BMC Medicine最新文献

Background: Low-density lipoprotein cholesterol (LDL-C) is a well-recognized risk factor for cardiovascular diseases. However, several clinical studies demonstrated an inverse association between LDL-C and mortality risk in patients with acute myocardial infarction (AMI), known as the lipid paradox. This study aims to investigate the potential impact of inflammation on the association between LDL-C levels and mortality risks.

Methods: A total of 5244 patients with AMI from a large nationwide prospective cohort were included in our analysis. Patients were stratified according to LDL-C quartiles. The primary outcome was all-cause mortality, and the secondary endpoint was cardiac mortality. High-sensitive C-reactive protein (hsCRP) > 3 mg/L was defined as high inflammatory risk.

Results: During a median follow-up of 2.07 years, 297 mortality events (5.5%) and 227 cardiac mortality events (4.2%) occurred. Patients in the lowest LDL-C quartile had the highest incidence of all-cause mortality (7.3%) and cardiac mortality (5.8%). A U-shaped association between LDL-C levels and mortality risk was observed after multivariable adjustment, which persisted only in patients with high hsCRP levels. In contrast, a linear association between LDL-C and mortality risk was shown in patients with low hsCRP levels.

Conclusions: AMI patients with lower LDL-C levels had a higher risk of mortality. However, this association was only observed in those with high inflammatory risk. In contrast, the relationship between LDL-C and mortality risk was linear in patients with low inflammatory risk. This suggests the importance of considering inflammation when managing LDL-C levels in AMI patients.

Background: The importance of routine hypertension screening in children and adolescents is now well recognized. However, it is often undiagnosed in clinical practice, partly due to the reliance on a complex blood pressure (BP) percentile-based table with hundreds of cutoffs by age, sex, and height.

Main text: Many studies have explored simplified tools for screening hypertension in children and adolescents, such as simplified formulas, simplified BP tables by age and sex group, by age group, or by height group, and the BP to height ratio. Nevertheless, validation studies have demonstrated that these simplified tools are prone to yielding many false-positive cases or remain inconvenient to use in primary pediatric care settings and large-scale screening surveys. To address this issue, we propose adopting static BP cutoffs of 120/80 mmHg for children aged 6-12 years and 130/80 mmHg for adolescents aged 13-17 years to simplify the definition of hypertension. Our proposed static BP cutoffs have shown comparable performance to the complex BP percentile-based table in predicting subclinical cardiovascular damage in both childhood and adulthood.

Conclusions: We recommend using static BP cutoffs (120/80 mmHg for children and 130/80 mmHg for adolescents) to facilitate the screening of pediatric hypertension in clinical practice, thereby bridging the gap between perception and action.

Background: Functional mitral regurgitation (MR) is a common form of mitral valve dysfunction that often persists even after surgical intervention, requiring reoperation in some cases. To advance our understanding of the pathogenesis of functional MR, it is crucial to characterize the cellular composition of the mitral valve leaflet and identify molecular changes in each cell subtype within the mitral valves of MR patients. Therefore, we aimed to comprehensively examine the cellular and molecular components of mitral valves in patients with MR.

Methods: We conducted a single-cell RNA sequencing (scRNA-seq) analysis of mitral valve leaflets extracted from six patients who underwent heart transplantation. The cohort comprised three individuals with moderate-to-severe functional MR (MR group) and three non-diseased controls (NC group). Bioinformatics was applied to identify cell types, delineate cell functions, and explore cellular developmental trajectories and interactions. Key findings from the scRNA-seq analysis were validated using pathological staining to visualize key markers in the mitral valve leaflets. Additionally, in vitro experiments with human primary valvular endothelial cells were conducted to further support our results.

Results: Our study revealed that valve interstitial cells are critical for adaptive valve remodelling, as they secrete extracellular matrix proteins and promote fibrosis. We discovered an abnormal decrease in a subpopulation of FABP4 (fatty acid binding protein 4)-positive proliferating valvular endothelial cells. The trajectory analysis identifies this subcluster as the origin of VECs. Immunohistochemistry on the expanded cohort showed a reduction of FABP4-positive VECs in patients with functional MR. Intervention experiments with primary cells indicated that FABP4 promotes proliferation and migration in mitral valve VECs and enhances TGFβ-induced differentiation.

Conclusions: Our study presented a comprehensive assessment of the mitral valve cellular landscape of patients with MR and sheds light on the molecular changes occurring in human mitral valves during functional MR. We found a notable reduction in the proliferating endothelial cell subpopulation of valve leaflets, and FABP4 was identified as one of their markers. Therefore, FABP4 positive VECs served as proliferating endothelial cells relates to functional mitral regurgitation. These VECs exhibited high proliferative and differentiative properties. Their reduction was associated with the occurrence of functional MR.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of cancer patients, but the emergence of ICI-related endocrinopathies (IREs) has introduced new clinical challenges. Despite worldwide recognition of these adverse effects, data from the Middle East is scarce.

Methods: This retrospective-observational study included adult cancer patients who received at least one dose of ICI between January 2015 and January 2023. Descriptive statistics and multivariable regression (MVR) models were applied to delineate the incidence and clinical impact of IREs.

Results: The median age of 649 included patients was 55 years, with male preponderance (70.7%). The incidence of IREs was 26.7%, dominated by primary hypothyroidism (62.4%), insulin deficiency (15%), and primary hyperthyroidism (13.9%). Pembrolizumab (62%) was the most utilized ICI among the study cohort, followed by nivolumab (23.7%), atezolizumab (12.5%), durvalumab (0.9%), avelumab (0.6%) and ipilimumab (0.1%). The mortality rates in the cohort and the IRE subgroup were 43.4% and 42.2%. MVR revealed age (OR 1.02, 95% CI (1.003-1.03), P = 0.02), pre-ICI white-cell (WBC) count (OR 0.94, 95% CI (0.89-0.99), P = 0.04), pembrolizumab (OR 2.6, 95% CI (1.05-6.3), P = 0.04), and nivolumab use (OR 2.6, 95% CI (1.04-6.6), P = 0.04) as significant predictors of IREs. After MVR, factors influencing mortality in the subgroup with IREs included a higher age (OR 1.1, 95% CI 1.04-1.2, P = 0.001) and platelet-to-lymphocyte ratio (OR 1.004, 95% CI 0.7-1.4, P = 0.006).

Conclusions: This first extensive Middle Eastern and South Asian cohort reported a higher-than-previously known incidence of IREs. Hypothyroidism, insulin deficiency, and hyperthyroidism were the commonest IREs, with pembrolizumab being the commonest ICI. IRE development was associated with higher age, a low WBC count, pembrolizumab, and nivolumab use. The development of IREs did not seem to influence mortality. Further research on IREs is imperative to optimize management guidelines in the era of precision medicine.

Background: Recent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial.

Methods: In this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms.

Results: This study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1-4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high "ABC transporters" signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes.

Conclusions: Adding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1-4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.

Background: Exposure to illicit substances during pregnancy may have long-term impacts on children's neurodevelopment. This study explores subsequent risks for intellectual disability, autistic disorders, and attention deficit and hyperactivity disorders in children born to mothers exposed to illicit substances before or during pregnancy.

Methods: We identified women with illicit drug use by linking the police records from the "Substance Abuse Control Databases" and Taiwan Birth Registration and Birth Notification records from 2004 to 2014. Children whose mothers that had exposed to illicit substances during pregnancy identified from the police records were the "substance-exposed cohort." A 1:1 ratio exact-matched comparison cohort based on child's gender, child's birth year, mother's birth year, and child's first use of the health insurance card, as well as a "propensity score (PS)-matched" comparison cohort of children born by substance-unexposed mothers, was established. Multivariate Cox regression analyses with competing risk models were performed.

Results: Higher incidences of intellectual disability (adjusted hazard ratio (aHR) = 2.41, 95% confidence interval (CI): 1.15-5.03) and attention deficit and hyperactivity disorder (ADHD) (aHR = 2.35, 95% CI: 1.63-3.28) were found in children prenatally exposed to illicit substances during pregnancy compared to exact-matched non-exposed cohorts. Adjusted risks of ADHD were significantly higher in mothers exposed to substances during pregnancy (aHR = 1.77 (1.42-2.21)) and before pregnancy (aHR = 1.43 (1.14-1.80)) compared to PS-matched unexposed cohorts after adjusting for covariates.

Conclusions: This is one of the first studies using large population-based data linked to criminal records to reveal increased risks of intellectual disability and ADHD in children with prenatal exposure to illicit substances compared to matched unexposed controls. Our results also highlight the importance of preventive measures and interventions for the well-being of both the mother and the child.

Background: Evidence indicates that neurodivergent (ND) populations may be more at risk of experiencing adverse childhood experiences (ACEs), compared to neurotypical (NT) populations. However, this evidence has typically not examined a comprehensive set of ACEs and has only included ND individuals on the basis that they have a diagnosis. Very little research has examined the impacts of ACEs on negative adulthood outcomes for ND populations. The current study aimed to examine the associations between neurodivergence and experiences of ACEs, and the impact of being ND and experiencing ACEs on health, wellbeing, and criminal justice outcomes.

Methods: From November 2023 to April 2024, a household survey using representative sampling was undertaken with 5395 residents of an English region aged 18 + years. Neurodivergence status was measured using one self-report item. Nine ACEs were measured using validated self-report items. Outcome measures included: poor general health, low mental wellbeing, ever being arrested, and ever being incarcerated. Multinomial regression models were used to examine relationships between neurodivergence status and ACEs. Binary logistic regression models were used to examine independent relationships between neurodivergence status and ACE count and each outcome measure. Generalised linear models with an estimated marginal means function were used to estimate the increased risk of each outcome for different combinations of neurodivergence and ACE count status (NT less than four ACEs (reference group), NT 4 + ACEs, ND less than four ACEs, ND 4 + ACEs).

Results: A higher proportion of ND individuals experienced each ACE type than NT individuals. While controlling for sociodemographics, ND individuals were more likely to experience a greater number of ACEs than their NT peers. While controlling for sociodemographics, each outcome measure was more likely amongst those who were ND, and each outcome measure except for poor general health was more likely amongst those with higher ACE counts.

Conclusions: The combination of being ND and experiencing ACEs could additively increase risks of experiencing poor wellbeing and criminal justice outcomes by a greater extent than expected. Preventing and responding to ACEs in ND populations should be a priority to reduce risks of poor health, wellbeing, and criminal justice outcomes in this population.

The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic dysglycemia is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners.

Background: Globally, dementia care is under strain. Rising rates across ageing populations, coupled with overstretched health and care systems, mean that people living with dementia and their carers are missing out on crucial support. Addressing dementia care is a key priority for the UK government. This has led to a period of care transformation, including the implementation of new dementia support services across integrated care systems (ICS). However, little is known about how these new services work. This evaluation identifies how a dementia care coordinator service, implemented in the largest ICS in England, works for people living with dementia, their carers and the workforce.

Methods: A realist evaluation using mixed methods was carried out between 2022 and 2024. This involved a repeat survey with dementia care coordinators, carried out a year apart, alongside 57 interviews with coordinators, service managers, healthcare practitioners, people living with dementia and their carers. A realist logic of analysis was applied across all data sets.

Results: Three broad concepts were identified including (1) workforce design and organisational culture, (2) meeting the needs of people living with dementia and their carers and (3) connecting to services and integrating care. A total of 23 context-mechanism-outcome configurations (CMOCs) across these concepts highlighted that whilst tensions exist between the service and wider system, dementia care coordinators ultimately act as bridge builders, connecting people to much-needed support. However, services like this could become a victim of their own success due to increasing caseloads and the risk of staff burnout.

Conclusions: The dementia care coordinator service is capable of supporting people who are pre- and post-dementia diagnosis despite the care system being under strain. This is a direct result of the bridge building work of the dementia care coordinators. Our findings support evidence-based recommendations for those wanting to implement and sustain a system-wide service and provide evidence for policy makers to consider increased funding for this service nationwide.

Background: Two phenotypes of insomnia disorder (ID) have been identified based on objective total sleep duration (TST): one with short sleep duration (ISSD) and another with normal sleep duration (INSD). Recent proposals suggested that insomnia with objective short-sleep duration (TST < 7 h) is associated with impaired inhibitory function, leading to a dysregulation of cortical inhibition, which may underlie its prevalence. This study investigated the status of impaired response inhibition in these two phenotypes and examined the potential different effect of response inhibition training on these two phenotypes.

Methods: Twenty-two healthy controls (HC) and eighty-one patients with ID were recruited, with IDs further categorized into ISSD and INSD (with TST ≥ 7 h). Clinical behavior measures, including the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Pre-sleep Arousal Scale (PSAS), objective sleep characteristics assessed by all-night sleep electroencephalography, and the accuracy of NoGo trials in the Go/NoGo task were compared among the three groups. Subsequently, within each ID phenotype, participants were divided into training and blank control sub-groups. The two training sub-groups completed Adaptive Go/NoGo training task (Through adaptive difficulty adjustment, the task trains participants' inhibitory control) 15 times over 3 weeks, and all IDs were assessed using sleep-related subjective and objective measures and Go/NoGo task before and after the intervention.

Results: ISSD patients exhibited significantly longer sleep latency (p = 0.003) compared to HC, while wakefulness duration (p = 0.004) and light sleep duration (p < 0.001) were shorter than INSD. No significant differences in objective sleep characteristics were observed between INSD and HC. Following adaptive training, the ISSD training sub-group showed decreased scores in PSQI (p = 0.039) and ISI (p = 0.053) compared to their blank control sub-group. In the INSD groups, both training and blank control sub-groups demonstrated reductions in PSQI (p < 0.001), ISI (p < 0.001), and the cognitive arousal sub-dimension of the PSAS scores (p = 0.003) in the post-session test.

Conclusions: Impaired response inhibition is a characteristic of ISSD, potentially indicating dysfunctional cortical inhibition, whereas INSD pathogenesis may be related to cognitive-emotional arousal. Response inhibition training effectively alleviates sleep problems in ISSD. These findings provide new insights for developing precise intervention strategies in ID.

Trial registration: The study was prospectively registered on May 30, 2024, in Chinese Clinical Trials registry (ChiCTR2400085063).