE‐ε4 have a synergistic effect on plasma biomarkers and longitudinal cognitive decline in older adults

Abstract Background Sleep disorders are prevalent among patients with Alzheimer's disease (AD), and the APOE ε4 genotype is a key genetic risk factor for sporadic AD. However, the combined effect of the genotype and sleep disorders on cognitive decline remains uncertain. Methods A total of 972 participants were drawn from the SILCODE cohort, comprising 655 without the ε4 allele (APOE−) and 317 with ε4 allele (APOE+). Data were collected, including neuropsychological assessments, sleep measurements, plasma biomarkers, and PET imaging. A Sleep Composite Index (SCI) was created, categorizing participants into high risk (Sleep+) and low risk (Sleep−). Results Significant predictions of dementia risk associated with plasma p‐tau181, neurofilament light chain (NfL), and SCI. Individuals with both Sleep+ and APOE+ had a higher risk of dementia compared to those with Sleep‐. The Sleep+/APOE+ group had higher plasma NfL levels than the Sleep−/APOE− group. Similar trends emerged in plasma NfL levels among the Aβ PET‐positive subgroup. Plasma NfL levels explained 23% of the relationship between SCI and cognitive impairment. Conclusion Our study highlights sleep disorder was associated with cognitive decline, with plasma NfL playing a partial mediating role. These findings explain how sleep disorders affect cognitive function and emphasize the importance of healthy sleep for older adults.