BACKGROUND:Evidence-based medicine(EBM) is widely used across various disciplines globally. However, in general practice, we need a more person-centered approach rather than a disease-centered one. The differentiation of evidence-based general practice (EBGP) is essential. This scoping review aims to extract a potential definition of EBGP and uncover its characteristics in implementation. METHODS:We conducted a comprehensive search across three databases - PubMed, Embase, and Cochrane Library - spanning from the inception of these databases to September 24, 2023. The inclusion criteria encompassed studies focusing on EBM in general practice, involving general practitioners as study participants, and reporting any aspects related to providing evidence-based care. Our screening process involved evaluating titles, abstracts, and full texts to extract definitions and characteristics from all relevant records discussing EBGP. These identified characteristics were then categorized and thematically grouped following the guidelines outlined in the Consolidated Framework for Implementation Research (CFIR). RESULTS:We initially retrieved 20,263 records from the original search. Among these, 40 records aligned with our inclusion criteria. The majority of these records took the form of reviews, qualitative studies, comments, cross-sectional surveys, or editorials. From these 40 studies, we extracted 33 unique characteristics of EBGP. Subsequently, these characteristics were thematically grouped into 19 categories, which fell under five overarching themes: evidence base, GP's role, person's role, care process, and care environment. CONCLUSIONS:We propose the following definition for EBGP: Applying a combination of the best available evidence, integrated within the inner and outer contexts of general practice, person preferences, and the expertise of the general practitioner to formulate shared, person-centered decisions aimed at holistic care. This definition provides a solid foundational framework for the development of EBGP guidelines and policies. REGISTRATION NUMBER:https://doi.org/10.17605/OSF.IO/2UNX7 .

AimsStroke is a leading cause of disability and death worldwide, with family support playing a pivotal role in the recovery process. This study aimed to evaluate the association between family support levels and the short-term functional prognosis of patients with acute ischemic stroke.Materials and methodsA total of 124 patients admitted to the Department of Neurology at Second People’s Hospital of Neijiang were included, with an average age of 68 years. Family support was assessed by the Family Support Questionnaire (FSQ) and the Family APGAR Questionnaire. The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0–2, assessed 6 months after discharge. Secondary outcomes included lifestyle behaviors and medication adherence. Multivariate logistic and linear regression were used to analyze the association between family support and functional independence.ResultsCompared to patients with FSQ of 0–5, FSQ of 10–15 were significantly associated with greater functional independence (OR: 1.666, 95% CI 1.236–2.214, P = 0.005) and mRS changes between baseline and follow-up at 6-months (β = −1.001, 95% CI −1.418 to −0.584, P < 0.001). However, the APGAR score was not significantly associated with functional recovery (P > 0.05). Lifestyle improvements were noted post-stroke, but no significant differences were observed among different family support levels (P > 0.05). Higher FSQ scores and APGAR scores were associated with better medication adherence (P < 0.001).ConclusionThe study concludes family support is positively associated with functional recovery and medication adherence, further studies are needed to clarify whether improved medication adherence mediates this association.

Objective:Liver fat content (LFC) and hepatic fibro-inflammation (HFI) accumulation are the primary pathological manifestation of steatohepatitis. The association between intake of sugary beverages (SBs), including artificially-sweetened beverages (ASB), sugar-sweetened beverages (SSB), and natural juices (NJs), and LFC or HFI remains unclear. Methods:The study included 25,885 participant who completed at least one online dietary assessment and magnetic resonance imaging. LFC and HFI were quantified using the liver proton density fat fraction (PDFF) and iron-corrected T1 (cT1). Results:Compared to those without ASB and SSB intake, the arithmetic mean difference (AMD) of PDFF was 0.15 (95% Cl: 0.06 to 0.24) and 0.21 (95% Cl, 0.12 to 0.29), and the AMD of cT1 was 3.86 (95% CI, 1.26 to 6.79) and 2.43 (95% CI, 1.31 to 3.57) in individuals with ≥1 serving/d, respectively. Individuals with 0-1 serving/d had lower PDFF (AMD: -0.10 95%Cl: -0.19 to -0.01) than those without NJs intake. In Quantile G-computation models, SSB and ASB contributed most in the AMD of PDFF (54.7%) and cT1 (53.1%), respectively. When replacing ASB and SSB with water, the progress of PDFF was improved. Conclusion:Artificially-sweetened beverages and SSB intake were positively associated with LFC and HFI, and moderate NJs intake was slightly negatively associated with LFC but not HFI.

Breast cancer is now the most common malignancy among females. Numerous highly effective small-molecule inhibitors, such as tamoxifen and fulvestrant, have received clinical approval, significantly enhancing the therapeutic landscape of breast cancer. However, the emergence of drug resistance in some patients presents an unmet clinical need. Identifying resistance-related targets has been a key therapeutic strategy in combating drug-resistant tumors. Studies investigating the molecular characteristics and resistance mechanisms of breast cancer have unveiled novel targets, including cell cycle checkpoint molecules, breast cancer stem cell-related molecules, and anti-apoptotic proteins. Relevant small-molecule inhibitors have shown promising potential in overcoming drug-resistant breast cancer in both preclinical and clinical trials. In this review, we evaluate the resistance mechanisms of available targeted inhibitors for breast cancer and summarize innovative targeted strategies with the potential to overcome resistance, guided by clinical research.

BACKGROUND/OBJECTIVES:The term metabolic dysfunction-associated steatotic liver disease (MASLD) reflects the key role of cardiometabolic dysfunction in steatotic liver disease. We aim to assess the association between cardiometabolic dysfunction burden and mortality outcomes in MASLD. METHODS:Participants with MASLD were selected from the National Health and Nutrition Examination Survey (NHANES) database between 1999 and 2018. The mortality outcomes of participants with different numbers of cardiometabolic risk factors were compared by using Kaplan-Meier curves and Cox regression analysis. RESULTS:This study included 9,017 participants with MASLD (4,613 men and 4,404 women, median age 49.0). With a median 115-month follow-up, 1,447 all-cause deaths and 407 cardiovascular-specific deaths were observed. Multivariate regression analysis showed that participants with five cardiometabolic risk factors had significantly increased all-cause mortality risk compared to those with one risk factor (adjusted hazard ratio [aHR] = 3.57, 95% confidence interval [CI]: 2.04-6.24, P < 0.001). Similarly, the cardiovascular mortality risk was markedly higher for participants with five risk factors (aHR = 7.72, 95% CI: 1.89-31.53, P = 0.004). Among participants with the same number of cardiometabolic risk factors, those with blood glucose or blood pressure abnormalities showed the lowest survival rates than other subgroups. Besides, participants with younger ages were more vulnerable to the harmful prognostic effects of cardiometabolic dysfunction burden on the mortality risks. CONCLUSIONS:The MASLD population with high cardiometabolic dysfunction burdens exhibits increased mortality risk. Assessing cardiometabolic dysfunction, particularly abnormalities in blood glucose and blood pressure, is crucial for effective management in this population.

BACKGROUND:Physical activity (PA) plays a crucial protective role in the overall health outcomes of individuals with chronic obstructive pulmonary disease. However, accurate recommendations for amount and categories of PA are still unclear for individuals with impaired pulmonary function (PF) in community environments. Thus, this study aims to investigate the independent and joint relationships of PA and PF with mortality. METHODS:In a prospective UK Biobank cohort study, PA was collected by touchscreen questionnaires, and metabolic equivalents of task (MET)-minutes/week of total exercise was calculated by walking plus moderate-intensity PA plus vigorous-intensity PA. According to the standard of the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) 2024, GOLD stage 1, GOLD stage 2 and GOLD stages 3-4 were classified as mild, medium and severe PF impairment, respectively. Cox regression was established to analyse the association between PA, PF and the risk of all-cause mortality. RESULTS:A total of 354 572 participants were included with mean age of 56.0 years. Compared with lowest quintile of PA, highest quintile of PA was associated with lower risk of mortality in individuals with normal PF (HR=0.828), mild (HR=0.768), medium (HR=0.697) and severe PF impairment (HR=0.588). Generally, PF impairment related to mortality, and this relationship was independent of PA (p<0.05), except for individuals adhering to third quintile (1378-2340 MET-minutes/week) of PA (p>0.05). In joint analysis, more severe PF impairment and lower PA had a dose-response relationship with mortality. Moreover, highest quintile of walking/total exercise was associated with elevated mortality, while adhering to high level of vigorous-intensity PA/total exercise ratio achieved lowest risk of mortality, regardless of individuals with or without PF impairment. CONCLUSIONS:There were significant independent and joint relationships of lower PA and PF impairment with the elevated risk of mortality. However, engaging in appropriate total exercise weekly can mitigate adverse effects associated with mild PF decline.

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Aims: To investigate the relationship between cardiorespiratory fitness (CRF) and liver fat content (LFC) in community-based participants and highlight their relationship in people with different body mass indices (BMIs). Materials and Methods: Using UK Biobank data, CRF was estimated with bicycle ergometer fitness testing and was evaluated based on physical work capacity at 75% maximum heart rate (PWC75%). LFC was quantified through liver proton density fat fraction (PDFF) on magnetic resonance imaging. Multivariate linear regression models were used to analyse the associations of CRF and BMI with absolute reduction and percentage change in PDFF (%). Results: In total, 5765 participants with a mean age of 55.57 years and a median (range) follow-up of 10.7 (4.0-17.7) years were included. Compared with the lowest PWC75% tertile, the absolute reduction and percentage change in PDFF in the highest PWC75% tertile were -0.450 (95% confidence interval [CI] -0.699 to -0.192) and -4.152 (95% CI -6.044 to -2.104), respectively. These associations were independent of BMI, and individuals with obesity and normal weight had the largest absolute reduction and percentage change in LFC, respectively (p for interaction <0.001). Joint analysis showed that PWC75% and BMI had a negative dose-response relationship with PDFF. These associations were consistent in different sex and age subgroups (p for interaction >0.05). Conclusions: There was a significant negative association between CRF and LFC, and this association was independent of BMI. The results of this study strongly recommend improving CRF to mitigate LFC.

BACKGROUND:Although healthy sleep patterns have been linked to a lower risk of cardiovascular disease in earlier research, it is unclear how beneficial they are for venous thromboembolism (VTE). AIM:This research aimed to examine the correlation between sleep patterns, genetic susceptibility, and VTE. METHODS:In the UK Biobank cohort, healthy sleep behaviors were defined as early chronotype, 7-8 hours of sleep each day, no snoring, infrequent insomnia, and infrequent daytime sleepiness. Each of the five criteria was given 1 point, creating a healthy sleep score ranging from 0 to 5. Cox proportional hazards regression models were utilized to examine the associations between genetic susceptibility, healthy sleep score and VTE. RESULTS:The UK Biobank study included 384,758 participants aged 56.6 ± 8.0 years. After a median of 11.9 years of follow-up, 8,885 (2.3%) participants were diagnosed with VTE. A healthy sleep score inversely affected VTE risk. For participants with a score of 5, the hazard ratio of VTE was 0.813 (95% confidence interval: 0.758-0.873, P<0.001) compared to those with a score ≤2. Early chronotype, sleeping 7-8 hours each day, infrequent insomnia, and infrequent daytime sleepiness were significantly associated with a 7.9%, 8.3%, 5.1%, and 20.7% lower risk of VTE, respectively. In addition, the correlation between sleep pattern and the incidence of VTE was consistent, regardless of genetic susceptibility (P for interaction = 0.366). CONCLUSIONS:Our secondary analysis of a large-scale prospectively gathered registry revealed that individuals with a healthy sleep pattern are significantly correlated with lower risk of developing VTE, irrespective of genetic susceptibility.

Aldosterone synthase (CYP11B2) is the rate-limiting enzyme in aldosterone production. In recent years, CYP11B2 has become an appealing target for treating conditions associated with excess aldosterone, such as hypertension, heart failure, and cardiometabolic diseases. Several small-molecule inhibitors of CYP11B2 have demonstrated efficacy in both preclinical studies and clinical trials. Among them, the tetrahydroisoquinoline derivative Baxdrostat has entered clinical trial phases and demonstrated efficacy in treating patients with hypertension. However, the high homology (>93%) between CYP11B2 and steroid-11β-hydroxylase (CYP11B1), which catalyzes cortisol production, implies that insufficient drug specificity can lead to severe side effects. Developing selective inhibitors for CYP11B2 remains a considerable challenge that requires ongoing attention. This review summarizes recent research progress on small-molecule inhibitors targeting CYP11B2, focusing on structure-activity relationships (SAR) and structural optimization. It discusses strategies for enhancing the specificity and inhibitory activity of inhibitors, while also exploring potential applications and future prospects for CYP11B2 inhibitors, providing a theoretical foundation for developing the new generation of CYP11B2-targeted medications.

BackgroundCardiometabolic multimorbidity (CMM) and aging are increasing public health concerns. This prospective study used UK Biobank cohort to investigate the relationship between biological aging and the trajectory of CMM to dementia and mortality.MethodsCMM is the coexistence of at least two cardiometabolic diseases (CMD), including stroke, ischemic heart disease, and diabetes. Biological age was calculated using the KDM-BA and PhenoAge algorithms. Accelerated aging indicated biological age advances more rapidly than chronological age.ResultsThe study included 415,147 individuals with an average age of 56.5 years. During the average 11-year follow-up period, CMD-free individuals with accelerated aging had a significantly greater risk of CMD (KDM-BA, HR 1.456; PhenoAge, HR 1.404), CMM (KDM-BA, HR 1.952; PhenoAge, HR 1.738), dementia (KDM-BA, HR 1.243; PhenoAge, HR 1.212), and mortality (KDM-BA, HR 1.821; PhenoAge, HR 2.047) in fully-adjusted Cox regression models (p < 0.05 for all). Accelerated aging had adjusted HRs of 1.489 (KDM-BA) and 1.488 (PhenoAge) for CMM, 1.434 (KDM-BA) and 1.514 (PhenoAge) for dementia, and 1.943 (KDM-BA) and 2.239 (PhenoAge) for mortality in participants with CMD at baseline (p < 0.05 for all). CMM significantly mediated accelerated aging’s indirect effects on dementia by 13.7% (KDM-BA, HR) and 21.6% (PhenoAge); those on mortality were 4.7% (KDM-BA) and 5.2% (PhenoAge). The population attributable-risk of Life’s Essential 8 score (≥80 vs. <80) were 0.79 and 0.43 for KDM-BA and PhenoAge accelerated aging, respectively.ConclusionBiological aging involves the entire trajectory of CMM from a CMD-free state to CMD, to CMM, and ultimately to dementia and death. Life’s Essential 8 may be a potential target to counter age acceleration.

Objectives To establish deep learning models for malignancy risk estimation of sub-centimeter pulmonary nodules incidentally detected by chest CT and managed in clinical settings. Materials and methods Four deep learning models were trained using CT images of sub-centimeter pulmonary nodules from West China Hospital, internally tested, and externally validated on three cohorts. The four models respectively learned 3D deep features from the baseline whole lung region, baseline image patch where the nodule located, baseline nodule box, and baseline plus follow-up nodule boxes. All regions of interest were automatically segmented except that the nodule boxes were additionally manually checked. The performance of models was compared with each other and that of three respiratory clinicians. Results There were 1822 nodules (981 malignant) in the training set, 806 (416 malignant) in the testing set, and 357 (253 malignant) totally in the external sets. The area under the curve (AUC) in the testing set was 0.754, 0.855, 0.928, and 0.942, respectively, for models derived from baseline whole lung, image patch, nodule box, and the baseline plus follow-up nodule boxes. When baseline models externally validated (follow-up images not available), the nodule-box model outperformed the other two with AUC being 0.808, 0.848, and 0.939 respectively in the three external datasets. The resident, junior, and senior clinicians achieved an accuracy of 67.0%, 82.5%, and 90.0%, respectively, in the testing set. The follow-up model performed comparably to the senior clinician. Conclusion The deep learning algorithms solely mining nodule information can efficiently predict malignancy of incidental sub-centimeter pulmonary nodules. Clinical relevance statement The established models may be valuable for supporting clinicians in routine clinical practice, potentially reducing the number of unnecessary examinations and also delays in diagnosis. Key Points • According to different regions of interest, four deep learning models were developed and compared to evaluate the malignancy of sub-centimeter pulmonary nodules by CT images. • The models derived from baseline nodule box or baseline plus follow-up nodule boxes demonstrated sufficient diagnostic accuracy (86.4% and 90.4% in the testing set), outperforming the respiratory resident (67.0%) and junior clinician (82.5%). • The proposed deep learning methods may aid clinicians in optimizing follow-up recommendations for sub-centimeter pulmonary nodules and may lead to fewer unnecessary diagnostic interventions.

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is a newly defined condition encompassing hepatic steatosis and metabolic dysfunction. However, the relationship between MAFLD and multi-system diseases remains unclear, and the time-dependent sequence of these diseases requires further clarification.MethodsAfter propensity score matching, 163,303 MAFLD subjects and 163,303 matched subjects were included in the community-based UK Biobank study. The International Classification of Diseases, Tenth Revision (ICD-10), was used to reclassify medical conditions into 490 and 16 specific causes of death. We conducted a disease trajectory analysis to map the key pathways linking MAFLD to various health conditions, providing an overview of their interconnections.ResultsParticipants aged 59 (51-64) years, predominantly males (62.5%), were included in the study. During the 12.9-year follow-up period, MAFLD participants were found to have a higher risk of 113 medical conditions and eight causes of death, determined through phenome-wide association analysis using Cox regression models. Temporal disease trajectories of MAFLD were established using disease pairing, revealing intermediary diseases such as asthma, diabetes, hypertension, hypothyroid conditions, tobacco abuse, diverticulosis, chronic ischemic heart disease, obesity, benign tumors, and inflammatory arthritis. These trajectories primarily resulted in acute myocardial infarction, disorders of fluid, electrolyte, and acid-base balance, infectious gastroenteritis and colitis, and functional intestinal disorders. Regarding death trajectories of MAFLD, malignant neoplasms, cardiovascular diseases, and respiratory system deaths were the main causes, and organ failure, infective disease, and internal environment disorder were the primary end-stage conditions. Disease trajectory analysis based on the level of genetic susceptibility to MAFLD yielded consistent results.ConclusionsIndividuals with MAFLD have a risk of a number of different medical conditions and causes of death. Notably, these diseases and potential causes of death constitute many pathways that may be promising targets for preventing general health decline in patients with MAFLD.

Dermatological toxicities are well-recognized immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) use. Corticosteroids are considered the first-line therapy for grade 3 or grade 4 skin irAEs, but long-term usage of corticosteroids may abolish the effect of ICIs. Multiple antitumor therapies might be an influencing factor in an increased incidence of skin irAEs. The safety and prognostic value in resuming ICIs after irAEs has been inconsistently reported, especially the severe skin irAE. We report a case of a 75-year-old man with non-small cell lung cancer (NSCLC) and prostate cancer with a Stevens-Johnson syndrome (SJS)-like eruption. The severe rash might have been induced by resuming pembrolizumab was successfully treated with a combination of corticosteroids, gamma globulin, and immunosuppressants. Early detection of dermatologic toxicity is crucial, especially for patients receiving multiple antitumor treatments. We should treat ICI resumption seriously after skin irAE.

IntroductionAtrial fibrillation (AF) is a challenging cardiovascular disease worldwide. Wearable electrocardiograph devices (WEDs) have great potential to improve the detection rate of AF in primary care. However, the factors that influence general practitioners’ (GPs) perception and acceptance of WEDs are not well understood. To identify factors that influence the intention of GPs to utilize WEDs in a clinical setting to screen patients for AF.MethodThe research hypotheses and questionnaire items were designed and developed based on the unified theory of acceptance and technology (UTAUT) framework. We used stratified sampling and obtained the data through an online survey. Structural equation modeling was used to analyze the collected data.Results: A total of 1,004 valid questionnaires from GPs across Sichuan province in China were collected. Three factors increased GPs’ intention to utilize WEDs to screen patients for AF, including performance expectancy (β = 0.121, p = 0.004), social influence (β = 0.356, p < 0.001), and price perception (β = 0.587, p < 0.001). Perception risk (β = −0.059, p < 0.001) decreased usage intention, while effort expectancy (β = −0.079, p = 0.155) and facilitating conditions (β = −0.014, p = 0.868) did not affect usage intention. Gender (β = −0.022, p = 0.179), age (β = 0.006, p = 0.699), education level (β = −0.22, p = 0.184) and training (β = 0.007, p = 0.69) were not significantly correlated with usage intention, and these four factors had no moderating effect on the path coefficients.DiscussionGPs’ intention to utilize WEDs is affected by performance expectancy, price perception, perception risk and social influence. Researcher should improve the usability and perception of WEDs for screening and carry out studies to provide high-quality evidence for the security and efficacy of wearable devices.

The "do not eat me" signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin ⅡA on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Both of them weaken the ability of macrophages to engulf tumor cells. Blocking the mutual recognition between CD47-SIRPα or CD24-Siglec10 using large molecular proteins or small molecular drugs represents a promising avenue for tumor immunotherapy. Doing so can inhibit signal transduction and enhance macrophage clearance rates of cancer cells. In this paper, we summarize the characteristics of the drugs that affect the "do not eat me" signaling pathway via classical large molecular proteins and small molecule drugs, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways. We expect it will offer insight into the development of new drugs centered on blocking the "do not eat me" signaling pathway.

The survival, motility and capacitation of sperm in the female reproductive tract are important prerequisites for fertilization. The uterus is the main location for sperm capacitation. One of the most important physiological functions of the endometrial epithelium is to create a suitable uterine environment under the regulation of ovarian hormones, to ensure sperm capacitation. The composition of uterine fluid directly affects sperm capacitation. Fructose is an important component of semen that supports sperm viability and motility. Aldose reductase, a rate-limiting enzyme in the polyol pathway, metabolizes sorbitol and fructose, thereby supplying cells with necessary energy for functional activities. Existing studies have reported the presence aldose reductase in the endometrium, leading us to hypothesize that its expression in endometrial epithelium might promote sperm capacitation by maintaining the uterine environment. Yet, the mechanism of regulation has not been clarified. In this study, we investigated the expression of aldose reductase in mouse endometrial epithelium and its potential role in sperm capacitation. We initially investigated the periodic characteristics of glucose, fructose and sorbitol in uterine fluid. We then studied the temporal and spatial characteristics of aldose reductase in the endometrial epithelium. Next, we examined the effect of aldose reductase on glucose, fructose and sorbitol in uterine fluid. Finally, we explored the effect of aldose reductase on sperm capacitation and fertilization. The results showed that glucose and fructose content in uterine fluid and the expression of aldose reductase fluctuated periodically during physiological periods. Inhibition of aldose reductase in the endometrial epithelium interfered with sperm capacitation and fertilization by reducing the fructose levels in the uterine fluid. To conclude, the aldose reductase-mediated polyol pathway in endometrial epithelial cells is essential to maintain an appropriate fructose environment in the uterine fluid for sperm capacitation and fertilization.

The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.