BMC Medicine最新文献

{"title":"School-age outcomes among IVF and ICSI-conceived children: a causal inference analysis using linked population-wide data.","authors":"Amber L Kennedy, Richard J Hiscock, Beverley J Vollenhoven, Catharyn J Stern, Lyle C Gurrin, Tiki Osianlis, Aleah Kink, Susan P Walker, Jeanie L Y Cheong, Jon L Quach, David Wilkinson, John McBain, Mark P Green, Jessica A Atkinson, Franca Agresta, Susan P Baohm, Stephen Tong, Roxanne Hastie, Anthea C Lindquist","doi":"10.1186/s12916-025-03963-w","DOIUrl":"10.1186/s12916-025-03963-w","url":null,"abstract":"<p><strong>Background: </strong>Use of intracytoplasmic sperm injection (ICSI) continues to increase as the most common mode of oocyte insemination during in vitro fertilisation (IVF), sometimes in the absence of clear indications (i.e. male factor infertility). Several studies suggest an increased risk of congenital abnormalities after ICSI. The association between the ICSI technique and long-term childhood development remains unclear.</p><p><strong>Methods: </strong>Our population-based study included singleton infants conceived via IVF and born between 2005 and 2013. The cohort included state-wide linked maternal and childhood administrative data from Victoria, Australia. The primary exposure was conception via ICSI (without severe male factor infertility), with those born following standard IVF as controls. Childhood development was examined using the Australian Early Development Census (AEDC), a broad assessment of childhood development across five domains of health and neurodevelopment performed in Australian schools every triennium at school entry (age 4-6 years). Our primary outcome used a validated global measure-developmental vulnerability-defined as scoring less than the 10th percentile in two or more of the five developmental domains (DV2). Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The adjustment variable set was determined a priori via a modified Delphi procedure. Given the use of observational data, there were missing data and inherent differences in the covariate profile between exposure cohorts. Multiple imputation, bootstrapping and doubly robust inverse probability weighted regression adjustment modelling was utilised to allow a causal interpretation of results.</p><p><strong>Results: </strong>Our cohort (N = 3656) included 1489 IVF and 2167 ICSI-conceived children. We found no causal effect of ICSI on the risk of AEDC-defined developmental vulnerability at school-entry age compared with children conceived via standard IVF; adjusted risk difference - 1.11% (95% CI - 4.23 to 2.01%) and adjusted risk ratio 0.90 (95% CI 0.68 to 1.21).</p><p><strong>Conclusions: </strong>Our findings suggest that the use of ICSI in IVF cycles without severe male factor infertility does not increase the risk of early childhood developmental vulnerability among children in their first year of school. These findings provide important reassurance for current and prospective parents and clinicians alike.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"194"},"PeriodicalIF":7.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762890","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":"tesG expression as a potential clinical biomarker for chronic Pseudomonas aeruginosa pulmonary biofilm infections.","authors":"Dhammika Leshan Wannigama, Cameron Hurst, Peter N Monk, Gunter Hartel, William Graham Fox Ditcham, Parichart Hongsing, Phatthranit Phattharapornjaroen, Puey Ounjai, Pattama Torvorapanit, Kamonwan Jutivorakool, Sirirat Luk-In, Sumanee Nilgate, Ubolrat Rirerm, Chanikan Tanasatitchai, Kazuhiko Miyanaga, Longzhu Cui, Naveen Kumar Devanga Ragupathi, S M Ali Hosseini Rad, Aisha Khatib, Robin James Storer, Hitoshi Ishikawa, Mohan Amarasiri, Somrat Charuluxananan, Asada Leelahavanichkul, Talerngsak Kanjanabuch, Paul G Higgins, Jane C Davies, Stephen M Stick, Anthony Kicic, Tanittha Chatsuwan, Kenji Shibuya, Shuichi Abe","doi":"10.1186/s12916-025-04009-x","DOIUrl":"10.1186/s12916-025-04009-x","url":null,"abstract":"<p><strong>Background: </strong>Pseudomonas aeruginosa infections in the lungs affect millions of children and adults worldwide. To our knowledge, no clinically validated prognostic biomarkers for chronic pulmonary P. aeruginosa infections exist. Therefore, this study aims to identify potential prognostic markers for chronic P. aeruginosa biofilm lung infections.</p><p><strong>Methods: </strong>Here, we screened the expression of 11 P. aeruginosa regulatory genes (tesG, algD, lasR, lasA, lasB, pelB, phzF, rhlA, rsmY, rsmZ, and sagS) to identify associations between clinical status and chronic biofilm infection.</p><p><strong>Results: </strong>RNA was extracted from 210 sputum samples from patients (n = 70) with chronic P. aeruginosa lung infections (mean age; 29.3-56.2 years; 33 female). Strong biofilm formation was correlated with prolonged hospital stays (212.2 days vs. 44.4 days) and increased mortality (46.2% (18)). Strong biofilm formation is associated with increased tesG expression (P = 0.001), influencing extended intensive care unit (P = 0.002) or hospitalisation stays (P = 0.001), pneumonia risk (P = 0.006), and mortality (P = 0.001). Notably, tesG expression is linked to the modulation of systemic and sputum inflammatory responses and predicts biofilm biomass.</p><p><strong>Conclusions: </strong>This study provides the first clinical dataset of tesG expression levels as a predictive biomarker for chronic P. aeruginosa pulmonary infections.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"191"},"PeriodicalIF":7.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750066","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":"Enhancing anti-CD3 mAb-mediated diabetes remission in autoimmune diabetes through regulation of dynamin-related protein 1(Drp1)-mediated mitochondrial dynamics in exhausted CD8⁺T-cell subpopulations.","authors":"Ruiling Zhao, Zhangyao Su, Junjie Gu, Hang Zhao, Lingling Bian, Yin Jiang, Yun Cai, Tao Yang, Yong Gu, Xinyu Xu","doi":"10.1186/s12916-025-04001-5","DOIUrl":"10.1186/s12916-025-04001-5","url":null,"abstract":"<p><strong>Background: </strong>Antigen-specific immunotherapy shows potential for inducing long-term immune tolerance in type 1 diabetes (T1D), yet its clinical application is hampered by uncertainty regarding dominant epitopes. Conversely, non-antigen-specific treatments such as anti-CD3 monoclonal antibodies (mAbs) present a more straightforward approach but struggle to maintain tolerance after treatment. Addressing these issues is critical for advancing T1D therapies.</p><p><strong>Methods: </strong>The phenotypic and metabolic properties of two subsets of exhausted CD8⁺ T cells were analyzed in both humans and NOD mice. T-cell receptor (TCR) diversity and Bulk RNA sequencing provided insights into the transcriptomic profiles and TCR reactivity of these cells. Mechanistic studies were conducted using the HEK-293 T cell line and primary cells. Single-cell RNA sequencing (scRNA-seq) was applied to evaluate the characteristics of different CD8⁺ T cell subsets following two types of immunotherapies. In NY8.3 mice, the effect of mitochondrial fission inhibitors on immunotherapy results was evaluated. Final validation was carried out with peripheral blood mononuclear cells (PBMCs) from T1D patients.</p><p><strong>Results: </strong>Our study reveals the diversity of two distinct exhausted CD8⁺ T cell subsets in T1D through flow cytometry, highlighting unique clinical features, phenotypes, and functions. Notable differences in TCR reactivity and metabolic pathways between these subsets were identified through TCR sequencing and transcriptomic analyses in NOD mice. Both antigen-specific and non-antigen-specific stimuli produced unique exhausted CD8⁺ T cell subsets. Our research identified leucine-rich repeat kinase 2 (Lrrk2) as a key regulator of mitochondrial fission, influencing the interconversion of exhausted CD8⁺ T cell subsets by phosphorylating dynamin-related protein 1 (DRP1) at serine 637 (Ser637) and serine 616 (Ser616). scRNA-seq confirmed that antigen-specific immunotherapy effectively suppresses T cell signaling, induces exhaustion, and promotes the development of terminally exhausted T (TEX) cells. Mitochondrial division inhibitor 1 (Mdivi-1) enhanced the therapeutic effect of anti-CD3 mAb treatment by promoting the development of more TEX cells.</p><p><strong>Conclusions: </strong>Our results point to a new immunotherapeutic approach that targets exhausted CD8⁺ T cells' energy metabolism, offering valuable insights for advancing clinical strategies in T1D therapy.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"189"},"PeriodicalIF":7.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751043","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":"Correction: The chemoprotective effect of anti-platelet agents on cancer incidence in people with non-alcoholic fatty liver disease (NAFLD): a retrospective cohort study.","authors":"Matthew Anson, Jun Shang Poon, Alex E Henney, David Riley, Gema H Ibarbaru, Cyril Sieberhagen, Daniel J Cuthbertson, Uazman Alam, Theresa Hydes","doi":"10.1186/s12916-025-04033-x","DOIUrl":"10.1186/s12916-025-04033-x","url":null,"abstract":"","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"193"},"PeriodicalIF":7.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751042","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":"Improving type 2 diabetes detection among at-risk individuals - comparing the effectiveness of active opportunistic screening using spot capillary-HbA1c testing and venous HbA1c testing: a cluster randomized controlled trial.","authors":"Linda Chan, Esther Yee Tak Yu, Eric Yuk Fai Wan, Samuel Yeung Shan Wong, David Vai Kiong Chao, Welchie Wai Kit Ko, Catherine Xiao Rui Chen, Paul Po Ling Chan, Emma Victoria Marianne Bilney, Eng Sing Lee, Wei Leik Ng, Cindy Lo Kuen Lam","doi":"10.1186/s12916-025-04007-z","DOIUrl":"10.1186/s12916-025-04007-z","url":null,"abstract":"<p><strong>Background: </strong>Delayed diagnosis and treatment of type 2 diabetes increases diabetes-related complications, making the high prevalence of undiagnosed type 2 diabetes in Hong Kong an important concern. Point-of-care capillary HbA1c (POC-cHbA1c) testing holds promise as a comparably accurate, convenient, and timely alternative to venous HbA1c (vHbA1c) for type 2 diabetes screening, yet randomized trials are lacking. This study compared the effectiveness of a 2-step active opportunistic screening strategy using POC-cHbA1c versus usual practice employing vHbA1c and multiple clinic visits in detecting type 2 diabetes among at-risk primary care patients. The primary outcomes were to identify the difference in the proportion of type 2 diabetes detected between intervention (POC-cHbA1c) and control (vHbA1c) groups and the uptake rate of POC-cHbA1c versus vHbA1c testing among consenting participants.</p><p><strong>Methods: </strong>A cluster randomized controlled trial was conducted in 8 General Out-Patient Clinics between June 2022 and January 2024 using 2-step active opportunistic screening. In step 1, risk factor count, 852 at-risk patients were identified through consecutive sampling during their primary care consultation by specific inclusion and exclusion criteria. In step 2, these at-risk patients then underwent POC-cHbA1c (intervention) or vHbA1c (control) testing. If preliminary HbA1c was ≥ 5.6%, a confirmatory oral glucose tolerance test was offered. Randomization occurred at the clinic level using a random allocation sequence generated by statistical software. Multilevel logistic regression analyses were employed to evaluate the effect of the intervention on the uptake rate, adjusting for patient characteristics and clinic clustering.</p><p><strong>Results: </strong>POC-cHbA1c had a higher uptake rate than vHbA1c (76.0% vs 37.5%; OR = 7.06, 95% CI [2.47-20.18], p < 0.001). A greater proportion of type 2 diabetes (4.2% vs 1.4%; p = 0.016) and pre-diabetes (11.8% vs 6.9%; p = 0.015) were detected using POC-cHbA1c versus vHbA1c. POC-cHbA1c was more likely to detect type 2 diabetes/pre-diabetes combined (OR = 1.99, 95% CI [1.01-3.95], p = 0.048). The number-needed-to-screen to detect one additional type 2 diabetes patient with POC-cHbA1c was 61 versus vHbA1c.</p><p><strong>Conclusions: </strong>POC-cHbA1c testing was associated with a higher uptake rate and detection of type 2 diabetes versus vHbA1c, underscoring its potential as an effective type 2 diabetes screening strategy in primary care.</p><p><strong>Trial registration: </strong>NCT06382363 (retrospectively registered: 2024-04-19).</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"190"},"PeriodicalIF":7.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751148","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":"Cancer risk subsequent to cardiovascular disease: a prospective population-based study and meta-analysis.","authors":"Chi Shu, Huiqiao Han, Hong Li, Linru Wei, Hong Wu, Changtao Li, Xuan Xie, Bin Zhang, Zhexuan Li, Xin Chen, Jichun Zhao, Yanhong Zhou, Yazhou He, Chuan Xu","doi":"10.1186/s12916-025-04013-1","DOIUrl":"10.1186/s12916-025-04013-1","url":null,"abstract":"<p><strong>Background: </strong>Previous preclinical studies have revealed the biological links between cardiovascular diseases (CVD) and cancer. However, population-based evidence remained inconclusive.</p><p><strong>Methods: </strong>We assessed cancer incidence among individuals with and without CVD condition in a prospective cohort from the UK Biobank (UKB). Multivariable Cox regression and competing risk models were fitted to estimate hazard ratios (HR). A systematic literature search was conducted in Medline, Embase and Cochrane Library databases to identify published population-based cohort studies (last updated on 1 October 2023) investigating the associations between CVD status and subsequent cancer risk. Random-effects meta-analysis was employed to pool relative effect estimates reported by eligible cohorts. Subgroup and sensitivity analyses were conducted to evaluate the associations across various CVD and cancer subtypes.</p><p><strong>Results: </strong>For the cohort study in the UKB, after a median follow-up of 11.58 years, a total of 18,471 and 66,891 cancer cases occurred among 94,845 CVD patients and 368,695 non-CVD individuals (Incidence rate: 25.62 vs. 15.41 per 1000 person-years). Individuals with prior CVD exhibited higher overall cancer risk (HR 1.14, 95% CI 1.12-1.17, p < 0.001), and we observed consistently higher cancer risk after adjusting for competing risk from non-cancer deaths. The effect size of CVD on cancer risk was greater among younger individuals (< 65 years) than those ≥ 65 years (p for interaction < 0.001). The meta-analysis included 47 population-based cohort studies where a total of 1.49 million cancer cases were documented among over 45 million participants (9.49 million CVD patients). A 13% higher risk of overall cancer was observed among individuals with prior CVD (pooled RR 1.13, 95% CI 1.11-1.15, p < 0.001). The associations remained significant between various CVD subtypes and cancer risk at multiple sites.</p><p><strong>Conclusions: </strong>Our study identified a significantly higher cancer risk among individuals with CVD conditions compared with the non-CVD population, underpinning the need for continued cancer surveillance among CVD patients and further exploration of the possible etiological relation between CVD and cancer.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"192"},"PeriodicalIF":7.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751041","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":"Ketorolac in the perioperative management of acute type A aortic dissection: a randomized double-blind placebo-controlled trial.","authors":"Zhi-Kang Lv, Hai-Tao Zhang, Xiu-Juan Cai, Wen-Xin Su, Er-Jun Zhu, Hoshun Chong, Xi-Yu Zhu, You-Ru Kong, Yu-Xian Tang, Xin Li, Yuan-Xi Luo, Han-Qing Luo, Hao-Dong Pan, Yan-Hua Sun, Kai Li, Min Jin, Shu-Chun Li, Hong-Yu Chen, Ze-Qi Bi, Ying-Liang Zhao, Zhen-Jun Xu, Yong-Qing Cheng, Wan-Zi Xu, Cheng Chen, Wei-Wei Zhao, Zhi-Gang Wang, Li-Chong Lu, Jun Pan, Fu-Dong Fan, Yun-Xing Xue, Bo-Ming Zhang, Min Ge, Jia-Xin Ye, Chui-Yu Kong, Bao-Dong Xie, Tuo Pan, Dong-Jin Wang","doi":"10.1186/s12916-025-04021-1","DOIUrl":"https://doi.org/10.1186/s12916-025-04021-1","url":null,"abstract":"<p><strong>Background: </strong>Acute Type A Aortic Dissection (aTAAD) is a severe and life-threatening condition. While animal studies have suggested that ketorolac could slow the progression of aortic aneurysms and dissections, clinical data on its efficacy in aTAAD patients remain limited. This study seeks to evaluate the safety and effectiveness of ketorolac in this patient group.</p><p><strong>Methods: </strong>Patients were randomly assigned to receive either ketorolac or a placebo (0.9% saline). Treatment began at least 2 h prior to surgery (60 mg ketorolac or 2 ml saline administered once intramuscularly) and continued for 48 h post-surgery (30 mg ketorolac or 1 ml saline administered intramuscularly twice daily). The primary endpoints included assessing the safety and efficacy of ketorolac in improving the prognosis of aTAAD, focusing on mortality and organ malperfusion syndrome. Secondary endpoints included drug-related adverse events, blood test results, and other postoperative outcomes.</p><p><strong>Results: </strong>Of 179 patients who underwent aTAAD repair, 110 met the inclusion criteria and were randomized into two groups of 55. One patient discontinued the intervention due to erythroderma on the first postoperative day, leaving 54 patients in the ketorolac group and 55 in the placebo group for analysis. No significant differences were found in the primary endpoints. However, the ketorolac group showed lower intraoperative bleeding (median: 1.8 L vs. 2.0 L, P = 0.03), shorter intensive care unit (ICU) stays (median: 6.5 days vs. 8 days, P = 0.04), and lower total hospital costs (median: ¥170,430 vs. ¥187,730, P = 0.03).</p><p><strong>Conclusions: </strong>Short-term ketorolac therapy did not alter the primary outcome but was associated with reduced intraoperative bleeding, shorter ICU stays, and potentially lower hospitalization costs. It demonstrates safety and a certain degree of effectiveness during the perioperative period. These findings suggest that ketorolac could be a viable option for perioperative management in patients with aTAAD.</p><p><strong>Trial registration: </strong>The trial was registered at the Chinese Clinical Trial Register ( www.chictr.org.cn , No: ChiCTR2300074394).</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"188"},"PeriodicalIF":7.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742351","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":"Exploratory analysis of the relationship between striatal connectivity and apathy during phosphodiesterase 10 inhibition in schizophrenia: findings from a randomized crossover trial.","authors":"Wolfgang Omlor, Giacomo Cecere, Gao-Yang Huang, Tobias Spiller, Akhil Ratan Misra, Finn Rabe, Nils Kallen, Matthias Kirschner, Werner Surbeck, Achim Burrer, George Garibaldi, Štefan Holiga, Juergen Dukart, Daniel Umbricht, Philipp Homan","doi":"10.1186/s12916-025-04004-2","DOIUrl":"https://doi.org/10.1186/s12916-025-04004-2","url":null,"abstract":"<p><strong>Background: </strong>Negative symptoms in schizophrenia remain a challenge with limited therapeutic strategies. The novel compound RG7203 promotes reward learning via dopamine D1-dependent signaling and therefore holds promise, especially to improve the apathy dimension of negative symptoms. When tested as add-on to antipsychotic medication, apathy did not change significantly with RG7203 versus placebo. However, the response varied across patients, and a subset showed clinically relevant improvement of apathy. It remains unclear if these interindividual differences are related to neurobiological correlates.</p><p><strong>Methods: </strong>Due to the predominant binding of RG7203 in the striatum, we investigated how apathy changes with RG7203 are related to changes in cortico-striatal connectivity by computing rank correlations (r_s). In a post hoc exploratory analysis, we focused on cortico-striatal circuits that have been associated with apathy and previously showed connectivity alterations in schizophrenia. In a double-blind, 3-way randomized and counterbalanced crossover study, resting-state functional magnetic resonance imaging was acquired from 24 individuals with schizophrenia following a 3-week administration of placebo, 5 mg, or 15 mg of RG7203 as an add-on to antipsychotics.</p><p><strong>Results: </strong>We found that 5 mg or 15 mg of RG7203 did not lead to significant changes in striatal connectivity. However, changes in the apathy response across individuals were reflected by striatal connectivity changes. Apathy improvement with 5 mg and 15 mg RG7203 vs. placebo was associated with increased striatal connectivity to paracingulate (r_s = - 0.58, p = 0.047 for both doses) and anterior cingulate regions (r_s = - 0.56, p = 0.047 for both doses). Such associations were not observed for the negative symptom dimension of expressive deficits. We additionally observed that lower striatal connectivity to paracingulate and anterior cingulate regions during placebo was linked to greater apathy improvement during RG7203 treatment at both doses (r_s = 0.61-0.79 and p = 0.0002-0.02 across regions and doses).</p><p><strong>Conclusions: </strong>These findings suggest that striatal connectivity with the paracingulate gyrus and anterior cingulate cortex may be associated with apathy modulation under RG7203 treatment. Replication and further elaboration of these findings in larger clinical studies could help to advance biologically informed and personalized treatment options for negative symptoms.</p><p><strong>Trial registration: </strong>NCT02824055, registered on ClinicalTrials.gov (2016-06-21).</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"187"},"PeriodicalIF":7.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742347","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":"Adjacent spillover efficacy of Wolbachia for control of dengue: emulation of a cluster randomised target trial.","authors":"Jue Tao Lim, Diyar Mailepessov, Chee Seng Chong, Borame Dickens, Yee Ling Lai, Youming Ng, Deng Lu, Caleb Lee, Li Yun Tan, Grace Chain, Soon Hoe Ho, Chia-Chen Chang, Pei Ma, Somya Bansal, Vernon Lee, Shuzhen Sim, Cheong Huat Tan, Lee Ching Ng","doi":"10.1186/s12916-025-03941-2","DOIUrl":"https://doi.org/10.1186/s12916-025-03941-2","url":null,"abstract":"<p><strong>Background: </strong>Matings between male Aedes aegypti mosquitoes infected with wAlbB strain of Wolbachia and wild-type females yield non-viable eggs, thereby suppressing Ae. aegypti abundance in the field. We evaluated the spillover efficacy of releasing wAlbB-infected Ae. aegypti male mosquitoes to suppress dengue in sites adjacent to release sites (spillover sites).</p><p><strong>Methods: </strong>The protocol of a two-arm cluster-randomised test-negative controlled trial (cRCT) was specified and emulated using a nationally representative dengue test-negative/positive database of 454,437 individuals reporting for febrile illness to primary or secondary care in public healthcare institutions. Spillover intervention sites were defined by geolocating locations which were adjacent to, i.e. shared geographical borders with, actual Wolbachia intervention sites. We built a cohort of individuals who resided in spillover sites versus a comparator control group who resided in sites which did not receive Wolbachia interventions. We emulated a constrained randomisation protocol used in cRCTs to balance dengue risk between spillover and control arms in the pre-intervention period. We matched individuals reporting for testing in intervention and control groups by calendar time and a high-dimensional battery of sociodemographic, environmental and anthropogenic variables. Intention-to-treat analysis was conducted to estimate the protective efficacy against dengue given spillover Wolbachia exposure.</p><p><strong>Results: </strong>The final cohort consisted of 2354 matched individuals residing in Wolbachia spillover and control sites for at least 3 months in the study period. Compared to the controls, individuals residing in spillover sites for 3 or more months were associated with a 45% (OR: 0.55, 95% CI: 0.42‒0.74) reduction in risk of contracting dengue. Higher durations of spillover Wolbachia exposure also modestly increased protective efficacies. Compared to the control arm, the proportion of virologically confirmed dengue cases was lower in the spillover arm overall and across each subgroup. Protective efficacies were found across all years, age and sex subgroups.</p><p><strong>Conclusions: </strong>Our results demonstrated the potential of Wolbachia-mediated sterility for reducing the risk of contracting dengue even in sites which were not directly treated by the intervention.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"184"},"PeriodicalIF":7.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742341","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 pilot cluster-controlled trial of interventions to improve detection of depression in primary healthcare in Ethiopia.","authors":"Abebaw Fekadu, Barkot Milkias, Rahel Birhane, Bethlehem Tekola, Mahlet Yared, Tigist Eshetu, Tomas Getahun, Heidi Lempp, Andre Tylee, Merga Belina, Girmay Medhin, Kassahun Habtamu, Atalay Alem, Crick Lund, Inge Petersen, Graham Thornicroft, Anthony J Cleare, Rosie Mayston, Esubalew A Assefa, Mekdes Demissie, Charlotte Hanlon, Martin J Prince","doi":"10.1186/s12916-025-04010-4","DOIUrl":"https://doi.org/10.1186/s12916-025-04010-4","url":null,"abstract":"<p><strong>Background: </strong>The low recognition of depression in primary healthcare (PHC) remains a major obstacle to rendering adequate care for people with depression globally. This study aimed to evaluate the feasibility and potential benefit of a contextually developed multicomponent and multilevel intervention to improve the identification of depression in PHC.</p><p><strong>Methods: </strong>A pilot, four-arm, parallel-group, cluster, non-randomised controlled trial was conducted in a predominantly rural district in Ethiopia. The active interventions were allocated to three PHC facilities: (1) a core multicomponent intervention focusing on providers-a manualised training package along with system intervention (mobile application, posters, quality improvement and supervision) (Level-I/Arm I), (2) Level-I intervention plus a 4-item screening questionnaire administered by triage nurses (Level-II/Arm II), (3) Level-II intervention plus service user awareness raising (Level-III/Arm III). In the control facility, standard integrated mental healthcare (care by providers trained in the standard WHO mhGAP intervention guide) was available. The outcomes were the identification of depression and the feasibility and acceptability of implementation by PHC clinicians. Quantitative and qualitative data were collected post-intervention. Descriptive analysis and thematic analysis were used to analyse the data.</p><p><strong>Results: </strong>A total of 21 providers (14 clinicians and 7 triage nurses) and 1659 adult outpatients participated in the study. Overall, 116 outpatients (7.0%) received a diagnosis of depression by PHC clinicians. Detection of depression was significantly better in the active intervention arms combined: 8.3% (n = 115/1380) vs. 0.4% (n = 1/279) in the control arm. Level-II and Level-III intervention arms had significantly higher rates of detection (10.1% Level II, 9.2% Level III) compared with Level I (5.2%); however, there was no significant difference between Level-II and Level-III. The interventions demonstrated very good acceptability, feasibility and appropriateness although screening, which was included in the Level II and Level III intervention arms, had relatively lower acceptability and an overall low positive predictive value.</p><p><strong>Conclusions: </strong>The tested interventions hold good promise of enhancing the identification of depression in PHC, with excellent feasibility and acceptability parameters. Although screening has good potential, implementation in routine care requires further optimisation and evaluation.</p><p><strong>Trial registration: </strong>Trial ID: PACTR202206723109626. Registration date: 21 June 2022. Retrospectively registered.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"185"},"PeriodicalIF":7.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742337","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}