Search Results (5,131)

Background: Polygenic risk scores for Alzheimer’s disease (AD), organized by gene networks shared between the blood and brain, may provide insights into underlying disease mechanisms common to both tissues. Methods: We derived a blood–brain network-based polygenic risk score (nbPRS) from AD-associated genetic variants for three blood-brain networks, selected by the preservation of blood and brain gene co-expression networks, and AD association. Participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 1109), Framingham Heart Study (FHS, n = 8310), the Religious Orders Study Memory Aging Project (ROSMAP, n = 1215), and Mount Sinai Brain Bank (MSBB, n = 323) were stratified into low- and high-nbPRS subgroups, then profiled using longitudinal and cross-sectional data. We compared the conversion from normal cognition to AD between nbPRS subgroups. Genes differentially expressed among low- and high-nbPRS individuals were profiled with classical neuropathological markers and we investigated potential biologically relevant pathways for the genes significantly expressed in high-risk individuals. Results: Individuals with high nbPRS in three AD-associated networks (M2, M6, M14) demonstrated significant impairment in executive function and memory performance, whereas high-risk individuals in networks M2 and M14 had significantly reduced hippocampal volume. We observed high-risk individuals in M2 and M14 developed AD at twice the rate of low-risk individuals in these networks. HLA genes were differentially expressed with transcriptome-wide significance among low- and high-nbPRS individuals in M14 and associated with neuroinflammatory and tau pathology. Conclusions: Polygenic risk scores derived from blood and brain networks can differentiate individuals with a high risk of AD conversion. Full article

Background: Effectively managing acute postoperative pain after laparoscopic surgery (M-PALS) is essential to optimize outcomes, enhance recovery, and mitigate opioid-related risks. We aimed to systematically map evidence on effectiveness and harms of pharmacologic and non-pharmacologic interventions for M-PALS. Methods: We searched three databases (2012–2025) for randomized clinical trials (RCTs) that reported postoperative opioid use and pain-related outcomes. We assessed study quality using the Cochrane Risk of Bias (ROB)-2 tool. Results: From 7638 citations, we included 101 RCTs. Postoperative opioid use was reported variably (e.g., total use over 24 or 48 h postoperatively, frequency of rescue-opioid use, and time to first rescue-opioid use). One out of 101 RCTs evaluated opioid prescription at discharge. No RCT reported opioid use at ≥3 months postoperatively. Eleven strategies were evaluated in ≥2 RCTs, with usual care/ sham as comparators. None of the 101 RCTs favored usual care over any intervention for pain or opioid use outcomes. For regional anesthesia (21 RCTs total; 12 with low ROB), intraperitoneal/preperitoneal local anesthetic instillation (10 RCTs; 4 with low ROB), intravenous dexamethasone (3 RCTs; 1 with low ROB), and the Enhanced Recovery After Surgery (ERAS) protocol (3 RCTs; 0 with low ROB), compared to usual care, >50% of RCTs favored the intervention for reducing pain and opioid use. For adverse events, only 3 out of 101 RCTs favored comparators. Inconsistent outcome reporting across all RCTs and, for multimodal strategies, the uniqueness of intervention–comparator combinations hindered comparisons. Conclusions: Interventions for M-PALS appear safe, with no RCT indicating worse efficacy of intervention than usual care; but evidence regarding superiority is conflicting. Future research should establish standardized and longer-term core outcome sets and make head-to-head comparisons between optimal strategies. Full article

Patients undergoing hemodialysis often experience reduced quality of life, with psychological symptoms and nutritional risk representing important determinants of patient functioning. This study aimed to examine the relationships between depression, anxiety, stress, nutritional risk, mental health, and physical functioning in patients undergoing hemodialysis, with particular emphasis on the mediating role of mental health. A cross-sectional study was conducted among 199 patients receiving hemodialysis in five Croatian hospitals. Depression, anxiety, and stress were assessed using the DASS-42, quality of life using the SF-36, and nutritional risk using the NRS-2002. Associations between variables were examined using Spearman’s correlation coefficient, while structural equation modeling was used to analyze direct and indirect relationships among psychological symptoms, nutritional risk, mental health, and physical functioning. Depression and stress showed significant negative effects on mental health, while mental health showed a significant positive effect on physical functioning. Nutritional risk had a significant direct negative effect on physical functioning. Mental health significantly mediated the relationship between depression and stress and physical functioning. These findings indicate that psychological symptoms and nutritional risk are important determinants of functioning and quality of life in hemodialysis patients and support the need for an integrated care approach that includes regular psychological and nutritional screening. Full article

Background: Intimate partner violence (IPV) is a pervasive medical concern affecting millions of people worldwide, with the majority being women. IPV is linked to a number of long-term physical and mental health consequences, including brain injuries and associated persistent post-concussion symptoms (PPCS) and post-traumatic stress disorder (PTSD). Despite the high prevalence of these conditions, there is sparse literature assessing accessible and effective therapeutic avenues specific to IPV victim-survivors. Methods: This narrative review had two aims: to identify therapeutic studies addressing PTSD and PPCS in women IPV survivors, and to provide a narrative overview of potential therapeutic categories, including psychotherapy, mindfulness and meditation, exercise, and pharmacotherapy. A comprehensive literature search was conducted using PubMed and Google Scholar. Inclusion criteria required full-text, peer-reviewed articles published in English, conducted in women with a history of IPV, reporting treatment outcomes related to PTSD or PPCS. Where no IPV-specific evidence was identified, findings from closely related populations including military veterans, athletes, and general TBI samples were narratively reviewed to inform potential therapeutic implications. Results: Nineteen studies addressing PTSD in women IPV survivors were identified, predominantly utilizing psychotherapeutic or mindfulness and meditation-based interventions. No intervention studies targeting PPCS specifically in IPV survivors were identified. Consequently, results for PPCS are largely extrapolated from adjacent populations. Although potential therapeutic avenues were narratively identified across psychotherapy, mindfulness and meditation, exercise, and pharmacotherapy, IPV-specific evidence remains limited, and validation for PTSD and PPCS in this population is needed before clinical recommendations can be made. Conclusions: While 19 studies identified promising therapeutic options for IPV-related PTSD, no IPV-specific PPCS interventions were identified, and implications for PPCS management remain largely inferential. Validation and integrated trauma-informed approaches addressing the intersection of PTSD and PPCS are needed for this understudied population. Full article

Background/Objectives: Automated localization of cystic lesions and benign tumors on panoramic radiographs may support lesion recognition in the maxillofacial region. This preliminary feasibility study aimed to develop and evaluate a deep learning model based on Mask R-CNN for the localization of dentigerous cysts (DCs), radicular cysts (RCs), odontogenic keratocysts (OKCs), and ameloblastomas using panoramic radiographs. Methods: A total of 215 panoramic radiographs were retrospectively collected from Taichung Veterans General Hospital (2018–2023). After excluding postoperative, recurrent, or low-quality images, 184 lesions were allocated to the training set and 47 lesions to the testing set. Lesions were annotated based on pathology-confirmed diagnoses. The Mask R-CNN model was trained to localize and classify four lesion types. Model performance was evaluated using precision, sensitivity (recall), and F1 score at an Intersection over Union (IoU) threshold of 0.1. Results: In the testing set (n = 47), 26 lesions were correctly localized, yielding an overall sensitivity of 55.3% and a precision of 83.9%. The corresponding F1 score was 66.7%. Lesion-specific sensitivities were 40.0% for ameloblastomas, 37.5% for OKCs, 36.8% for RCs, and 93.3% for DCs. Conclusions: This study suggests the preliminary feasibility of a deep learning-assisted approach for lesion localization on panoramic radiographs. However, the absence of lesion-free control images and the limited dataset size restrict the generalizability and clinical applicability of the findings. Further validation using larger and more balanced datasets is required. Full article

Background: Post-Traumatic Stress Disorder (PTSD) is among the most prevalent and disabling mental health conditions affecting military veterans in Western countries. In recent decades, PTSD has increasingly been conceptualized as a systemic neuropsychological injury shaped not only by individual psychopathology, but also by institutional, cultural, and political contexts, particularly in settings of prolonged conflict and political violence. This shift has given rise to diverse national rehabilitation models that extend beyond symptom-focused care. This narrative comparative review aims to examine national models of PTSD rehabilitation among military veterans and to derive policy-relevant insights for Israel. Methods: We conducted a narrative comparative review of peer-reviewed literature and national policy documents published between 2014 and 2023, examining military and veteran PTSD rehabilitation frameworks in six Western countries: the United States, Canada, the United Kingdom, Germany, Australia, and the Netherlands. Sources were identified through PubMed, PsycINFO, Google Scholar, and governmental repositories. The review focused on system-level rehabilitation structures, including clinical services, peer-based programs, occupational integration, community and cultural components, and national monitoring practices. Results: Across countries, recurring challenges included persistent stigma limiting help-seeking, fragmented service delivery, inconsistent access to evidence-based care and a lack of standardized outcome indicators capturing functional and social recovery. Innovative approaches included biopsychosocial-spiritual rehabilitation models, peer-led interventions, intra-systemic employment pathways, and symbolic forms of social recognition. In this context, the biopsychosocial-spiritual approach refers to integrative rehabilitation models that extend beyond traditional frameworks by incorporating meaning-making, identity reconstruction, and value-based recovery processes. Conclusions: The findings highlight the need to reconceptualize PTSD rehabilitation as a multidimensional, system-level process. In light of the 2023 “Iron Swords” war and the scale of trauma exposure in Israel, the review informs actionable recommendations for developing a coordinated national rehabilitation strategy that integrates clinical care with occupational, community and cultural recovery. Full article

Background: Statins have been associated with a reduced risk of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC). However, the optimal use for effective protection and whether benefits vary by patient characteristics remain unclear. We evaluated the association between statin use and PLC risk in metabolic-dysfunction-associated steatotic liver disease (MASLD), considering cumulative exposure and potential effect modifiers. Methods: We conducted a retrospective cohort study using the Veteran Affairs electronic health records. Patients with chronically elevated liver enzymes and metabolic dysfunction, without other chronic liver diseases, were identified between 2007 and 2009 and followed through 2019 for incident PLC. Statin exposure was assessed at baseline and during the follow-up, with dose standardization by LDL-lowering potency (simvastatin-equivalent units). Time to PLC was analyzed using Cox models adjusted for covariates, considering potential interactions. Results: Among 329,577 patients (92% male; median age 62 years), 0.82% developed PLC (median follow-up of 9.7 years). Baseline statin use showed a significantly lower PLC risk (adjusted hazard ratio 0.64; 95% CI, 0.57–0.71; p < 0.0001). No significant interaction was observed with age, sex, metabolic syndrome, or cirrhosis. Higher cumulative statin exposure demonstrated a dose-dependent risk reduction, remaining significant at simvastatin-equivalent doses > 15,561 mg annually after accounting for incident cirrhosis. Atorvastatin/rosuvastatin use provided comparable protection, despite different lipophilicity, and demonstrated stronger effects than others. Conclusions: In MASLD, statin therapy was associated with a dose-dependent PLC risk reduction. High-intensity therapy (simvastatin-equivalent > 40 mg daily) conferred substantial protection regardless of age, sex, insulin resistance, or cirrhosis, supporting a potential statin-based PLC chemoprevention in MASLD. Full article

Therapist shortages make home-based rehabilitation an essential component of post-stroke care, yet patients often exhibit reduced adherence when functional gains are difficult to quantify and interpret. This study presents a cloud-enabled assessment framework centered on a dynamic reaching task for upper-limb rehabilitation in individuals with mild stroke. The proposed system combines wearable sensing and Internet of Things (IoT) connectivity to stream kinematic data to the cloud for near real-time analysis, and integrates a force-feedback rehabilitation robot to deliver motion guidance during training. The pipeline proceeds in three stages. First, smoothness-related kinematic descriptors are extracted and fed into a deep multi-class classifier to discriminate the affected side (left, right, or healthy). Second, movement quality is modeled using a Gaussian Mixture Model (GMM) trained on IoT-acquired trajectories to quantify performance via probabilistic similarity. Third, a calibrated scoring function transforms GMM log-likelihood into a normalized 0–1 quality index, producing visual reports that support interpretable feedback for patients and therapists. The framework is validated using motion data collected from stroke patients at Taipei Veterans General Hospital. Experimental results demonstrate that the neural network multi-classifier achieved an F1-score of 0.95. Incorporating robot-derived interaction signals further improved classification performance by approximately 5%. For movement quality assessment, the derived scores showed a significant positive correlation (Pearson correlation = 0.632, p = 0.02) with therapist-defined gold reference standards for right-affected patients. Additionally, integrating robot force-feedback signals and AIoT-enabled dynamic streams improved score accuracy by 8% and score responsiveness by 10%. These quantitative outcomes substantiate the efficacy of combining IoT-driven sensing and robot-assisted training for objective, interpretable, and remotely deployable motor assessment. Full article

To date, Lyme vaccine development has largely overlooked the vaccinee’s human leukocyte antigen (HLA) genetic makeup on which antibody production critically depends. Here, we evaluated in silico the predicted binding affinities of 192 HLA-II alleles with all 15-mer peptide sequences of five Borrelia burgdorferi proteins to identify peptides with strong binding affinity, as they would be the best candidates for antibody production in response to vaccination. We found the following: (a) 226 of the 1067 peptides tested (21.2%) were found to bind strongly to HLA-II molecules; (b) decorin-binding protein A had the greatest number of strongly binding peptides; and (c) 69 HLA-II alleles (primarily of the DRB1 gene) bound with strong affinity to peptides from Borrelia burgdorferi proteins. Finally, we tested for possible susceptibility to autoimmunity by any one of the 226 peptides above by searching for their occurrence in ~84,000 proteins of the human proteome and found overlap with only two 8-mer peptide sequences (embedded within the 226 15-mer peptides), neither of which was characterized by strong binding to HLA-I, suggesting a reduced likelihood of autoimmunity. These findings emphasize the importance of a personalized vaccine approach based on the vaccinee’s human leukocyte antigen genetic makeup and offer specific vaccine-candidate peptides that are predicted to maximize vaccine effectiveness and safety. The results of this computational study provide novel directions for future development of Lyme vaccines. Full article

Background: HIMALAYA demonstrated that STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) compared with sorafenib in participants with unresectable hepatocellular carcinoma (HCC). This retrospective, real-world cohort study evaluated outcomes with STRIDE in veterans with HCC. Methods: Patients diagnosed with HCC between 1 January 2008 and 28 February 2024 who received ≥1 dose of STRIDE for unresectable disease were included. Data were collected from the Veteran Affairs Corporate Data Warehouse. Safety and efficacy were evaluated overall and for subgroups of patients with Child–Pugh A versus Child–Pugh B cirrhosis, viral versus non-viral HCC, and those with versus without prior non-systemic therapies. Results: Overall, 107 patients (100.0% male) were included. Median (interquartile range) age was 72.2 (68.0–76.1) years. There were 22 Grade 3–4 adverse events reported (three in patients with Child–Pugh B cirrhosis). Median OS (95% CI) was 12.4 (9.1–22.1) months and 5.2 (1.5–9.3) months in patients with Child–Pugh A (n = 81; 75.7%) and Child–Pugh B cirrhosis (n = 26; 24.3%), respectively. In patients with viral (n = 64; 59.8%) versus non-viral etiology (n = 43; 40.2%), median OS (95% CI) was 10.5 (7.0–25.6) months versus 9.0 (4.6–16.0) months, respectively. In patients without (n = 30; 28.0%) versus with prior non-systemic therapies (n = 77; 72.0%), median OS (95% CI) was 7.7 (2.8–17.3) months versus 11.1 (7.6–17.6) months, respectively. Conclusions: These results suggest that STRIDE is well tolerated and may offer a survival benefit to a broad range of patients with unresectable HCC, representing populations that are more reflective of real-world clinical practice. Full article

Agonists of the G protein-coupled receptor TGR5 have long been sought-after for their metabolic benefits. Intestinal TGR5 activation induces secretion of the antidiabetic hormone GLP-1, which can systemically improve diabetes phenotypes in multiple organs. However, no TGR5 agonist drug candidate has succeeded in clinical trials due to their low potency and unwanted side effects. A challenge in the field has been the development of TGR5 agonists that are non-toxic, long-acting, and have functional selectivity for G protein-biased agonism. In this study, we propose a systematic pipeline for engineering optimal TGR5 agonists with antidiabetic properties. This pipeline is interdisciplinary, combining in silico, in vitro, and in vivo assays to design and validate drug candidates. We identify 2 lead compounds that outline the necessary beneficial properties for a successful TGR5 agonist against diabetes. We uncover the molecular mechanisms that allow TGR5 agonists to induce the transcription of their target, TGR5, in intestinal enteroendocrine cells. Lastly, we investigate the molecular interactions of our lead candidates in the TGR5 binding pocket to identify optimal parameters for stability and biological activity. Our strategy for TGR5 agonist design and evaluation has the potential to guide the discovery process for targeted TGR5 therapeutics for metabolic diseases. Full article

Schizophrenia has an estimated population prevalence of 1%, but the etiology of this devastating psychiatric condition remains largely uncharacterized. A pronounced genetic component underlies schizophrenia, with heritability estimates ranging from 60% to 80%. Until now, genome-wide association studies have successfully identified 287 distinct genetic loci associated with schizophrenia, but these primarily involve common variants that have minimal individual risk. The recent advent of exome sequencing and genome sequencing has identified ultra-rare sequence variants associated with schizophrenia in familial cases as well as in large cohorts. These studies have implicated multiple gene variants that individually have a large effect size in contributing to schizophrenia. A comparison indicates that these genes exhibit high expression levels in the central nervous system and their protein products participate in many converging pathways encompassing synaptic transmission, glutamatergic neurotransmission, chromatin modification processes, transcriptional regulation, and ubiquitin–proteasome degradation. Although model systems have been established for some genes, most remain to be further studied to identify how gene dysfunction correlates with disease. Full article

Two-pore domain potassium (K₂P) channels are the most recently identified family of potassium channels. They are regarded as the largest group of background “leak” channels, encoded by 15 mammalian KCNK genes, and divided into six subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). These channels have a role in stabilizing the resting membrane potential. Their widespread presence in the heart and vasculature supports cellular homeostasis by regulating cardiac rhythm, vascular tone, and protection against ischemic stress. The TASK, TWIK, and TREK subfamilies are the most abundantly expressed K₂P channel subfamilies in the cardiovascular system, and dysregulation of specific members has been strongly linked to the development of major cardiovascular diseases. Mutations in TASK-1 have been identified in patients with pulmonary arterial hypertension, providing human genetic evidence linking K₂P dysfunction to pulmonary vascular disease. While alterations in other K₂P channels, such as TREK-1, have been demonstrated in preclinical studies where reduced channel activity is associated with ischemia–reperfusion injury and promotes cardiac arrhythmias. Growing evidence suggests that K₂P channels could serve as promising therapeutic targets, with pharmacological activation of TASK-1 and TREK-1, for instance, that might help restore vascular tone, reduce remodeling, and offer cardioprotection. Their unique leak-channel properties enable the development of highly selective treatments. This review addresses the molecular biology, physiological roles, and disease relevance of K₂P channels in the cardiovascular and pulmonary systems, emphasizing their potential as targets for innovative therapies in cardiovascular diseases. Full article

Background: Activity trackers support physical activity, yet evidence on their effectiveness among older adults and care partners is limited. This study assesses the relationship between activity-tracking frequency and engagement in consistent physical activity among older adults and care partners. Methods: For this cross-sectional study, 615 older adults and care partners completed online surveys assessing the frequency of activity tracking (predictor) and the regularity in physical activity engagement (outcome). Using multivariable logistic regression, we assessed the association between the predictors and the outcome across the entire population and separately among older adults (n = 310) and care partners (n = 305), adjusting for sociodemographic, mobility, and health-related covariates. We reported the adjusted odds ratio (aOR) and 95% confidence intervals (CI). Results: Older adult (OA) and care partner (CP) respondents were predominantly female (OA: 57%, CP: 53%) and non-Hispanic White (OA: 51%, CP: 43%). Across the entire population, frequent tracking of physical activity was associated with a 2.4-fold increase in the odds of engaging in consistent physical activity (aOR: 2.40; 95% CI: 1.45–3.96). Older adults who frequently track their physical activity were 2.5 times more likely to engage in consistent physical activity (aOR: 2.47; 95% CI: 1.08–5.64). Care partners who occasionally tracked their physical activity were 3.5 times more likely to engage in consistent physical activity (aOR: 3.54; 95% CI: 1.54–8.11). Conclusions: Physical activity tracking is associated with greater physical activity engagement among older adults and care partners. These findings contribute to understanding factors associated with physical activity behavior in this population. Full article