BMC Medicine最新文献

Background: Cholangiocarcinoma (CCA) remains a highly lethal malignancy with a dismal prognosis, primarily driven by therapeutic resistance. A dominant resistance mechanism involves overexpression of anti-apoptotic BCL-2 proteins (BCL-XL, BCL-2, MCL-1). While direct inhibition of these proteins shows efficacy, its clinical utility is frequently limited by dose-dependent hematotoxicity-as exemplified by ABT263, a BCL-XL/BCL-2 dual inhibitor that induces severe thrombocytopenia.

Methods: We performed integrated analyses of BCL-2 family mRNA/protein expression in clinical CCA specimens and preclinical cell lines. Leveraging proteolysis-targeting chimera (PROTAC) technology, we investigated the therapeutic application of BCL-XL-specific degraders, both as monotherapy and in combination with gemcitabine, to selectively target CCA cells while minimizing hematologic toxicity.

Results: Integrated clinical-experimental data identified BCL-XL as a principal determinant of therapeutic sensitivity in CCA. In vitro, the cereblon (CRBN)-based PROTAC XZ739 demonstrated superior efficacy to its von Hippel-Lindau tumor suppressor (VHL)-based counterpart DT2216, reducing CCA cell viability via apoptosis induction. In vivo, XZ739 synergized with gemcitabine to suppress tumor growth in a CCA xenograft model, achieving robust efficacy without significant thrombocytopenia-a critical advance over conventional BCL-XL inhibitors.

Conclusions: These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.

Background: Light exposure over 24 h is a modifiable environmental influence on human physiology and behavior with significant implications for health and well-being, yet the field lacks coordinated research infrastructure, standardized methodologies, and translational pathways.

Methods: To address this, we convened a multi-disciplinary consensus workshop and expert consultation process with 13 experts from academia, public health, radiation protection, and occupational health institutions. The aim was to identify key research gaps and to define priority areas to guide future work.

Results: Through an in-person and hybrid meeting, followed by iterative refinement and feedback, we identified nine critical gaps: (1) lack of standardized measurement tools, (2) inadequate exposure estimation infrastructure, (3) inconsistent descriptors and metrics, (4) absence of outcome standards, (5) limited dose-response evidence beyond the laboratory, (6) insufficient data on intervention effectiveness, (7) poor characterization of globally representative and vulnerable populations, (8) fragmented data harmonization, and (9) limited integration into public health frameworks. To address these gaps, we propose 11 research priority areas spanning measurement, methodology, data infrastructure, ethics, and implementation, as well as four capacity-building priority areas.

Conclusions: This agenda provides a strategic foundation for building an integrated and evidence-based approach to studying and understanding light exposure as a determinant of health.

Background: As the number and complexity of patients living with serious illness continue to rise, delivering care that is both effective and responsive to individual life contexts has become increasingly important. Despite its potential benefits, the implementation of contextualized care in the management of serious illness remains limited and poorly understood. To address this gap, this study aimed to identify barriers and facilitators influencing the delivery of contextualized care for patients with serious illness, as perceived by healthcare professionals (HCPs), and to generate recommendations for improving its implementation.

Methods: Three focus groups were conducted with 20 HCPs from multiple disciplines and hospital settings in the Netherlands, all involved in the care of patients with serious illness. Discussions were guided and analysed using a directed content analysis informed by the COM-B model (Capability, Opportunity, Motivation-Behaviour) combined with the Theoretical Domains Framework. Factors were mapped to intervention functions from the Behaviour Change Wheel (BCW) to provide recommendations.

Results: Nine factors influencing contextualized care were identified across COM-B components. Capability-related factors included skills and knowledge to engage with the relevant patient context and the ability to distinguish between general and clinically relevant context. Opportunity-related factors included environmental conditions, fragmented information systems, systemic incentives misaligned with contextual care, a lack of shared team norms, collaboration challenges, and the perceived emotional complexity of contextual conversations in the palliative phase. Motivation-related factors included strong intrinsic commitment to person-centred care and awareness of the consequences of overlooking context for patients, HCPs, and the overall system. Most barriers were concentrated in the Opportunity component, with environmental and team-level constraints often outweighing individual motivation and basic skills.

Conclusions: Delivering contextualized care for patients with serious illness is not primarily limited by individual willingness or basic capability but by environmental and systemic feasibility. Sustainable implementation requires multilevel strategies targeting team culture, interprofessional collaboration, and a supportive infrastructure. Moving from individual intent to shared norms may improve both patient outcomes and resource efficiency. Key steps include continuous education, embedding contextual care in team culture, adapting workflows and documentation, and integrating contextualization into quality measures and incentives.

Background: Australia has previously experienced adverse trends in overweight- and obesity-related cardiovascular disease (CVD) mortality. Its obesity prevalence is relatively high, increasing and shows wide socio-economic inequalities. However, socio-economic inequalities in premature overweight- and obesity-related CVD mortality rate and their trends are unknown. This study measures recent trends in premature overweight- and obesity-related CVD mortality in Australia from 2007 to 2022 and their area-level socio-economic inequalities.

Methods: Premature overweight- and obesity-related CVD mortality was measured as deaths at ages 35-74 years with a CVD reported with at least one (DKOLH-CVD) or two (DKOLH2-CVD) of diabetes, chronic kidney disease, obesity, lipidemias and hypertension. Age-standardised death rates (ASDR) from Australian death registration data were calculated. Inequalities were measured using the Index of Relative Socio-economic Advantage and Disadvantage (IRSAD) and analysed using rate ratios and the Relative Index of Inequality. Obesity prevalence data and their inequalities were also assessed using National Health Survey data.

Results: Premature overweight- and obesity-related CVD mortality, measured as the DKOLH-CVD ASDR, rose from 87.0 (95% confidence interval 84.6-89.5) per 100,000 in 2014 to 103.8 (101.1-106.5) in 2022 for males, or 19%, and from 44.6 (42.9-46.4) in 2013 to 50.5 (48.7-52.4) in 2022 for females, or 13%. When measured as DKOLH2-CVD ASDR, it increased by 37% for males and 21% for females from 2012 to 2022. DKOLH-CVD in ages 35-54 years rose by at least 45% from 2014 to 2022; average obesity prevalence since childhood or young adulthood of these age groups increased by approximately 50% from 2007 to 2022. The ratio of the male DKOLH-CVD ASDR of the most disadvantaged to the most advantaged IRSAD decile increased from 3.16 (2.93-3.41) in 2013-2015 to 3.51 (3.27-3.77) in 2020-2022 and for females from 4.55 (4.08-5.08) to 5.00 (4.51-5.54). Rate ratios were particularly high for DKOLH2-CVD and in ages 35-54 years. Similar socio-economic inequalities were found according to obesity prevalence.

Conclusions: The recent rise in premature overweight- and obesity-related CVD mortality in Australia, especially among those aged 35-54 years and in the most disadvantaged socio-economic deciles, closely mirrors Australia's increasing obesity prevalence. Failure to effectively tackle Australia's high obesity prevalence may have a significant detrimental long-term impact on mortality.

Background: Adolescence is a critical period for brain development, during which dietary patterns may influence neuropsychological functioning.

Objective: To examine cross-sectional associations and determine if baseline adherence to the Mediterranean diet (MD) and ultra-processed food (UPF) consumption is associated with changes in adolescent neuropsychological outcomes over 6 months.

Methods: This study represents a secondary analysis of the WALNUTs Smart-Snack Trial. We evaluated 653 adolescents (aged 12-16 years) from Barcelona at baseline and at 6-month follow-up. All dietary data used for these analyses were collected at the baseline timepoint only. MD adherence was measured with the KIDMED index and UPF consumption was assessed using a food frequency questionnaire and classified using the NOVA system. Cognitive domains were assessed at both time points using standardised computer-based tasks: attention (alerting, orienting, executive control) with the Attention Network Test; working memory (4-back) with the N-back task; fluid intelligence with the Primary Mental Abilities-Revised; decision-making with the Roulettes Task; and emotion recognition with the Emotion Recognition Task. Behavioural outcomes were also evaluated at both time points using the self-reported Strengths and Difficulties Questionnaire and teacher-reported Attention-Deficit/Hyperactivity Disorder-DSM-IV scales. Associations were examined using multivariable generalised linear models. To further validate UPF consumption estimations, polyphenol biomarkers were measured in urine in a subsample of 257 participants.

Results: Greater adherence to the MD was cross-sectionally linked to fewer behavioural problems and higher scores of executive functioning, while higher UPF consumption was associated with poorer emotion recognition, reduced alerting attention, less advantageous decision-making, more behavioural problems and internalising symptoms. Longitudinally, higher UPF consumption was associated with more internalising symptoms and less advantageous decision-making, whereas MD adherence showed no associations.

Conclusions: Greater MD adherence appears associated with more favourable behavioural and cognitive profiles. In contrast, higher UPF consumption seems to be associated with less favourable profiles across multiple neuropsychological domains in adolescents. However, the limited longitudinal evidence points to complex relationships that warrant further investigation. Overall, these findings highlight the importance of promoting healthier dietary habits during adolescence.

Background: Air pollution is a complex mixture of closely correlated pollutants, making it challenging to assess both the overall mixture effect and to isolate the individual impact of each pollutant on breast cancer (BC) risk. This study assessed the effect of exposure to a mixture of seven correlated air pollutants (benzo[a]pyrene, cadmium, dioxins, polychlorinated biphenyl 153 (PCB153), nitrogen dioxide (NO₂), particulate matter (PM_2.5 and PM₁₀)) on BC risk.

Methods: The study was based on a case-control study nested within the French E3N-Generations cohort (5222 incident BC cases/5222 matched controls). Annual average concentrations of each pollutant were estimated using the CHIMERE chemistry-transport model, based on participants' residential addresses from 1990 to the index date. Bayesian kernel machine regression (BKMR) and quantile G-computation (QGC) were used to evaluate the joint effect of the pollutant mixture, individual pollutant contributions, and potential interactions.

Results: In all women, the BKMR model showed an increasing trend in BC risk associated with a joint increase in exposure to the seven pollutants. Among individual pollutants, NO₂, PCB153, and PM showed the strongest positive dose-response associations. The QGC model also found a significant association between the pollutant mixture and BC risk (odds ratio (OR) = 1.12; 95% confidence interval (CI) = 1.02-1.24) per quartile increase in the mixture.

Conclusions: This study provides evidence of a positive association between exposure to a mixture of seven air pollutants and the risk of BC for the two statistical approaches. NO₂ contributed most significantly to the overall effect, followed by PCB153 and PM. These findings underscore the necessity of evaluating combined pollutant mixtures in risk assessment, identifying high-risk subpopulations, and designing targeted preventive strategies.

Background: Neutrophils contribute critically to adverse cardiac remodeling following acute myocardial infarction (AMI), yet the precise regulatory mechanisms remain unclear. Our previous findings identified methylmalonic acid (MMA) as a novel cardiovascular prognostic biomarker. Thus, we aimed to investigate whether neutrophil-derived MMA mediates neutrophil extracellular trap (NET) formation and subsequent adverse cardiac remodeling post-MI, and to elucidate potential underlying mechanisms.

Methods: Serum and neutrophil MMA levels were measured in humans and mice with AMI. Neutrophil-specific Mmut knockout mice (S100a8^Cre Mmut^flox/flox) were treated with GSK484 (PAD4 inhibitor) or DNase I (NET-degrading agent) to evaluate the role of neutrophil-derived MMA in cardiac NET formation and adverse remodeling after MI. High-throughput RNA sequencing was performed on isolated neutrophils to identify molecular mechanisms.

Results: Compared with patients with angina, patients with AMI displayed significantly increased MMA levels in serum and neutrophils, particularly pronounced in neutrophils. Elevated NET markers were observed in thrombus tissue from patients with AMI with higher neutrophil MMA. Similarly, Mmut knockout mice exhibited increased NET formation, greater microthrombus burden, and worsened cardiac dysfunction 4 weeks after MI compared with S100a8Cre controls. NETosis-targeted interventions (GSK484 or DNase I) substantially reduced microthrombus formation and adverse cardiac remodeling, especially in Mmut knockout mice. Integrated transcriptomic and multifactorial analyses revealed that activation of the neutrophil IL-6/JAK1/STAT3 signaling pathway plays a key role in MMA-induced NETosis, which was largely compromised by the treatment with an IL-6 neutralizing antibody. Moreover, colchicine, an FDA-approved anti-inflammatory agent, significantly inhibited neutrophilic IL-6 expression, NETosis, and microthrombus formation, thereby attenuating post-MI cardiac remodeling against the hazards of neutrophil MMA elevation.

Conclusions: Neutrophil-derived MMA promotes NETosis and microthrombus formation through IL-6 activation, contributing to maladaptive cardiac remodeling post-MI. These findings identify neutrophil MMA as a novel immunometabolic trigger driving NET-mediated adverse cardiac remodeling and suggest colchicine as a promising therapeutic strategy to prevent heart failure post-MI, particularly in patients with elevated neutrophil MMA contents.

Background: The aim of this secondary analysis of the BENEFIT randomized controlled trial was to investigate the effects of aerobic training (AT) or resistance training (RT) during neoadjuvant chemotherapy (NACT) on sleep and cancer-related fatigue (CRF), compared to a waitlist control group (WCG) that performed RT after surgery.

Methods: In the BENEFIT study, 184 patients with breast cancer with scheduled NACT (mean age = 50 years, standard deviation = 11) were randomized to AT (n = 62), RT (n = 62), or WCG (n = 60). While the AT and RT groups trained during NACT (two supervised and one home-based session weekly), the WCG completed the same training as the RT group but only after breast surgery. Self-reported sleep quality (Pittsburgh Sleep Quality Index) and CRF (EORTC QLQ-FA12) were collected before NACT (T0), after 9 weeks (T1), after NACT and before surgery (T2), 6 months after surgery (T3), and 12 months after surgery (T4). At T0, T2, and T3, sleep was additionally objectively measured by actigraphy.

Results: Longitudinal analyses of covariance examining changes from baseline suggested no clear difference of AT and RT compared to the WCG regarding sleep and CRF parameters post-intervention (T2). In contrast, at T3 the WCG, which exercised between T2 and T3, showed more favorable mean values compared to the AT group in total CRF (adjusted mean difference (AMD): - 10.53, 95% CI [- 19.63, - 1.42]) and physical CRF (AMD: - 14.28 [- 26.02, - 2.54] on 0-100 scale), and a tendency toward lower scores in self-reported global sleep quality (AMD: - 0.24 [- 0.48, 0.01] on log-transformed scale). Moderation analyses further suggested that group differences in total CRF at T3 in favor of the WCG were more pronounced among participants with at least mild emotional distress at baseline. There were no clear differences between groups in objective sleep parameters at T2 or T3, or regarding self-reported sleep or fatigue endpoints at T4.

Conclusions: The findings suggest that exercise interventions in the post-NACT phase may be more effective than during NACT for managing fatigue, while providing limited benefits for sleep.

Trial registration: The BENEFIT study has been registered at ClincialTrials.gov (NCT02999074).

Background: Evidence for the net benefit of aspirin for primary prevention of cardiovascular disease (CVD) is finely balanced, leading to variation in guideline recommendations internationally. External validity of randomised clinical trial (RCT) evidence may therefore be of particular importance. The aim of this study is to characterise real-world patients according to their eligibility for guideline-cited aspirin RCTs for primary CVD prevention.

Methods: Eligibility criteria from 14 RCTs were applied to a linked primary care/hospital discharge dataset of people ≥ 40 years without CVD. Proportions eligible for each trial were calculated, and characteristics of eligible and ineligible patients compared for each trial, including Cox regression analysis of event rates for major adverse cardiovascular events (MACE), major bleeding events, and non-cardiovascular mortality.

Results: Of 570,211 included patients (300,500 [52.7%] women, 336,877 [59%] < 60 years), the median proportion ineligible for 14 RCTs was 90.7% (range 42.5-99.4%) and 24.0% of patients were ineligible for all RCTs. On average, trial-ineligible populations were younger (median age trial-ineligible 57.8 vs trial-eligible 62.6 years, p = 0.008) and a lower proportion had hypertension (23.9% vs 50.9%, p = 0.004), diabetes (6.4% vs 11.5%, p = 0.015), or a regular statin prescription (11.8% vs 26.7%, p = 0.001). Trial-ineligible populations had a higher hazard of MACE compared to trial-eligible in four RCTs and lower in ten (hazard ratio [HR] range across all RCTs 0.45 [95%CI 0.40-0.51] to 2.78 [95%CI 2.61-2.96]). Hazards of bleeding events in the trial-ineligible were lower than the trial-eligible in eight RCTs and higher in four (HR range across all RCTs 0.63 [95%CI, 0.59-0.66] to 1.69 [95%CI, 1.53-1.86]), and time-varying hazards of non-CVD death were consistently lower in four RCTs and higher in five (HR range across all RCTs and time points 0.29 [95%CI 0.24-0.36] to 11.42 [95%CI 9.91-13.17]).

Conclusions: Compared with trial-ineligible populations within the same age and sex strata, RCTs recruited people of varying CVD risk but often excluded people at high risk of bleeding or non-CVD death, highlighting that many trials may overestimate the net benefit of aspirin for primary prevention.

Background: Healthcare delivery produces substantial emissions that contribute to climate change and harm human health. Patient perspectives on ethical dilemmas, such as tradeoffs between individual health choices and public health harms mediated by climate change, are unclear.

Methods: This cross-sectional survey randomly sampled adult patients across four US health systems to assess their perspectives on ethical dilemmas in climate change and healthcare delivery; results were compared to a previous nationwide survey of US-based physicians. The mailed survey was developed iteratively through pre-testing and was designed to detect a 15% difference in the proportion willing to limit treatment options because of environmental impact according to respondents' perceived impact of climate change on their health. Secondary outcomes included physician responsibilities for healthcare sustainability and acceptability of environmentally motivated treatment tradeoffs.

Results: Between 11/2023 and 9/2024, 289 of 516 patient surveys and 304 of 529 physician surveys were delivered and returned, for response rates of 56.0% and 57.5%, respectively. Most patients (79.1%) believed that environmental factors impacted their medical conditions, and 36.3% reported a moderate-to-high health impact from climate change, while 5.2% reported speaking with their doctor about climate and health interactions a moderate amount or more. Similar proportions of patients (35.8%) and physicians (35.0%) agreed with reducing healthcare's environmental impact even if it required limiting treatment options. Like physicians, patients' perceived health impact (moderate-to-high versus low-to-no) was associated with willingness to place such limits (adjusted OR 1.85; 95% CI 1.01, 3.41). Most patients (77.1%) were willing to accept some reduction in the likelihood of treatment response if that treatment was less environmentally impactful; unlike physicians, this did not vary by health impact (adjusted OR 1.16; 95% CI 0.63, 2.20). Almost all patients (96.8%) reported that physicians should help make healthcare sustainable, and 64.7% thought this included changing clinical practices.

Conclusions: Many US patients and physicians recognize connections between health, healthcare delivery, and climate change, and accept environmentally motivated treatment tradeoffs, but do not discuss them in the clinic. Patient views largely parallel those of physicians, suggesting support for climate-informed medical practice and for incorporating environmental considerations into clinical decision-making.