Post-translational regulation of transcription factor EB

The bHLH-LZ transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, it also plays an important role in lipid and glucose metabolism, mitochondrial biogenesis, integrated stress response and immunity. Dysregulation of TFEB family is implicated in cancer as well as neurodegenerative diseases. TFEB subcellular localisation and transcriptional activity are regulated by cellular nutrient and energy status. Elucidating the mechanism of TFEB regulation is the key to understanding its role in maintaining cellular homeostasis as well as providing therapeutic insights. In this study we showed that TFEB subcellular localisation is regulated by both amino acids and glucose availability. Low glucose levels activate mTORC2-AKT signalling, leading to the inactivation of GSK3β, and GSK3β kinase activity is required for TFEB cytoplasmic localisation. We also demonstrated that GSK3β phosphorylates TFEB at S138 only after a priming phosphorylation event at S142. The sequential phosphorylation is required for CRM1-depedent nuclear export of TFEB via a novel nuclear export signal. This mechanism is important for the rapid cytoplasmic relocalisation and inactivation of TFEB upon nutrient replenishment. Additionally, we performed a high-throughput screen of 1,600 FDA-approved drugs and identified around 100 chemical modulators of TFEB and TFE3, of which around 50 % exhibited lysosomal biogenesis promoting potential. In particular, trifluoperazine, pimozide and loperamide induce TFEB nuclear translocation, lysosomal biogenesis and autophagy in an mTORC1- and AMPK- independent manner

Costs of bleeding on long-term antiplatelet treatment without routine co-prescription of proton-pump inhibitors

Background: Long-term antiplatelet treatment is associated with major bleeding. Aims: To determine the costs associated with major bleeding in patients treated with aspirin-based antiplatelet treatment for secondary prevention of vascular events without routine prescription of proton-pump inhibitors and to estimate the likely long-term savings from routine co-prescription. Methods: In a prospective population-based cohort study of TIA, ischemic stroke, and MI treated with antiplatelet drugs, we evaluated hospital care costs associated with bleed management during 10-year follow-up. Bleeding-associated costs were averaged across all patients. For upper GI-bleeds, mean costs were compared with the cost of routine co-prescription of proton-pump inhibitor. Results: Among 3166 patients on antiplatelet therapy with 405 first bleeding events, the average cost of major bleeding was $13,093 (S.D. 20,501), with similar costs for upper GI bleeds and intracranial bleeds (p = 0.235). However, total costs among the 3166 patients were higher for upper GI bleeds ($1,158,385 vs. $740,123). Averaged across all patients, the 10-year cost of major bleeding was$838 (95%CI: 680–1007), $411 due to upper GI bleeding, the cost of which increased from$175 in those aged <75 years to $644 at age ≥75 years (p  Conclusions: In secondary prevention with aspirin-based antiplatelet treatment without routine proton-pump inhibitor use, the long-term costs of upper-GI bleeding at age ≥75 years are much higher than at younger age groups, and are at least 10-fold greater than the drug cost of routine co-prescription of proton-pump inhibitor

Prevalence of patent foramen ovale in cryptogenic TIA and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis

Background Percutaneous closure of patent foramen ovale (PFO) has been shown to be superior to medical treatment alone for prevention of recurrent stroke after cryptogenic transient ischaemic attack or non-disabling stroke in patients aged 60 years or younger. The justification for trials in older patients with transient ischaemic attack or stroke depends on whether PFO is shown to be associated with cryptogenic events at older ages, for which existing evidence is conflicting, and on the population burden of PFO-associated events. Therefore, we did a population-based screening study using contrast-enhanced transcranial Doppler (bubble-TCD) to detect probable PFO as indicated by a right-toleft shunt (RLS); we also did a systematic review and meta-analysis to compare our results with previous studies. Methods In this population-based study, nested in the Oxford Vascular Study (OXVASC), we established the prevalence of any RLS, and of large RLS (>20 microbubbles), in consecutive patients attending a rapid-access transient ischaemic attack and stroke clinic, or at 1-month follow-up after stroke unit admission, with transient ischaemic attack or non-disabling ischaemic stroke, comparing cryptogenic events with those of known cause (according to Trial of Org 10172 in Acute Stroke Treatment [TOAST] criteria). We stratified participants by age, and extrapolated data to the UK population. We also did a systematic review of published studies of PFO prevalence (using transthoracic or transoesophageal echocardiography or bubble-TCD) according to stroke subtype, which included older patients and reported age-specific results, and determined by meta-analysis (including the OXVASC data) the pooled odds ratio (95% CI) of finding PFO of any size in cryptogenic events compared with events of known cause, stratified by screening modality (transthoracic or transoesophageal echocardiography or bubble-TCD). The study protocol is registered with PROSPERO, number CRD42018087074. Findings Among 572 consecutive patients with transient ischaemic attack or non-disabling stroke between Sept 1, 2014, and Oct 9, 2017 (439 [77%] patients aged >60 years, mean age 70·0 years [SD 13·7]), bubble-TCD was feasible in 523 patients (91%) of whom 397 were aged older than 60 years. Compared with those with transient ischaemic attack or stroke of known cause, patients with cryptogenic events had a higher prevalence of RLS overall (odds ratio [OR] 1·93, 95% CI 1·32–2·82; p=0·001), and in those aged older than 60 years (2·06, 1·32–3·23; p=0·001). When we pooled the OXVASC data with that from two previous smaller studies of bubble-TCD in patients aged 50 years or older, we found an association between RLS and cryptogenic events (OR 2·35, 95% CI 1·42–3·90; p=0·0009; pheterogeneity=0·15), which was consistent with the equivalent estimate from transoesophageal echocardiography studies (2·20, 1·15–4·22; p=0·02; pheterogeneity=0·02). No data on large RLS in patients with TOAST-defined cryptogenic events compared with other events were available from previous studies, but we found no evidence that the association was diminished in such cases. Of 41 patients with large RLS and cryptogenic transient ischaemic attack or non-disabling stroke in our study, 25 (61%) were aged older than 60 years, which extrapolates to 5951 patients per year in the UK (data from mid-2016). Interpretation Bubble-TCD was feasible in most older patients with transient ischaemic attack or non-disabling stroke, the association of RLS with cryptogenic events remained at older ages, and the population burden of PFO-associated events is substantial. Randomised trials of PFO closure at older ages are required and should be feasible

Age-specific sex-differences in cerebral blood flow velocity in relation to haemoglobin levels

Introduction: Cerebral blood flow (CBF) declines with age and abnormalities in CBF are associated with age-related cerebrovascular disease and neurodegeneration. Women have higher CBF than men, although this sex-difference diminishes to some extent with age in healthy subjects. The physiological drivers of these age/sex differences are uncertain, but might be secondary to age and sex-differences in haemoglobin (Hb) level. Hb levels are inversely correlated with CBF, are lower in women, and decline with age in men, but the interrelations between these factors have not been explored systematically either in healthy subjects or across the full age-range in patients with vascular risk factors. We aimed to determine the age-specific interrelations between sex, Hb, and CBF velocity in a large cohort of patients with cerebrovascular disease. Patients and methods: In patients with a recent transient ischaemic attack or minor stroke (Oxford Vascular Study) and no ipsilateral or contralateral stenosis of the carotid or intracranial arteries, we related peak-systolic velocity (PSV) and other parameters on transcranial Doppler ultrasound (TCD) of the middle cerebral artery to sex, age, Hb and vascular risk factors. Results: Of 958 eligible subjects (mean age/SD = 68.04/14.26, 53.2% male), younger women (age < 55 years) had higher CBF velocities than men (mean sex difference in PSV at age < 55 years = 16.31 cm/s; p < 0.001), but this difference declined with age (interaction p < 0.001), such that it was no longer significant at age 75–84 (∆PSV = 3.26 cm/s; p = 0.12) and was reversed at age ⩾ 85 (∆PSV = −7.42 cm/s; p = 0.05). These changes mirrored trends in levels of Hb, which were higher in men at age < 55 (∆Hb = 1.92 g/dL; p < 0.001), but steadily decreased with age in men but not in women (interaction p < 0.001), with no residual sex-difference at age ⩾ 85 (∆Hb = 0.12 g/dL; p = 0.70). There was an inverse correlation between Hb and PSV in both women and men (both p ⩽ 0.01), and the sex-difference in PSV at age < 55 was substantially diminished after adjustment for Hb (∆PSV = 6.92; p = 0.036; ∆PSV = 5.92, p = 0.13 with further adjustment for end-tidal CO2). In contrast, the sex difference in PSV was unaffected by adjustment for systolic and diastolic blood pressure, heart rate, and vascular risk factors (history of hypertension, diabetes, hyperlipidaemia and smoking). Discussion: CBF velocity is strongly correlated with Hb level at all ages, and sex-differences in CBF velocity appear to be explained in major part by age-related sex-differences in Hb

Better Explain Transformers by Illuminating Important Information

Transformer-based models excel in various natural language processing (NLP) tasks, attracting countless efforts to explain their inner workings. Prior methods explain Transformers by focusing on the raw gradient and attention as token attribution scores, where non-relevant information is often considered during explanation computation, resulting in confusing results. In this work, we propose highlighting the important information and eliminating irrelevant information by a refined information flow on top of the layer-wise relevance propagation (LRP) method. Specifically, we consider identifying syntactic and positional heads as important attention heads and focus on the relevance obtained from these important heads. Experimental results demonstrate that irrelevant information does distort output attribution scores and then should be masked during explanation computation. Compared to eight baselines on both classification and question-answering datasets, our method consistently outperforms with over 3\% to 33\% improvement on explanation metrics, providing superior explanation performance. Our anonymous code repository is available at: https://github.com/LinxinS97/Mask-LR

The Relationship Between Educational Achievement and Oral Health Status: A Systematic Review of Cross-Sectional Studies

Background: Oral health status significantly affects general health and quality of life, with mounting evidence suggesting a positive correlation between educational level and oral health outcomes. However, comprehensive synthesis of this relationship across diverse populations and healthcare systems remains limited. Objective: To systematically review and analyze the relationship between educational level and oral health status across global populations, providing evidence-based insights for health policy development and oral health improvement strategies. Methods: A systematic literature search was conducted using PubMed and The Cochrane Library databases from January 2007 to January 2025. Search terms included "oral health," "education level," "caries," "periodontosis," and "tooth loss." Cross-sectional studies examining the relationship between educational attainment and oral health outcomes were included. Study quality was assessed using the Agency for Healthcare Research and Quality 11-item checklist. Data extraction focused on correlations between educational level and dental caries, periodontal disease, and tooth loss across different populations and healthcare systems. Results: A total of 236 articles were identified, with 32 cross-sectional studies meeting inclusion criteria after systematic screening. The studies encompassed populations from both developed countries (Britain, United States, Germany, Denmark, Belgium, Finland) and developing nations (Chile, Egypt, India, Thailand, Colombia, Nigeria, China). Consistent evidence demonstrated that educational level was negatively correlated with the prevalence of dental caries, periodontal disease, and tooth loss across all examined populations. This inverse relationship persisted even in developed countries with established national public health insurance systems, indicating that educational gradients in oral health transcend healthcare access barriers. Conclusions: Educational level demonstrates a robust and consistent association with oral health outcomes across diverse global populations and healthcare systems. The universality of this relationship suggests that expanding educational opportunities represents a promising upstream intervention strategy for improving population oral health. These findings support the integration of educational advancement into comprehensive oral health promotion policies and highlight the potential for educational interventions to address oral health disparities at the population level

Temporal trends in the accuracy of hospital diagnostic coding for identifying acute stroke: a population-based study

Introduction: Administrative hospital diagnostic coding data are increasingly being used in identifying incident and prevalent stroke cases, for outcome audit and for ‘big data’ research. Validity of administrative coding has varied in previous studies, but little is known about the temporal trends of coding accuracy, which could bias analyses. Patients and Methods: Using all incident and recurrent strokes in a population-based cohort (Oxford Vascular Study/OXVASC) with multiple sources of ascertainment as the reference, we determined the temporal trends in sensitivity and positive predictive value of hospital diagnostic codes for identifying acute stroke from 2002 to 2017. Results: Of 1883 hospitalised strokes, 1341 (71.2%) were correctly identified by coding. Sensitivity of coding improved over time for all strokes (ptrend = 0.005) and for incident cases (ptrend = 0.002). Of 1995 apparent stroke admissions identified by International Classification of Disease-10 stroke codes (I60–I68), 1588 (79.6%) used the stroke-specific codes (I60–I61/I63–I64). Positive predictive value was higher with the use of specific codes (83.2% vs. 69.2% for all codes) and highest if combined with the first admission only (88.5%), particularly during more recent time periods (2014–2017 = 90.3%). Of 2254 OXVASC incident strokes, 833 (37.0%) were not hospitalised. Sensitivity of coding increased over time for non-disabling stroke (ptrend = 0.001), but not for disabling/fatal stroke (ptrend = 0.40). Conclusions: Although accuracy of hospital diagnostic coding for identifying acute strokes improved over the last 15 years, residual insensitivity supports linkage to other sources in large epidemiological studies. Moreover, differences in the time trends of coding sensitivity in relation to stroke severity might bias studies of trends in stroke outcome if only administrative coding is used

Ethnic Contrasts in Stroke Risk Factors and the Atrial Fibrillation Paradox in the United Kingdom: Population-Based Study and Meta-Analysis

Background and objectivesStudies in northern America report lower prevalence of atrial fibrillation (AF) in Black people than in White people despite higher vascular risk factor prevalence. However, it remains unclear whether these differences are driven by biology vs variations in health care access or alcohol use. We aimed to determine whether ethnic differences in AF persist in the United Kingdom, where the National Health Service provides equitable access to care, and whether they are robust to adjustment for deprivation and alcohol use and are also seen for covert paroxysmal AF on ambulatory screening.MethodsWe performed a systematic review of UK-based studies reporting AF and vascular risk factor prevalence across ethnic groups and pooled estimates by random-effects meta-analysis. Findings were validated in a prospective population-based cohort (Oxford Vascular Study, OxVasc) of patients with suspected TIA or stroke in Oxfordshire, United Kingdom (April 2002-March 2023), through logistic regression adjusted for deprivation and alcohol use, and in a subset of participants recruited after October 2010 who were systematically screened for left atrial dilatation and paroxysmal AF.ResultsAmong UK-based studies of patients with stroke, Black and Asian people had lower prevalence of AF (pooled OR, 95% CI, number of studies: 0.25, 0.20-0.32, n = 3; 0.37, 0.28-0.49, n = 6), alcohol consumption (0.42, 0.36-0.49, n = 2; 0.26, 0.13-0.49, n = 3), and smoking (0.70, 0.50-0.97, n = 2; 0.57, 0.44-0.74, n = 5), but higher rates of hypertension (1.95, 1.47-2.60, n = 3; 1.47, 1.02-2.12, n = 6) and diabetes (2.78, 2.40-3.22, n = 3; 4.15, 3.11-5.53, n = 6). In stroke-free populations, similar differences were observed, especially for AF (0.47, 0.12-1.86, n = 2; 0.34, 0.15-0.74, n = 5). Among 7,297 OxVasc participants (47.4% women, 71.0 ± 15.5 years, 335 non-White), AF prevalence was lower in non-White people even after adjustment for age, sex, vascular risk factors, deprivation, and alcohol consumption (adjusted odds ratio [OR] = 0.52, 0.32-0.82, p = 0.005). Among 2,221 participants with routine cardiac investigation, non-White people had lower prevalence of paroxysmal AF (2.3% vs 9.1%, OR = 0.24, 0.07-0.75, p = 0.004) or atrial dilatation (17.7% vs 27.2%, OR = 0.58, 0.34-0.99, p = 0.04).DiscussionAn AF paradox exists in ethnic minority groups in the United Kingdom, for permanent and paroxysmal AF, which is independent of vascular risk factors, deprivation, and alcohol consumption, suggesting different biological susceptibilities

NLPBench: Evaluating Large Language Models on Solving NLP Problems

Recent developments in large language models (LLMs) have shown promise in enhancing the capabilities of natural language processing (NLP). Despite these successes, there remains a dearth of research dedicated to the NLP problem-solving abilities of LLMs. To fill the gap in this area, we present a unique benchmarking dataset, NLPBench, comprising 378 college-level NLP questions spanning various NLP topics sourced from Yale University's prior final exams. NLPBench includes questions with context, in which multiple sub-questions share the same public information, and diverse question types, including multiple choice, short answer, and math. Our evaluation, centered on LLMs such as GPT-3.5/4, PaLM-2, and LLAMA-2, incorporates advanced prompting strategies like the chain-of-thought (CoT) and tree-of-thought (ToT). Our study reveals that the effectiveness of the advanced prompting strategies can be inconsistent, occasionally damaging LLM performance, especially in smaller models like the LLAMA-2 (13b). Furthermore, our manual assessment illuminated specific shortcomings in LLMs' scientific problem-solving skills, with weaknesses in logical decomposition and reasoning notably affecting results