BMC Medicine最新文献

{"title":"Healthy eating patterns associated with reduced risk of inflammatory bowel disease by lowering low-grade inflammation: evidence from a large prospective cohort study.","authors":"Bin Xia, Yan Li, Linmin Hu, Peng Xie, Ningning Mi, Liyuan Lv, Zixin Liang, Yuxuan Sun, Ying Li, Xiaodong Jiang, Guinan Liu, Yuanyuan Feng, Yingxin Zhu, Bo Zhan, Qiangsheng He, Pingguang Lei, Jian Qi, Pengpeng Wang, Jinqiu Yuan","doi":"10.1186/s12916-024-03809-x","DOIUrl":"10.1186/s12916-024-03809-x","url":null,"abstract":"<p><strong>Background: </strong>Limited epidemiological evidence exists regarding the role of healthy eating patterns in reducing the risk of Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to investigate the association between adherence to four established healthy eating patterns and subsequent CD or UC risk, and further examined whether these associations are linked to anti-inflammatory mechanisms.</p><p><strong>Methods: </strong>We conducted a prospective cohort study of 197,391 participants from the UK Biobank who completed at least one dietary questionnaire and were free from inflammatory bowel disease or cancer at baseline. Four dietary patterns were assessed, including Alternate Mediterranean Diet (AMED), Healthy Eating Index 2015 (HEI-2015), Healthful Plant-based Diet Index (HPDI), and EAT-Lancet. Cox proportional models with restricted cubic splines were applied to explore the associations. The potential role of low-grade inflammation in these associations was examined through mediation analysis.</p><p><strong>Results: </strong>During 2,193,436 person-years follow-up, 260 CD and 601 UC cases were identified. Higher AMED and HEI-2015 scores were associated with a reduced risk of CD but no UC, with no evidence against nonlinearity. These associations remained consistent across multiple sensitive and subgroup analyses. For dietary components, the fruits and monounsaturated fatty acids: saturated fatty acids ratio in AMED, and total fruits, total protein foods and fatty acid in HEI-2015 were linked to a decreased CD risk. Both diets were also associated with lower plasma inflammation biomarkers. Mediation analysis indicated that 7.66% and 13.40% of the reductions in CD risk attributed to AMED and HEI-2015 diets, respectively, were mediated by low-grade inflammation scores.</p><p><strong>Conclusions: </strong>Higher adherence to AMED and HEI-2015 might significantly reduce CD risk, partly due to their anti-inflammatory properties.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"589"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852849","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":"Pain can't be carved at the joints: defining function-based pain profiles and their relevance to chronic disease management in healthcare delivery design.","authors":"Daniel S Barron, Karin Saltoun, Hannah Kiesow, Melanie Fu, Jessica Cohen-Tanugi, Paul Geha, Dustin Scheinost, Zacharia Isaac, David Silbersweig, Danilo Bzdok","doi":"10.1186/s12916-024-03807-z","DOIUrl":"10.1186/s12916-024-03807-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pain is a complex problem that is triaged, diagnosed, treated, and billed based on which body part is painful, almost without exception. While the \"body part framework\" guides the organization and treatment of individual patients' pain conditions, it remains unclear how to best conceptualize, study, and treat pain conditions at the population level. Here, we investigate (1) how the body part framework agrees with population-level, biologically derived pain profiles; (2) how do data-derived pain profiles interface with other symptom domains from a whole-body perspective; and (3) whether biologically derived pain profiles capture clinically salient differences in medical history.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To understand how pain conditions might be best organized, we applied a carefully designed a multi-variate pattern-learning approach to a subset of the UK Biobank (n = 34,337), the largest publicly available set of real-world pain experience data to define common population-level profiles. We performed a series of post hoc analyses to validate that each pain profile reflects real-world, clinically relevant differences in patient function by probing associations of each profile across 137 medication categories, 1425 clinician-assigned ICD codes, and 757 expert-curated phenotypes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We report four unique, biologically based pain profiles that cut across medical specialties: pain interference, depression, medical pain, and anxiety, each representing different facets of functional impairment. Importantly, these profiles do not specifically align with variables believed to be important to the standard pain evaluation, namely painful body part, pain intensity, sex, or BMI. Correlations with individual-level clinical histories reveal that our pain profiles are largely associated with clinical variables and treatments of modifiable, chronic diseases, rather than with specific body parts. Across profiles, notable differences include opioids being associated only with the pain interference profile, while antidepressants linked to the three complimentary profiles. We further provide evidence that our pain profiles offer valuable, additional insights into patients' wellbeing that are not captured by the body-part framework and make recommendations for how our pain profiles might sculpt the future design of healthcare delivery systems.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Overall, we provide evidence for a shift in pain medicine delivery systems from the conventional, body-part-based approach to one anchored in the pain experience and holistic profiles of patient function. This transition facilitates a more comprehensive management of chronic diseases, wherein pain treatment is integrated into broader health strategies. By focusing on holistic patient profiles, our approach not only addresses pain symptoms but also supports the management of underlying chronic conditions, thereby enhancing patie","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"594"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852851","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":"The association of HDL-cholesterol levels with incident major adverse cardiovascular events and mortality in 0.6 million individuals with type 2 diabetes: a population-based retrospective cohort study.","authors":"David Tak Wai Lui, Lanlan Li, Xiaodong Liu, Xi Xiong, Eric Ho Man Tang, Chi Ho Lee, Yu Cho Woo, Brian Hung Hin Lang, Carlos King Ho Wong, Kathryn Choon Beng Tan","doi":"10.1186/s12916-024-03810-4","DOIUrl":"10.1186/s12916-024-03810-4","url":null,"abstract":"<p><strong>Background: </strong>High levels of high-density lipoprotein cholesterol (HDL-C) are previously considered protective against cardiovascular diseases (CVD), but recent studies suggest an increased risk of adverse events at very high HDL-C levels in the general population. It remains to be elucidated such a relationship in diabetes, a condition with high cardiovascular risks. We examined the association of HDL-C levels with the risk of major adverse cardiovascular events (MACE) and mortality in type 2 diabetes.</p><p><strong>Methods: </strong>This retrospective cohort study identified individuals with type 2 diabetes who had HDL-C records (2008-2020) from the electronic health record database of the Hong Kong Hospital Authority. They were classified into three groups based on their first-recorded HDL-C levels following diabetes diagnosis: low (≤ 40 mg/dL), medium (> 40 and ≤ 80 mg/dL) and high HDL-C (> 80 mg/dL) groups. The primary outcome was incident MACE (composite of myocardial infarction, stroke, heart failure, and cardiovascular mortality). Cox regression model and restricted cubic spline analysis were employed to assess the relationship between HDL-C and adverse outcomes.</p><p><strong>Results: </strong>Among 596,943 individuals with type 2 diabetes included, 168,931 (28.30%), 412,863 (69.16%), and 15,149 (2.54%) were classified as low HDL-C, medium HDL-C, and high HDL-C groups, respectively. Over a median follow-up of 79.5 months, both low and high HDL-C groups had higher risk of incident MACE compared to the medium HDL-C group (HR 1.24, 95% CI 1.23-1.26, P < 0.001; HR 1.09, 95% CI 1.04-1.13, P < 0.001). The spline curves revealed a U-shaped association between HDL-C levels and incident MACE (non-linear p < 0.001). Similar U-shaped relationship was observed for all-cause and non-cardiovascular mortality.</p><p><strong>Conclusions: </strong>Our study demonstrated a U-shaped association between HDL-C levels and incident MACEs and all-cause and non-cardiovascular mortality in individuals with type 2 diabetes, highlighting the need for mechanistic studies on the adverse outcomes seen at high HDL-C levels in type 2 diabetes.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"586"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852856","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":"Coffee consumption and adverse cardiovascular events in patients with atrial fibrillation.","authors":"Vasco Iten, Elena Herber, Michael Coslovsky, Elisa Hennings, Rebecca E Paladini, Tobias Reichlin, Nicolas Rodondi, Andreas S Müller, Annina Stauber, Juerg H Beer, Roman Brenner, Giulio Conte, Richard Kobza, Marcello Di Valentino, Patricia Chocano Bedoya, Freschteh Moradi, Tim Sinnecker, Leo H Bonati, Michael Kühne, Stefan Osswald, David Conen, Stefanie Aeschbacher, Christine S Zuern","doi":"10.1186/s12916-024-03817-x","DOIUrl":"10.1186/s12916-024-03817-x","url":null,"abstract":"<p><strong>Background: </strong>There is some evidence of reduced major cardiovascular event (MACE) rates associated with moderate coffee consumption in the general population. However, there is concern about the potential risks of coffee consumption in patients with atrial fibrillation (AF). Therefore, we aimed to investigate the association between coffee consumption and MACE in AF patients.</p><p><strong>Methods: </strong>Data of patients with documented AF enrolled in two large prospective observational multicenter cohort studies (Swiss-AF and Beat-AF) were analyzed. Follow-up information was obtained on a yearly basis. Coffee consumption was categorized into two main groups: \"daily\" and \"not-daily\" coffee consumers as well as additional subcategories. The primary endpoint was MACE, defined as a composite of stroke or systemic embolism, myocardial infarction, hospitalization for acute heart failure, and cardiovascular mortality. Secondary endpoints were the individual components of MACE and all-cause mortality. We performed time-updated multivariable adjusted Cox regression analyses to investigate the association between coffee consumption and MACE.</p><p><strong>Results: </strong>The incidence rate for MACE was 5.09 per 100 person-years (py) in daily and 7.49 per 100 py in not-daily consumers (median follow-up duration: 4.7 years). After adjustment for pre-selected confounding variables, daily coffee consumption was associated with a 23% lower hazard for MACE compared to not-daily consumption (hazard ratio (HR) (95% confidence interval (CI)) 0.77 (0.66; 0.89)). Patients with moderate coffee consumption (2-3 cups/day) had the lowest hazard for MACE compared to patients with not-daily coffee consumption (HR (95% CI) 0.74 (0.63; 0.87)).</p><p><strong>Conclusions: </strong>In a population of AF patients, daily coffee consumption was associated with a reduced risk for MACE, hospitalization for acute heart failure, and all-cause mortality. The results were inconclusive for stroke or systemic embolism, myocardial infarction, and cardiovascular death. In this analysis, we found no evidence of an unfavourable association of daily coffee consumption in AF Patients with adverse outcome events.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT02105844.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"593"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852847","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":"Immune changes in pregnancy: associations with pre-existing conditions and obstetrical complications at the 20th gestational week-a prospective cohort study.","authors":"David Westergaard, Agnete Troen Lundgaard, Kilian Vomstein, Line Fich, Kathrine Vauvert Römmelmayer Hviid, Pia Egerup, Ann-Marie Hellerung Christiansen, Josefine Reinhardt Nielsen, Johanna Lindman, Peter Christoffer Holm, Tanja Schlaikjær Hartwig, Finn Stener Jørgensen, Anne Zedeler, Astrid Marie Kolte, Henrik Westh, Henrik Løvendahl Jørgensen, Nina la Cour Freiesleben, Karina Banasik, Søren Brunak, Henriette Svarre Nielsen","doi":"10.1186/s12916-024-03797-y","DOIUrl":"10.1186/s12916-024-03797-y","url":null,"abstract":"<p><strong>Background: </strong>Pregnancy is a complex biological process and serious complications can arise when the delicate balance between the maternal and semi-allogeneic fetal immune systems is disrupted or challenged. Gestational diabetes mellitus (GDM), pre-eclampsia, preterm birth, and low birth weight pose serious threats to maternal and fetal health. Identification of early biomarkers through an in-depth understanding of molecular mechanisms is critical for early intervention.</p><p><strong>Methods: </strong>We analyzed the associations between 47 proteins involved in inflammation, chemotaxis, angiogenesis, and immune system regulation, maternal and neonatal health outcomes, and the baseline characteristics and pre-existing conditions of the mother in a prospective cohort of 1049 pregnant women around the 20th gestational week. We used Bayesian linear regression models to examine the impact of risk factors on biomarker levels and Bayesian cause-specific parametric proportional hazards models to analyze the effect of biomarkers on maternal and neonatal outcomes. We evaluated the predictive value of baseline characteristics and 47 proteins using machine-learning models and identified the most predictive biomarkers using Shapley additive explanation scores.</p><p><strong>Results: </strong>Associations were identified between specific inflammatory markers and several conditions, including maternal age and pre-pregnancy body mass index, chronic diseases, complications from prior pregnancies, and COVID-19 exposure. Smoking during pregnancy affected GM-CSF and 9 other biomarkers. Distinct biomarker patterns were observed for different ethnicities. Within obstetric complications, IL-6 inversely correlated with pre-eclampsia risk, while birth weight to gestational age ratio was linked to markers including VEGF and PlGF. GDM was associated with IL-1RA, IL-17D, and eotaxin-3. Severe postpartum hemorrhage correlated with CRP, IL-13, and proteins of the IL-17 family. Predictive modeling yielded area under the receiver operating characteristic curve values of 0.708 and 0.672 for GDM and pre-eclampsia, respectively. Significant predictive biomarkers for GDM included IL-1RA and eotaxin-3, while pre-eclampsia prediction yielded the highest predictions when including MIP-1β, IL-1RA, and IL-12p70.</p><p><strong>Conclusions: </strong>Our study provides novel insights into the interplay between preexisting conditions and immune dysregulation in pregnancy. These findings contribute to our understanding of the pathophysiology of obstetric complications and the identification of novel biomarkers for early intervention(s) to improve maternal and fetal health.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"583"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852850","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":"Physiological measures variability and risks of heart disease and stroke: evidence from three cohort studies.","authors":"Wei Liu, Lieyang Fan, Da Shi, Linling Yu, Jiahao Song, Ruyi Liang, Xuefeng Lai, Hao Wang, Yongfang Zhang, Shuhui Wan, Yueru Yang, Bin Wang","doi":"10.1186/s12916-024-03805-1","DOIUrl":"10.1186/s12916-024-03805-1","url":null,"abstract":"<p><strong>Background: </strong>The overall effect of long-term variability in physiological measures on cardiovascular health of older adults and the underlying mechanic pathway remain uncertain.</p><p><strong>Methods: </strong>We constructed a composite score (0 ~ 3) of variability in physiological measures, including blood pressure, pulse rate, and body mass index, in older adults from the China Health and Retirement Longitudinal Study (CHARLS) 2011 ~ 2015, the Health and Retirement Study (HRS) 2006/2008 ~ 2014/2016, and the UK Biobank 2006 ~ 2019. The associations of the composite score with incident risks of heart disease and stroke were assessed. The mediation roles of several biomarkers were explored.</p><p><strong>Results: </strong>A higher composite score was related to increased incident risk of heart disease in older adults from the US and the UK and increased incident risk of stroke in all three cohorts. Upon pooling the results, each 1-point increment in the composite score was associated with a 19% (hazard ratio: 1.19; 95% confidence interval: 1.14, 1.30) and a 23% (1.23; 1.12, 1.35) increments in incident risks of heart disease and stroke, respectively. The composite score also exhibited an inverse relationship with grip strength while displaying positive associations with C-reactive protein, glycosylated hemoglobin Alc (HbAlc), and cystatin C. Reduced grip strength, elevated HbAlc, and elevated cystatin C significantly mediated the composite score-associated elevated risks of heart disease and stroke.</p><p><strong>Conclusions: </strong>Long-term variability in physiological measures was associated with increased incident risks of heart disease and stroke, and the associations were partially mediated through deteriorated biomarkers of muscle strength, hyperglycemia, and kidney function.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"590"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852852","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":"Telomere length in relation to fecundability and use of assisted reproductive technologies: the Norwegian Mother, Father, and Child Cohort Study.","authors":"Karoline H Skåra, Yunsung Lee, Astanand Jugessur, Håkon K Gjessing, Abraham Aviv, Ben Brumpton, Øyvind Næss, Álvaro Hernáez, Hans Ivar Hanevik, Per Magnus, Maria C Magnus","doi":"10.1186/s12916-024-03795-0","DOIUrl":"10.1186/s12916-024-03795-0","url":null,"abstract":"<p><strong>Background: </strong>Telomere length (TL) has been reported to be associated with conditions such as endometriosis and polycystic ovary syndrome, with some studies finding associations with shorter TL and others with longer TL. In men, studies mostly report associations between shorter TL and sperm quality. To our knowledge, no studies have thus far investigated associations between TL and fecundability or the use of assisted reproductive technologies (ART).</p><p><strong>Methods: </strong>This study is based on the Norwegian Mother, Father, and Child Cohort (MoBa) Study and uses data from the Medical Birth Registry of Norway (MBRN). We included women (24,645 with genotype data and 1054 with TL measurements) and men (18,339 with genotype data and 965 with TL measurements) participating between 1998 and 2008. We investigated associations between leukocyte TL (LTL) and fecundability (defined as the probability to conceive within a given menstrual cycle), infertility (defined has having spent 12 months or more trying to conceive without success), and ART use. We also repeated the analyses using instrumental variables for LTL consisting of genetic risk scores for LTL and genetically predicted LTL.</p><p><strong>Results: </strong>Approximately 11% of couples had experienced infertility and 4% had used ART. LTL was not associated with fecundability in women (fecundability ratio [FR], 0.98; 95% confidence interval [CI], 0.92-1.04) or men (FR, 0.99; CI, 0.93-1.06), nor with infertility in women (odds ratio [OR], 1.03; CI, 0.85-1.24) or men (OR, 1.05; CI, 0.87-1.28). We observed an increased likelihood of using ART with increasing LTL in men (OR, 1.22; CI, 1.03-1.46), but not in women (OR, 1.10; CI, 0.92-1.31). No significant associations were observed using the instrumental variables for LTL.</p><p><strong>Conclusions: </strong>We found no indication that LTL is a suitable biomarker for assessing fecundability, infertility, or ART use. Additional studies are required to replicate the association observed between LTL and ART use in men.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"580"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852855","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":"Strength of clinical evidence supporting the United States Food and Drug Administration Accelerated Approvals from 2015 to 2022.","authors":"Xiaofang Zhang, Carl C Peck, Yaning Wang, Thomas D Szucs, Wan Sun, Xue Bai, Siyu Chen, Fengzhi Wang, Yangfeng Wu","doi":"10.1186/s12916-024-03800-6","DOIUrl":"10.1186/s12916-024-03800-6","url":null,"abstract":"<p><strong>Background: </strong>The Food and Drug Administration (FDA)'s Accelerated Approval (AA) pathway has increasingly used to authorize market approval of new drugs amid controversy. The present study aims to inform the most recent data on the strength of clinical evidence supporting such approvals.</p><p><strong>Methods: </strong>Evidentiary characteristics of pre-approval pivotal clinical studies and regulator-required post-approval confirmatory studies supporting AAs between 2015 and 2022 were extracted from publicly available FDA documents. Descriptive analyses were conducted for each of the characteristic including study design, study phase, primary endpoint, number of participants, and magnitude of effect. Trends of these characteristics over time were documented and accounted for class of drugs, application type, novelty, orphan status, and oncology/non-oncology indications.</p><p><strong>Results: </strong>During 2015-2022, 156 drug-indication pairs received AA. To support these AAs, 77% of pre-approval pivotal trials employed single-arm designs, and 22% were phase I trials, with a median of 92 participants (IQR, 45-125); 61% of post-approval confirmatory studies were required by FDA to use randomized controlled design, 25% to use clinical endpoints, and 33% specified the number of participants requirement. During the 8-year observation period, the pairs approved via AA pathway almost tripled from 20 (2015-2016) to 59 (2019-2020) and fell to 36 (2021-2022); the corresponding proportion to all new drug approvals showed the same trend. Single-arm pre-approval pivotal studies increased from 55% (2015-2016) to 91% (2019-2020) and fell to 69% (2021-2022), while the median number of participants decreased from 106 (2015-2016) to 59 (2019-2020) and rose to 106 (2021-2022). Randomized controlled post-approval confirmatory studies decreased from 75% (2015-2016) to 42% (2019-2020) and rebounded to 75% (2021-2022), while those using surrogate endpoints increased from 50% (2015-2016) to 72% (2021-2022). Analyses adjusting for drug class, application type, novelty, orphan status, and oncology/non-oncology showed similar results.</p><p><strong>Conclusions: </strong>The number of drug-indication pairs receiving AA increased sharply during 2015-2016 to 2019-2020 but fell in 2021-2022. Meanwhile, the strength of clinical evidence supporting FDA's AAs appeared to decline from 2015 to 2020 but seems to have improved in 2021-2022. Measures should be taken to further improve the strength of evidence in Accelerated Approvals.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"587"},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852854","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":"Cognitive benefits of folic acid supplementation during pregnancy track with epigenetic changes at an imprint regulator.","authors":"L Hilman, M Ondičová, A Caffrey, M Clements, C Conway, M Ward, K Pentieva, R E Irwin, H McNulty, C P Walsh","doi":"10.1186/s12916-024-03804-2","DOIUrl":"10.1186/s12916-024-03804-2","url":null,"abstract":"<p><strong>Background: </strong>The human ZFP57 gene is a major regulator of imprinted genes, maintaining DNA methylation marks that distinguish parent-of-origin-specific alleles. DNA methylation of the gene itself has shown sensitivity to environmental stimuli, particularly folate status. However, the role of DNA methylation in ZFP57's own regulation has not been fully investigated.</p><p><strong>Methods: </strong>We used samples and data from our previously described randomised controlled trial (RCT) in pregnancy called Folic Acid Supplementation in the Second and Third Trimester (FASSTT), including follow-up of the children at age 11. Biometric and blood biochemistry results were examined for mothers and children. Methylation of ZFP57 was analysed by EPIC arrays, pyrosequencing and clonal analysis, and transcription assessed by PCR-based methods. Functional consequences of altered methylation were examined in cultured cells with mutations or by inhibition of the main DNA methyltransferases. DNA variants were examined using pyrosequencing and Sanger sequencing, with results compared to published studies using bioinformatic approaches. Cognitive outcomes were assessed using the Wechsler Intelligence Scale for Children 4th UK Edition (WISC-IV), with neural activity during language tasks quantified using magnetoencephalography (MEG).</p><p><strong>Results: </strong>Here we show that methylation at an alternative upstream promoter of ZFP57 is controlled in part by a quantitative trait locus (QTL). By altering DNA methylation levels, we demonstrate that this in turn controls the expression of the ZFP57 isoforms. Methylation at this region is also sensitive to folate levels, as we have previously shown in this cohort. Fully methylated alleles were associated with poorer performance in the Symbol Search and Cancellation subtests of WISC-IV in the children at age 11 years. There were also differences in neural activity during language tasks, as measured by MEG. Analysis of published genome-wide studies indicated other SNPs in linkage disequilibrium with the mQTL were also associated with neurodevelopmental outcomes.</p><p><strong>Conclusions: </strong>While numbers in the current RCT were small and require further validation in larger cohorts, the results nevertheless suggest a molecular mechanism by which maternal folic acid supplementation during pregnancy may help to counteract the effects of folate depletion and positively influence cognitive development in the offspring.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"579"},"PeriodicalIF":7.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833780","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":"Gabapentinoid use and the risk of fractures in patients with inflammatory arthritis: nested case-control study in the Clinical Practice Research Datalink Aurum.","authors":"Ian C Scott, Noor Daud, James Bailey, Helen Twohig, Samantha L Hider, Christian D Mallen, Kelvin P Jordan, Sara Muller","doi":"10.1186/s12916-024-03774-5","DOIUrl":"10.1186/s12916-024-03774-5","url":null,"abstract":"<p><strong>Background: </strong>Gabapentinoids are increasingly prescribed in inflammatory arthritis (IA), despite no trial evidence for efficacy at managing pain in this population. Observational studies in non-IA populations suggest gabapentinoids are associated with fractures but are limited by methodological heterogeneity/potential residual confounding. Patients with IA generally have an increased risk of fracture so may be particularly vulnerable. We examined the relationship between fractures and gabapentinoids in patients with IA who had all been prescribed a gabapentinoid at some point (to minimise confounding by indication).</p><p><strong>Methods: </strong>Our matched case-control study used linked national data from English primary care (Clinical Practice Research Datalink Aurum) and Hospital Episode Statistics. A cohort was constructed of adults with IA, contributing data 01/01/2004-31/03/2021, and ever prescribed oral gabapentinoids. Cases with an incident fracture post-cohort inclusion were ascertained and 1:5 risk set-matched (on age/gender/gabapentinoid type) with controls. Gabapentinoid prescription exposure was categorised as follows: (a) current (overlapping with fracture date); (b) recent (ending 1-60 days pre-fracture); and (c) remote (ending > 60 days pre-fracture). Conditional logistic regression models determined ORs with 95% CIs for fractures with current or recent vs. remote gabapentinoid use, adjusting for confounders.</p><p><strong>Results: </strong>A total of 2485 cases (mean age 63.0 years; 79.4% female) and 12,244 controls (mean age 62.7 years; 79.6% female) were included. Of cases: 1512 received gabapentin, 910 pregabalin, and 63 both drugs; 65.6% were remote, 5.5% recent, and 28.9% current users. In adjusted models, current gabapentinoid use had an increased risk of fracture (OR vs. remote: 1.36 [95% CI 1.22, 1.51]). Similar associations were seen with gabapentin (OR 1.38 [1.19, 1.60]) and pregabalin (OR 1.40 [1.18, 1.66]). Similar or higher levels of association were seen for all gabapentin/pregabalin doses except moderate/very high dose gabapentin. Associations were strongest in those starting gabapentinoids more recently.</p><p><strong>Conclusions: </strong>Our study suggests a modest association between current gabapentinoid use and fractures in patients with IA, after accounting for measured and time-invariant unmeasured confounding. Whilst other unmeasured confounding remains possible, given the absence of evidence for gabapentinoid efficacy in patients with IA who are particularly vulnerable to fractures, this highlights a need for efforts to deliver safer gabapentinoid prescribing in this population.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"575"},"PeriodicalIF":7.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811721","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}