BMC Medicine最新文献

Background: Antenatal corticosteroids are recommended for women at risk of preterm birth from 24 to 34 weeks' gestation as they reduce neonatal morbidity and mortality, but evidence regarding their long-term effects on offspring is limited. This study assessed general health and social outcomes 50 years after antenatal exposure to corticosteroids.

Methods: We assessed 424 adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. The first 717 mothers received two intramuscular injections of betamethasone (6 mg betamethasone sodium phosphate and 6 mg betamethasone acetate) or placebo given 24 h apart and the subsequent 398 received two injections of double dose betamethasone (12 mg betamethasone sodium phosphate and 12 mg betamethasone acetate) or equivalent volume of placebo. Follow-up included a health questionnaire and consent for access to administrative data sources. Outcome categories included mental health (depression, anxiety, bipolar affective disorder, schizophrenia and treatment or hospital admission for any mental health disorder), general health (chronic kidney disease, cancer diagnosis, bone fracture, oral health, allergies, functional difficulties and physical activity) and social outcomes (educational attainment, employment and criminal convictions). Investigators remained blinded to treatment allocation. Analyses were adjusted for gestational age at entry, sex and clustering.

Results: We assessed 424 adult offspring (46% of survivors; mean [SD] age 49.3 [1.0] years; 212 [50%] female). There was no difference in mental health, general health and social outcomes between those exposed to betamethasone and those exposed to placebo, with the exception that osteoporotic site fracture in adulthood was more likely to have occurred in the betamethasone group compared with placebo (adjusted relative risk 1.57, 95% CI 1.00, 2.48, p = 0.05). No dose-effect relationship was evident and there was no difference in the proportion with at least one fracture. Follow-up rate and lack of in-person assessments were the main limitations.

Conclusions: There is no evidence that antenatal corticosteroids have clinically important effects on general health and social outcomes up to 50 years of age.

Background: External causes of death, such as accidents, substance use, and suicide, contribute substantially to mortality during adolescence and early adulthood and show marked sex differences. Individuals born preterm are at increased risk of mental disorders, and impaired cognitive and executive functions, potentially increasing their vulnerability to death from external causes. We investigated sex-specific associations between gestational age at birth and mortality from external causes during late adolescence and early adulthood.

Methods: Individual level data from national health registries in Denmark (1978-2001), Finland (1987-2003), Norway (1967-2002), and Sweden (1974-2001) were linked to form nationwide cohorts. In total, 6,924,697 participants were followed from age 15 years to a maximum of 50 years in 2016-2018. Gestational age was categorized as "very/moderately preterm" (23-33 weeks), "late preterm" (34-36 weeks), "early term" (37-38 weeks), "full term" (39-41 weeks), and "post term" (42-44 weeks). Outcomes were mortality from external causes overall and from the largest subgroups transport accidents, suicide, and drugs or alcohol. We estimated sex-specific hazard ratios (HRs), with full term as the reference, and pooled each country's estimates in meta-analyses.

Results: Across gestational ages mortality was higher for males than females. Individuals born very/moderately preterm had higher mortality from external causes, with HRs 1.11 (95% confidence interval [CI] 0.99-1.24) for males and 1.55 (95% CI 1.28-1.88) for females. Corresponding estimates for late preterm born were 1.11 (95% CI 1.04-1.18) and 1.15 (95% CI 1.02-1.29), respectively. Those born very/moderately preterm had higher mortality from transport accidents, but precision was low. For females, suicide mortality was higher following very/moderately preterm birth (HR 1.76, 95% CI 1.34-2.32), but not for males. Mortality from drugs or alcohol was higher in very/moderately and late preterm born males (HRs 1.23 [95% CI 0.99-1.53] and 1.29 [95% CI 1.16-1.45], respectively) and females (HRs 1.53 [95% CI 0.97-2.41] and 1.35 [95% CI 1.07-1.71], respectively, with some heterogeneity across countries).

Conclusions: Mortality from external causes overall was higher in preterm than full term born among both males and females. A clear sex difference was seen for suicide, where preterm birth was a risk factor in females, but not in males.

Background: Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear.

Methods: The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR.

Results: Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD.

Conclusions: S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD.

Background: Transmembrane 9 superfamily member 1 (TM9SF1) is involved in inflammation. Since both inflammatory and autoimmune diseases are linked to immune cells regulation, this study investigated the association between TM9SF1 expression and autoimmune disease activity. As B cell differentiation and autoantibody production exacerbate autoimmune disease, the signaling pathways involved in these processes were explored.

Methods: Tm9sf1^-/- mouse rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) models were used to verify the relationship between gene expression and disease severity. Peripheral blood mononuclear cells (PBMCs) from 156 RA and 145 SLE patients were used to explore the relationship between TM9SF1 expression and disease activity. The effectiveness of TM9SF1 as a predictor of disease activity was assessed using multiple logistic regression and receiver operating characteristic (ROC) curves. The signaling pathways regulated by TM9SF1 in B cell maturation and antibody production were conducted by plasma cell induction experiment in vitro.

Results: The Tm9sf1^-/- RA and SLE model mice produced fewer autoantibodies and showed reduced disease severity relative to wild-type (WT) mice. TM9SF1 levels in PBMCs of patients were higher than those in healthy controls, and were reduced in patients with low disease activity relative to those with active RA and SLE. Furthermore, TM9SF1 levels were positively linked with autoantibody titers and pro-inflammatory cytokine levels in both diseases. ROC analyses indicated TM9SF1 outperformed several important clinical indicators in predicting disease activity (area under the curve (AUC) were 0.858 and 0.876 for RA and SLE, respectively). In vitro experiments demonstrated that Tm9sf1 knockout blocked differentiation of B cells into antibody-producing plasma cells by activating mTOR and inhibiting autophagy, and mTOR inhibitors such as rapamycin could reverse this effect.

Conclusions: The primary finding was the identification of the molecular mechanism underlying autophagy regulation in B cells, in which Tm9sf1 knockout was found to modulate mTOR-dependent autophagy to block B cell differentiation into antibody-secreting plasma cells. It was also found that TM9SF1 expression level in PBMCs was an accurate indicator of disease activity in patients with RA and SLE, suggesting its clinical potential for monitoring disease activity in these patients.

Background: This study aimed to characterise patterns of tobacco smoking and vaping among older adults (≥ 65 years) in England, to explore harm perceptions of e-cigarettes among those who smoke, and to estimate the real-world effectiveness of e-cigarettes for helping older adults to stop smoking.

Methods: Data were collected as part of a representative monthly cross-sectional household survey in England between April 2014 and April 2024 (n = 197,219). We analysed differences between older (≥ 65 years) and younger/middle-aged adults (18-64 years) in (a) time trends in tobacco smoking and vaping, (b) harm perceptions of e-cigarettes vs. cigarettes (adjusting for gender, socioeconomic position, and vaping status), and (c) the real-world effectiveness of e-cigarettes for smoking cessation (adjusting for gender, socioeconomic position, characteristics of the quit attempt, and use of other evidence-based cessation aids).

Results: Tobacco smoking prevalence remained relatively unchanged over time among older adults (at ~ 9%; 9.5% [8.5-10.6%] in April 2014 and 8.7% [7.7-9.8%] in April 2024) but vaping prevalence increased (from 2.1% [1.6-2.7%] to 3.7% [3.0-4.6%], respectively). These trends differed from those observed among younger/middle-aged adults, among whom there was a clear decline in smoking (from 21.8% [21.0-22.7%] to 18.2% [17.3-19.0%]) and a larger increase in vaping (from 5.6% [5.2-6.1%] to 16.2% [15.3-17.0%]). Older adults were consistently less likely than younger/middle-aged adults to use e-cigarettes to support attempts to quit smoking (26.8% [17.2-39.3%] vs. 43.7% [39.6-48.0%] in April 2024). Older smokers reported greater uncertainty about the harms of e-cigarettes compared with cigarettes (OR_adj = 2.48 [2.28-2.69]). E-cigarettes appeared to be effective for helping older adults to stop smoking (OR_adj = 1.50 [0.96-2.34]); whether effectiveness was lower than for younger/middle-aged adults was inconclusive.

Conclusions: Over the past decade, smoking prevalence has remained stable among older adults while decreasing among the rest of the adult population in England. Older adults are more unsure about the relative harms of e-cigarettes and less likely to use them to support attempts to quit smoking, despite evidence that they are effective for smoking cessation in this population.

Background: We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors.

Methods: Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel's C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer-Lemeshow goodness of fit test along calibration plots.

Results: Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65).

Conclusions: The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

Background: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. Examining gender (socio-cultural) in addition to sex (biological) is required to untangle socio-cultural characteristics contributing to inequities within or between sexes. This study aimed to develop a gender measure including four gender dimensions and examine the association between this gender measure and CVD incidence, across sexes.

Methods: A cohort of 9188 white-collar workers (49.9% females) in the Quebec region was recruited in 1991-1993 and follow-up was carried out 28 years later for CVD incidence. Data collection involved a self-administered questionnaire and extraction of medical-administrative CVD incident cases. Cox proportional models allowed calculations of hazard ratios (HR) and 95% confidence intervals (CI), stratified by sex.

Results: Sex and gender were partly independent, as discordances were observed in the distribution of the gender score across sexes. Among males, being in the third tertile of the gender score (indicating a higher level of characteristics traditionally ascribed to women) was associated with a 50% CVD risk increase compared to those in the first tertile (HR = 1.50; 95% CI: 1.24 to 1.82). This association persisted after adjustment for several CVD risk factors (HR = 1.42; 95% CI: 1.16 to 1.73). Conversely, no statistically significant association between the third tertile of the gender score and CVD incidence was observed in females (HR = 0.79, 95% CI: 0.60-1.05).

Conclusions: The findings suggested that males within the third tertile of the gender score were more likely to develop CVD, while females with those characteristics did not exhibit an increased risk. These findings underline the necessity for clinical and population health research to integrate both sex and gender measures, to further evaluate disparities in cardiovascular health and enhance the inclusivity of prevention strategies.

Background: Migrants to the UK face disproportionate risk of infections, non-communicable diseases, and under-immunisation compounded by healthcare access barriers. Current UK migrant screening strategies are unstandardised with poor implementation and low uptake. Health Catch-UP! is a collaboratively produced digital clinical decision support system that applies current guidelines (UKHSA and NICE) to provide primary care professionals with individualised multi-disease screening (7 infectious diseases/blood-borne viruses, 3 chronic parasitic infections, 3 non-communicable disease or risk factors) and catch-up vaccination prompts for migrant patients.

Methods: We carried out a mixed-methods process evaluation of Health Catch-UP! in two urban primary healthcare practices to integrate Health Catch-UP! into the electronic health record system of primary care, using the Medical Research Council framework for complex intervention evaluation. We collected quantitative data (demographics, patients screened, disease detection and catch-up vaccination rates) and qualitative participant interviews to explore acceptability and feasibility.

Results: Ninety-nine migrants were assessed by Health Catch-UP! across two sites (S1, S2). 96.0% (n = 97) had complete demographics coding with Asia 31.3% (n = 31) and Africa 25.2% (n = 25), the most common continents of birth (S1 n = 92 [48.9% female (n = 44); mean age 60.6 years (SD 14.26)]; and S2 n = 7 [85.7% male (n = 6); mean age 39.4 years (SD16.97)]. 61.6% (n = 61) of participants were eligible for screening for at least one condition and uptake of screening was high 86.9% (n = 53). Twelve new conditions were identified (12.1% of study population) including hepatitis C (n = 1), hypercholesteraemia (n = 6), pre-diabetes (n = 4), and diabetes (n = 1). Health Catch-UP! identified that 100% (n = 99) of patients had no immunisations recorded; however, subsequent catch-up vaccination uptake was poor (2.0%, n = 1). Qualitative data supported acceptability and feasibility of Health Catch-UP! from staff and patient perspectives, and recommended Health Catch-UP! integration into routine care (e.g. NHS health checks) with an implementation package including staff and patient support materials, standardised care pathways (screening and catch-up vaccination, laboratory, and management), and financial incentivisation.

Conclusions: Clinical Decision Support Systems like Health Catch-UP! can improve disease detection and implementation of screening guidance for migrant patients but require robust testing, resourcing, and an effective implementation package to support both patients and staff.

Background: The dietary glycemic index (GI) and load (GL) reflect carbohydrate quality and quantity, potentially impacting fertility through modulation of insulin sensitivity and generation of oxidative stress. While fertility is influenced by both women and men, reproductive research often emphasizes maternal factors. We first examined periconception dietary intake in both women and male partners, and subsequent associations of dietary GI and GL with fecundability and subfertility.

Methods: Among 830 women and 651 male partners, participating in a population-based prospective cohort study from preconception onwards, we assessed periconception dietary intake and calculated GI and GL, using a food frequency questionnaire (FFQ) at median 12.4 weeks gestation (95% range 10.9, 18.4). Information on time to pregnancy was obtained through questionnaires, with subfertility defined as a time to pregnancy ≥ 12 months or use of assisted reproductive technology.

Results: In the periconception period, mean energy intake in women was 1870 kcal (SD: 500; 46% carbohydrates, 16% protein, 33% fat; dietary GI 56.2 (SD: 3.5) and GL 141.4 (SD: 67.4)). Mean energy intake in men was 2350 kcal (SD: 591; 43% carbohydrates, 16% protein, 33% fat; dietary GI 56.8 (SD: 3.2) and GL 156.7 (SD: 75.4)). Median time to pregnancy was 4.8 months (IQR: 1.2, 16.4), with 30.6% of 830 women experiencing subfertility. Dietary GI and GL were not associated with fertility outcomes in women. In men, higher dietary GI and GL across the full range were associated with decreased fecundability, after adjusting for socio-demographic and lifestyle factors, as well as dietary GI or GL of female partners [FR: 0.91, 95% CI 0.83, 0.99; FR: 0.90, 95% CI 0.81, 0.99, per SDS increase in dietary GI and GL, respectively]. When assessing the combined influence of dietary GI clinical categories in women and men, both partners adhering to a low GI diet tended to be associated with increased fecundability, but not with subfertility risk.

Conclusions: Suboptimal periconception carbohydrate intake may be negatively associated with male fertility, but not with fertility outcomes in women. Further studies are needed to assess whether a lower GI and GL diet is a feasible lifestyle intervention to improve couples fertility.

Background: Neoadjuvant chemotherapy may be considered for patients with ovarian cancer (OC) whose tumors are deemed unlikely to be completely cytoreduced to no gross residual disease (R0) or who are poor surgical candidates. This Ib/II study was designed to assess the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin as neoadjuvant chemotherapy for stages III-IV, unresectable OC.

Methods: Eligible patients with stage III-IV, unresectable OC were enrolled in this phase Ib/II study. All patients received neoadjuvant nab-paclitaxel (260 mg/m², day 1, every 3 weeks) plus carboplatin (AUC 5, day 1, every 3 weeks) for 3 cycles before surgery, followed by 3-6 cycles of adjuvant chemotherapy. The phase Ib primary endpoint was safety; the phase II primary endpoint was the R0 resection rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety (for all populations).

Results: Sixty-two patients were enrolled and were given neoadjuvant therapy treated between October 2019 and December 2020, of whom 9 were in the phase Ib portion and 53 in the phase II portion. A total of 53 patients underwent surgery with an R0 resection rate of 73.6% (95% CI, 59.7-84.7%). With a median follow-up of 17.5 (range 0.7-36.7) months, for all patients, the best ORR was 83.9% (95% CI, 71.7-92.4%) with 47 partial responses, the median PFS was 18.6 (95% CI, 13.8-23.3%) months, and median OS was not reached. During the neoadjuvant chemotherapy, treatment-related adverse events (TRAEs) of any grade occurred in 91.9% (57/62) of all patients. The most common hematologic TRAEs were neutropenia (55/62, 88.7%), and non-hematologic toxicity was alopecia (36/62, 58.1%). Forty-nine patients (79.0%) experienced at least one grade 3-4 TRAEs, with the most common was neutropenia (44/62, 71.0%). Besides, delays in neoadjuvant chemotherapy and surgery due to AEs were observed in 9 (1 in phase Ib; 8 in phase II) and 7 (phase II) patients, respectively.

Conclusions: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant chemotherapy nab-paclitaxel plus carboplatin in stage III-IV, unresectable OC. In addition, AEs resulting in chemotherapy and surgery delays should be cautiously considered in this clinical setting.

Trial registration: ClinicalTrials.gov, ChiCTR1900026893. Registered at 25 October 2019.