BMC Medicine最新文献

Background: Recent evidence from both randomized controlled trials and cohort studies in adults suggests that plasma remnant cholesterol (RC) levels predict cardiovascular disease. In children, studies are scarce, although high levels of RC might represent a marker of early atherosclerotic damage. Thus, the aim of this study was to explore the cardiometabolic risk associated with RC, which extends beyond low-density lipoprotein cholesterol (LDL-c) in children.

Methods: Cardiometabolic risk factors (plasma insulin levels, homeostatic model assessment for insulin resistance, mean arterial blood pressure (MAP), waist circumference (WC), and cardiorespiratory fitness (CRF)) were examined in 3417 Spanish schoolchildren aged 8-11 years. The children were categorized into four subgroups (low vs. high) based on the cutoff of ≥ 110 mg/dL for LDL-c and of ≥ 15 mg/dL for RC to define higher levels, and ANCOVA models were applied to assess the role of both lipid parameters in cardiometabolic risk. Additionally, multilevel mixed-effects generalized linear regression models were used to assess the associations of RC or LDL-c with cardiometabolic risk factors and to examine whether the associations between RC and these factors varied in children with low or high LDL-c levels.

Results: Children in the high-RC subgroups, specifically those with low LDL-c/high RC and high LDL-c/high RC, presented significantly greater insulin levels and WC than did their peers in the low-RC subgroups. RC was more strongly associated with cardiometabolic risk factors than LDL-c (insulin β = 2.073/ - 0.026; HOMA-IR β = 0.451/ - 0.002; MAP β = 1.214/0.300; WC β = 2.842/1.058; and CRF β = - 0.316/ - 0.194 for RC and LDL-c, respectively). Furthermore, RC exhibited associations even in children with low LDL-c levels: insulin (β = 2.305; p < 0.001), HOMA-IR (β = 0.499; p < 0.001), MAP (β = 1.397, p < 0.001), WC (β = 2.842; p < 0.001), and CRF (β = - 0.367; p < 0.001).

Conclusions: The associations between RC and cardiometabolic risk factors were stronger than those between LDL-c and cardiometabolic risk, extending its significance even in children with low LDL-c levels. These findings may be clinically useful for cardiovascular risk stratification and for guiding future interventions in children, although they should be confirmed by longitudinal studies.

Background: Maternal stress during pregnancy may impact offspring development via changes in the intrauterine environment. However, genetic and environmental factors shared between mothers and children might skew our understanding of this pathway. This study assesses whether prenatal maternal stress has causal links to offspring outcomes: birthweight, gestational age, or emotional and behavioral difficulties, triangulating across methods that account for various measured and unmeasured confounders.

Methods: We used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), including maternal reports on prenatal stress at work, at home, and via stressful life events as exposures. Outcomes were children's birthweight and gestational age, from the Medical Birth Registry of Norway, and maternal reports on early offspring emotional and behavioral difficulties. We assessed associations using four approaches: sibling control analyses, gene-environment interaction analyses, intergenerational Mendelian randomization (MR), and negative control (i.e., postnatal stress) analyses.

Results: Maternal prenatal stress was observationally associated with offspring lower birthweight (e.g., β_work = - 0.01 [95%CI: - 0.02, - 0.01]), earlier birth (e.g., β_work = - 0.04 [95%CI: - 0.04, - 0.03])), and more emotional (e.g., β_events = 0.08 [95%CI: 0.07, 0.09]) and behavioral difficulties (e.g., β_relationship = 0.08 [95%CI: 0.07, 0.09]) in the full sample (N = 112,784). However, sibling control analyses (N = 36,511) revealed substantial attenuation of all associations after accounting for familial factors. Gene-environment interaction models (N = 76,288) showed no clear evidence of moderation of associations by mothers' polygenic scores for traits linked to stress sensitivity. Intergenerational MR analyses (N = 29,288) showed no clear evidence of causal effects of maternal plasma cortisol on any offspring outcomes. Negative control exposure analyses revealed similar effect sizes whether exposures were measured prenatally or postnatally.

Conclusions: Our results indicate that links between prenatal maternal stress and variation in early offspring outcomes are more likely to be confounded than causal. While no observational study can rule out causality, the consistency of our findings across different approaches is striking. Other sources of prenatal stress or more extreme levels may represent intrauterine causal risk factors for offspring development. Nonetheless, our research contributes to identifying boundary conditions of the fetal programming and developmental origins of health and disease hypotheses, which may not be as universal as sometimes assumed.

Background: Current research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF.

Methods: We employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions.

Results: Multiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300-1.961; Pval = 8.290 × 10 - 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses.

Conclusions: BRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes.

Background: The NHS App launched in 2019 as the 'digital front door' to the National Health Service in England with core features including General Practitioner (GP) appointment booking, repeat prescriptions, patient access to records and, later on, COVID-19 vaccination certification. Similar patient portals have been adopted in different formats and with variable levels of success. In this longitudinal study (2021-2023) we examined how the NHS App became implemented in the pandemic context and beyond.

Methods: We recruited 88 participants in 62 qualitative interviews and four focus groups. Participants included patients, carers, members of the public, clinical/non-clinical NHS staff from five GP practices (where we also conducted over 60 h of observations) across England, as well as other industry, policy and civil rights stakeholders. Document analysis also contributed to participant recruitment and data interpretation. Data collection and analysis was informed by the Non-Adoption, Abandonment, Scale-up, Spread and Sustainability (NASSS) framework.

Results: Our study identified the various ways in which complexity manifested as part of the implementation, use and roll-out of the NHS App. Patients had diverse (positive and negative) user experiences as the app evolved, with some of its features described as more useful than others (e.g. prescription ordering, COVID Pass). As the app primarily provided a gateway to general practice systems and infrastructures, not all features were available by default or consistently to all users, with information often appearing fragmented or system-facing (e.g. coded). NHS staff viewed the app as constituting core NHS infrastructure in the long term which made it appealing, even though initially there was less recognition of its immediate value. There was variable organisational capacity to enable implementation and to put in place processes and staff roles required to support patient adoption. Shifting emphasis towards in-person care, challenges with digital inclusion and controversies related to features such as patient access to own records further complicated roll-out.

Conclusions: As the NHS App remains a complex innovation in a shifting landscape, it is clear ongoing work is needed to ensure its potential can be sustained to meet patient, service and policy needs.

Clinical study registration: ISRCTN72729780.

Background: Tecovirimat, an antiviral treatment for smallpox, was approved as a treatment for mpox by the European Medicines Agency in January 2022. Approval was granted under "exceptional circumstances" based on effectiveness found in pre-clinical challenge studies in animals and safety studies in humans showing minimal side effects. As clinical efficacy studies are still ongoing, there is currently limited information with regard to the acceptability of tecovirimat to treat mpox. The aim of this study is to understand prospective acceptability of use of tecovirimat as treatment for mpox.

Methods: A co-produced, qualitative, focus group study design was conducted with a theoretically informed sample of people from communities at higher risk and with experience of mpox illness. Thirteen participants took part: all self-identified as cisgender male, 1 self-identified as Black British, 1 as British Asian, 5 as White, 3 as White British, 3 as White Other. Inclusion criteria were as follows: experience of mpox illness; age 18 and over; living in the United Kingdom (UK); living in the UK during 2022 mpox outbreak. Focus groups were recorded, transcribed and thematically analysed using a combination inductive and deductive coding informed by the Treatment Acceptability Framework.

Results: Very few participants were aware of tecovirimat as a treatment option and none were offered it during their mpox illness. Key factors influencing acceptability found in this study were as follows: levels of trust in medicine; level of information; provider communication approach; quality of experience of mpox care. Marginalised communities at highest risk of mpox may have prior experience of structural discrimination which can greatly influence treatment acceptability.

Conclusions: This exploratory study suggest that offering tecovirimat (or comparable emergency-licensed treatments) to people with mpox is acceptable, although uptake will depend on knowledge of mpox treatment options, trust in medicine and medical professionals and provision of relevant information and choice. To increase acceptability of such treatments, clinicians should ensure patients are aware of mpox symptom management options, including pain relief; acknowledge and address patient concerns upfront and within the context of non-stigmatising care; and communicate offers in a consistent and supportive manner in line with locally approved eligibility criteria and protocols at the time.

Background: Cigarette smoking is posited as a potential factor in disrupting the balance of the human gut microbiota. However, existing studies with limited sample size have yielded inconclusive results.

Methods: Here, we assessed the association between cigarette smoking and gut microbial profile among Chinese males from four independent studies (N total = 3308). Both 16S rRNA and shotgun metagenomic sequencing methods were employed, covering 206 genera and 237 species. Microbial diversity and abundance were compared among non-smokers, current smokers, and former smokers.

Results: Actinomyces[g], Atopobium[g], Haemophilus[g], Turicibacter[g], and Lachnospira[g] were found to be associated with smoking status (current smokers vs. non-smokers). Metagenomic data provided a higher resolution at the species level, particularly for the Actinomyces[g] branch. Additionally, serum γ-glutamylcysteine (γ-Glu-Cys) was found to have a potential role in connecting smoking and Actinomyces[g]. Furthermore, we revealed putative mediation roles of the gut microbiome in the associations between smoking and common diseases including cholecystitis and type 2 diabetes.

Conclusions: We characterized the gut microbiota profile in male smokers and further revealed their potential involvement in mediating the impact of smoking on health outcomes. These findings advance our understanding of the intricate association between cigarette smoking and the gut microbiome.

Background: Polypharmacy (i.e., treatment with ≥ 5 drugs) is common in patients with atrial fibrillation (AF) and has been associated with suboptimal management and worse outcomes. Little is known about how prescribed drug patterns affect management and prognosis in patients with AF.

Methods: Based on data from the prospective global GLORIA-AF Registry Phase III (recruiting patients with AF and CHA₂DS₂-VASc score ≥ 1), we performed a latent class analysis to identify treatment patterns based on 14 drug classes including cardiovascular (CV) and non-CV drugs. We analysed associations with oral anticoagulant (OAC) use and risk of a composite primary outcome (all-cause death and major adverse cardiovascular events (MACE)) and secondary outcomes.

Results: Among 21,245 patients (mean age 70.2 ± 10.3 years, 44.9% females), we identified 6 patterns: i) Low Medicated pattern (18.3%); ii) Hypertension pattern (21.1%); iii) Heart Failure pattern (20.0%); iv) CV Prevention pattern (21.0%); v) Mixed Morbidity pattern (4.5%); and vi) High Medicated pattern (15.0%). All groups had higher odds of OAC use vs the Low Medicated pattern, with highest prevalences in the Heart Failure pattern (OR [95%CI]: 2.17 [1.90-2.48]) and the High Medicated pattern (OR [95%CI]: 2.08 [1.77-2.44]). Over 3-year follow-up, Heart Failure, Mixed Morbidity and High Medicated patterns were associated with higher risk of the primary composite outcome (aHR [95%CI]: 1.32 [1.14-1.53]; 1.45 [1.17-1.80] and 1.35 [1.14-1.60], respectively). Similar results were observed for all-cause mortality.

Conclusions: In patients with AF, different treatment patterns can be identified. Each pattern was associated with unique OAC use and long-term clinical outcomes.

Background: To provide estimates and trends for burdens of early-onset colorectal cancer (EOCRC) from 1990 to 2021 at the global, regional, and national levels, and to provide projections of EOCRC burden through 2030.

Methods: A trend analysis based on the Global Burden of Diseases 2021. The joinpoint regression model was used to analyze the temporal trends on EOCRC burden by calculating the corresponding average annual percent changes (AAPCs). A decomposition analysis was used to understand the drivers of the changes in EOCRC burden. The relationship between socio-demographic index (SDI) and disease burden was assessed by the concentration index of inequality. In addition, we constructed a Bayesian age-period-cohort model to predict the burden of EOCRC worldwide from 2022 to 2030.

Results: Globally, the burden of EOCRC increased significantly between 1990 and 2021, with the incidence rising from 5.43/100000 to 6.13/100000 (AAPC = 0.39), and the prevalence increasing from 29.65/100000 to 38.86/100000 (AAPC = 0.87). Over the same period, the death rate decreased from 2.98/100000 to 2.30/100000 (AAPC = - 0.84), whereas the disability-adjusted life-year (DALY) decreased from 148.46/100000 to 115.42/100000 (AAPC = - 0.82). In 2021, East Asia and China had the highest burden of EOCRC regionally and nationally. Decomposition analysis indicated the increase in EOCRC burden was mainly driven by population growth. The concentration index revealed that high-SDI countries had a greater burden of EOCRC than low-SDI countries. The global incidence and prevalence of EOCRC will rise continuously from 2022 to 2030.

Conclusions: Between 1990 and 2021, the incidence and prevalence of EOCRC have escalated, whereas the death rate and DALY rate have declined. The burden varied with sex, SDI, and geographical locations. Given the rising trend of EOCRC burden, coordinated efforts are needed to reduce the burden posed by this malignancy.

Background: The co-occurrence of diabetes and mental disorders is an exceedingly common comorbidity with poor prognosis. We aim to investigate the impact of green space, garden space, and the natural environment on the risk of mental disorders among the population living with diabetes.

Methods: We performed a longitudinal analysis based on 39,397 participants with diabetes from the UK Biobank. Residential green and garden space modeled from land use data and the natural environment from Land Cover Map were assigned to the residential address for each participant. Cox proportional hazards model was used to analyze the associations between nature exposures and mental disorders of diabetes. Casual mediation analysis was used to quantify indirect effect of air pollution.

Results: During a mean follow-up of 7.55 years, 4513 incident mental disorders cases were identified, including 2952 depressive disorders and 1209 anxiety disorders. Participants with natural environment at 300 m buffer in the second and third tertiles had 7% (HR = 0.93, 95%CI: 0.86-0.99) and 12% (HR = 0.88, 95%CI: 0.82-0.94) lower risks of incident mental disorders compared with those in the first tertile, respectively. The risk of mental disorders incidence among diabetes patients will decrease by 13% when exposed to the third tertile of garden space at 300 m buffer. The natural environment and garden space individually prevented 6.65% and 10.18% of mental disorders incidents among diabetes patients. The risk of incident mental disorders was statistically decreased when exposed to the third tertile of green space at 1000 m buffer (HR = 0.84, 95% CI: 0.78-0.90). Protective effects of three nature exposures against depressive and anxiety disorders in diabetes patients were also observed. Air pollution, particularly nitrogen dioxide, nitrogen oxides, and fine particulate matter, significantly contributed to the associations between nature exposures and mental disorders, mediating 48.3%, 29.2%, and 62.4% of the associations, respectively.

Conclusions: Residential green and garden space and the natural environment could mitigate mental disorders risk in diabetes patients, with air pollution playing a vital mediator. This highlights the potential for local governments to enhance the sustainability of such interventions, grounded in public health and urban planning, through strategic planning initiatives.

Background: Pediatric obesity is a growing global health challenge, with long-term implications for individuals and healthcare systems. Existing studies on the association between pediatric obesity and healthcare use in adulthood are limited and often rely on mathematical simulation models. This study aims to provide real-world data on the impact of adolescent obesity on specialized healthcare utilization and costs in early adulthood.

Methods: This study analyzed data from two longitudinal cohorts: a population-based cohort from Norway (Young-HUNT) and a clinical cohort from Sweden (BORIS), the latter with matched general population comparators. Individuals included were born between 1987 and 1994, with BMI measurements at ages 13-19, and follow-up data from ages 20 to 30 years. Healthcare utilization and costs were assessed using national patient registries.

Results: A total of 7592 individuals from Norway (5.7% with adolescent obesity) and 1543 individuals from Sweden with adolescent obesity, accompanied with 7330 matched general population comparators, were included. Among females, adolescent obesity was associated with significantly higher specialized healthcare utilization and costs in young adulthood, e.g., in Sweden, females with adolescent obesity had a 57% probability of annual specialized healthcare visits at ages 25-29, compared to 49% among the general population, p < 0.0001. In Norway, a similar pattern was observed. Among males, the association between obesity and healthcare utilization/annual specialized visits was less prominent. Annual excess costs for females with a history of adolescent obesity ranged from €578 to €835, while males showed minimal or no annual excess costs.

Conclusions: Analyses of real-world data cohorts from Norway and Sweden reveal that adolescent obesity is associated with increased healthcare utilization and costs in young adulthood, exceeding previous estimates. A distinct sex difference was evident, with females incurring higher costs compared to males.