BMC Medicine最新文献

{"title":"Involvement of sphingosine-1-phosphate receptor 1 in pain insensitivity in a BTBR mouse model of autism spectrum disorder.","authors":"Lili Fan, Qi Li, Yaxin Shi, Xiang Li, Yutong Liu, Jiaqi Chen, Yaqi Sun, Anjie Chen, Yuan Yang, Xirui Zhang, Jia Wang, Lijie Wu","doi":"10.1186/s12916-024-03722-3","DOIUrl":"10.1186/s12916-024-03722-3","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"504"},"PeriodicalIF":7.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TM9SF1 expression correlates with autoimmune disease activity and regulates antibody production through mTOR-dependent autophagy.","authors":"Juan Xiao, Zhenwang Zhao, Fengqiao Zhou, Jinsong Xiong, Zean Yang, Baoxian Gong, Lei Xiang, Mingming Liu, Fengsheng Cao, Hong Xiao, Huabo Chen, Anbing Zhang, Ke Wang","doi":"10.1186/s12916-024-03729-w","DOIUrl":"10.1186/s12916-024-03729-w","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"502"},"PeriodicalIF":7.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use, perceptions, and effectiveness of e-cigarettes for smoking cessation among older adults in England: a population study, 2014-2024.","authors":"Sarah E Jackson, Jamie Brown, Lion Shahab, Sharon Cox","doi":"10.1186/s12916-024-03728-x","DOIUrl":"10.1186/s12916-024-03728-x","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"500"},"PeriodicalIF":7.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single risk assessment for the most common diseases of ageing, developed and validated on 10 cohort studies.","authors":"Md Hamidul Huque, Scherazad Kootar, Kim M Kiely, Craig S Anderson, Martin van Boxtel, Henry Brodaty, Perminder S Sachdev, Michelle Carlson, Annette L Fitzpatrick, Rachel A Whitmer, Miia Kivipelto, Louisa Jorm, Sebastian Köhler, Nicola T Lautenschlager, Oscar L Lopez, Jonathan E Shaw, Fiona E Matthews, Ruth Peters, Kaarin J Anstey","doi":"10.1186/s12916-024-03711-6","DOIUrl":"10.1186/s12916-024-03711-6","url":null,"abstract":"<p><strong>Background: </strong>We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"501"},"PeriodicalIF":7.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing a gender measure and examining its association with cardiovascular diseases incidence: a 28-year prospective cohort study.","authors":"Mahée Gilbert-Ouimet, Azita Zahiriharsini, Caty Blanchette, Denis Talbot, Xavier Trudel, Alain Milot, Chantal Brisson, Peter Smith","doi":"10.1186/s12916-024-03706-3","DOIUrl":"10.1186/s12916-024-03706-3","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"498"},"PeriodicalIF":7.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health Catch-UP!: a realist evaluation of an innovative multi-disease screening and vaccination tool in UK primary care for at-risk migrant patients.","authors":"Jessica Carter, Lucy P Goldsmith, Felicity Knights, Anna Deal, Subash Jayakumar, Alison F Crawshaw, Farah Seedat, Nathaniel Aspray, Dominik Zenner, Philippa Harris, Yusuf Ciftci, Fatima Wurie, Azeem Majeed, Tess Harris, Philippa Matthews, Rebecca Hall, Ana Requena-Mendez, Sally Hargreaves","doi":"10.1186/s12916-024-03713-4","DOIUrl":"10.1186/s12916-024-03713-4","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"497"},"PeriodicalIF":7.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of periconception dietary glycemic index and load with fertility in women and men: a study among couples in the general population.","authors":"Mireille C Schipper, Aline J Boxem, Sophia M Blaauwendraad, Annemarie G M G J Mulders, Vincent W V Jaddoe, Romy Gaillard","doi":"10.1186/s12916-024-03718-z","DOIUrl":"10.1186/s12916-024-03718-z","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"499"},"PeriodicalIF":7.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of nanoparticle albumin-bound paclitaxel plus carboplatin as neoadjuvant chemotherapy for stages III-IV, unresectable ovarian cancer: a single-arm, open-label, phase Ib/II study.","authors":"Lina Yin, Wei Jiang, Shuai Liu, Yi Fu, Lin Zhou, Xuan Pei, Shuang Ye, Wenbin Shen, Huijuan Yang, Boer Shan","doi":"10.1186/s12916-024-03697-1","DOIUrl":"10.1186/s12916-024-03697-1","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, ChiCTR1900026893. Registered at 25 October 2019.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"496"},"PeriodicalIF":7.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerating adverse pregnancy outcomes research amidst rising medication use: parallel retrospective cohort analyses for signal prioritization.","authors":"Yeon Mi Hwang, Samantha N Piekos, Alison G Paquette, Qi Wei, Nathan D Price, Leroy Hood, Jennifer J Hadlock","doi":"10.1186/s12916-024-03717-0","DOIUrl":"10.1186/s12916-024-03717-0","url":null,"abstract":"<p><strong>Background: </strong>Pregnant women are significantly underrepresented in clinical trials, yet most of them take medication during pregnancy despite the limited safety data. The objective of this study was to characterize medication use during pregnancy and apply propensity score matching method at scale on patient records to accelerate and prioritize the drug effect signal detection associated with the risk of preterm birth and other adverse pregnancy outcomes.</p><p><strong>Methods: </strong>This was a retrospective study on continuously enrolled women who delivered live births between 2013/01/01 and 2022/12/31 (n = 365,075) at Providence St. Joseph Health. Our exposures of interest were all outpatient medications prescribed during pregnancy. We limited our analyses to medication that met the minimal sample size (n = 600). The primary outcome of interest was preterm birth. Secondary outcomes of interest were small for gestational age and low birth weight. We used propensity score matching at scale to evaluate the risk of these adverse pregnancy outcomes associated with drug exposure after adjusting for demographics, pregnancy characteristics, and comorbidities.</p><p><strong>Results: </strong>The total medication prescription rate increased from 58.5 to 75.3% (P < 0.0001) from 2013 to 2022. The prevalence rate of preterm birth was 7.7%. One hundred seventy-five out of 1329 prenatally prescribed outpatient medications met the minimum sample size. We identified 58 medications statistically significantly associated with the risk of preterm birth (P ≤ 0.1; decreased: 12, increased: 46).</p><p><strong>Conclusions: </strong>Most pregnant women are prescribed medication during pregnancy. This highlights the need to utilize existing real-world data to enhance our knowledge of the safety of medications in pregnancy. We narrowed down from 1329 to 58 medications that showed statistically significant association with the risk of preterm birth even after addressing numerous covariates through propensity score matching. This data-driven approach demonstrated that multiple testable hypotheses in pregnancy pharmacology can be prioritized at scale and lays the foundation for application in other pregnancy outcomes.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"495"},"PeriodicalIF":7.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of inverse publication bias in safety outcomes: an empirical analysis.","authors":"Xing Xing, Jianan Zhu, Linyu Shi, Chang Xu, Lifeng Lin","doi":"10.1186/s12916-024-03707-2","DOIUrl":"10.1186/s12916-024-03707-2","url":null,"abstract":"<p><strong>Background: </strong>The aims of this study were to assess the presence of inverse publication bias (IPB) in adverse events, evaluate the performance of visual examination, and explore the impact of considering effect direction in statistical tests for such assessments.</p><p><strong>Methods: </strong>We conducted a cross-sectional study using the SMART Safety, the largest dataset for evidence synthesis of adverse events. The visual assessment was performed using contour-enhanced funnel plots, trim-and-fill funnel plots, and sample-size-based funnel plots. Two authors conducted visual assessments of these plots independently, and their agreements were quantified by the kappa statistics. Additionally, IPB was quantitatively assessed using both the one- and two-sided Egger's and Peters' tests.</p><p><strong>Results: </strong>In the SMART Safety dataset, we identified 277 main meta-analyses of safety outcomes with at least 10 individual estimates after dropping missing data. We found that about 13.7-16.2% of meta-analyses exhibited IPB according to the one-sided test results. The kappa statistics for the visual assessments roughly ranged from 0.3 to 0.5, indicating fair to moderate agreement. Using the one-sided Egger's test, 57 out of 72 (79.2%) meta-analyses that initially showed significant IPB in the two-sided test changed to non-significant, while the remaining 15 (20.8%) meta-analyses changed from non-significant to significant.</p><p><strong>Conclusions: </strong>Our findings provide supporting evidence of IPB in the SMART Safety dataset of adverse events. They also suggest the importance of researchers carefully accounting for the direction of statistical tests for IPB, as well as the challenges of assessing IPB using statistical methods, especially considering that the number of studies is typically small. Qualitative assessments may be a necessary supplement to gain a more comprehensive understanding of IPB.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"494"},"PeriodicalIF":7.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}