BMC Medicine最新文献

{"title":"Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.","authors":"Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried","doi":"10.1186/s12916-024-03775-4","DOIUrl":"10.1186/s12916-024-03775-4","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"578"},"PeriodicalIF":7.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784093","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":"Ethics practices associated with reusing health data: an assessment of patient registries.","authors":"Olmo R van den Akker, Susanne Stark, Daniel Strech","doi":"10.1186/s12916-024-03799-w","DOIUrl":"10.1186/s12916-024-03799-w","url":null,"abstract":"<p><strong>Background: </strong>As routinely collected patient data have become increasingly accessible over the years, more attention has been directed at the ethics of using such data for research. Patient data is often available to researchers through patient registries that typically collect data of patients with a specific condition. While ethical guidelines for using patient data are presented frequently in the literature, it is currently unknown how patient registries implement the recommendations from these guidelines in practice and how they communicate their practices. In this project, we assessed to what extent a sample of 51 patient registries provides information about a range of ethics practices.</p><p><strong>Methods: </strong>We searched for patient registries in the resource database of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Our ethics reporting checklist was based on three sources: the Registry Evaluation and Quality Standards Tool (REQueST), the Agency for Healthcare Research and Quality (AHRQ) guide for good registry practices, and a systematic review of the principles and norms related to health data sharing by Kalkman and colleagues. The checklist includes 26 questions about five ethics components: governance, conflicts of interest, informed consent, privacy and data protection, and use-and-access.</p><p><strong>Results: </strong>We found substantial heterogeneity in the way patient registries provide information about ethics practices. Patient registries often mentioned their governance structure and any potential conflicts of interests but typically did not describe the responsibilities and rights allocated to their funders. Information about informed consent was often provided to patients, but the available documents often lacked relevant information like the benefits and risks of participation. Privacy and data protection and use-and-access policies were typically discussed but not very concretely.</p><p><strong>Conclusions: </strong>We conclude that registries typically provide information about key ethics practices such as governance, conflicts of interest, informed consent, privacy and data protection, and use-and-access procedures, but this information is often not as detailed as recommended in existing guidelines. The ethics reporting checklist we designed could be helpful for the ethical assessments of patient registries and other types of registries in the future as well as for self-assessment of registries aiming to improve their ethics practices.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"577"},"PeriodicalIF":7.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779335","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":"Impact of HIV exposure without infection on hospital course and mortality among young children in sub-Saharan Africa: a multi-site cohort study.","authors":"Christopher Lwanga, Peace Aber, Kirkby D Tickell, Moses M Ngari, John Mukisa, Michael Atuhairwe, Lindsay Brown, Ezekiel Mupere, Isabel Potani, Lubaba Shahrin, Brooks Morgan, Benson O Singa, Victoria Nankabirwa, Richard K Mugambe, Zakaria Mukasa, Judd L Walson, James A Berkley, Christina L Lancioni","doi":"10.1186/s12916-024-03790-5","DOIUrl":"10.1186/s12916-024-03790-5","url":null,"abstract":"<p><strong>Background: </strong>Although mortality risk associated with HIV is well described, HIV-exposed uninfected (HEU) young children are also at increased risk of hospitalization and death as compared to HIV-unexposed uninfected (HUU) children. The drivers of poor outcomes among HEU children remain unknown, limiting the development of interventions to support this vulnerable population.</p><p><strong>Methods: </strong>We performed a secondary analysis of data from a large multi-country prospective cohort [Childhood Acute Illness and Nutrition (CHAIN) Network] study. Data from 5 sites in Uganda, Kenya, and Malawi were included. Hospitalized children aged 2-23 months were followed from an index admission for 6 months after discharge to determine acute and long-term outcomes. Using perinatal HIV exposure (HEU and HUU) as the primary exposure and adjusting for child, caregiver, and household characteristics, we compared inpatient and 30-day survival outcomes, nutritional status, hospital length of stay, illness severity, and utilization of inpatient resources.</p><p><strong>Results: </strong>We included 1486 children: 217 HEU and 1269 HUU. HEU children had an increased risk of mortality both during hospitalization [adjusted OR 1.96, 95% CI (1.14-3.37)] and in the 30 days following hospital admission [adjusted hazard ratio 2.20, 95% CI (1.10-4.42)]. Wasting and stunting were more frequent in HEU than HUU children, with adjusted OR 1.41, 95% CI (1.03-1.95) and adjusted OR 1.91, 95% CI (1.34-2.70), respectively. HEU children were also more likely to have a prolonged hospital stay compared to HUU children [adjusted OR 1.58, 95% CI (1.08-2.29)], although admission diagnoses, illness severity at admission, and use of inpatient resources (supplemental oxygen, nasogastric tube, and second-line antibiotics) did not differ significantly between groups.</p><p><strong>Conclusions: </strong>HEU children are more likely to die during hospitalization and within 30 days of admission, to be wasted and stunted upon hospital admission, and to require a prolonged hospital stay, as compared to HUU children. Hospitals in settings with a high prevalence of women-living-with-HIV should ensure that maternal HIV status is established among children requiring admission and build capacity to provide additional hospital monitoring and early post-discharge support for HEU children.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"573"},"PeriodicalIF":7.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766200","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 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/s12916-024-03802-4","DOIUrl":"10.1186/s12916-024-03802-4","url":null,"abstract":"<p><strong>Background: </strong>Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of hepatic and extrahepatic cancers, in particular those linked to obesity. In people with chronic liver disease, aspirin may confer protection against hepatocellular carcinoma (HCC). We explore the potential chemoprotective effect of aspirin/other anti-platelet agents on obesity-related cancers, including HCC in people with NAFLD.</p><p><strong>Methods: </strong>We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (Cambridge, MA, USA), a global federated database. We identified adults aged 18 or over with a diagnosis of NAFLD, prior to commencing antiplatelet agents. Two groups were created: antiplatelet (1) versus no antiplatelet use (2). We propensity score matched for nine variables. Antiplatelet use was defined as aspirin, ticagrelor, cangrelor, clopidogrel or prasugrel use for at least 1 year. The outcomes of interest were incidence of HCC and other obesity-related cancers. Follow-up was for 5 years. We performed subgroup analyses on aspirin users only and stratified findings for sex and age. Sensitivity analysis was conducted on individuals with 3- and 5-year aspirin exposure.</p><p><strong>Results: </strong>Post matching, there were 42,192 people per group. Antiplatelet use in people with NAFLD was associated with statistically significant reduction in all obesity-related cancers (HR 0.71, 95% CI 0.65-0.78, p < 0.001) and individually for HCC (HR 0.52, 95% CI 0.40-0.68, p < 0.001), breast carcinoma (HR 0.78, 95% CI 0.66-0.92, p = 0.003), pancreatic carcinoma (HR 0.61, 95% CI 0.47-0.78, p < 0.001) and colorectal carcinoma (HR 0.68, 95% CI 0.56-0.84, p < 0.001). For women, there was a significant reduction in risk of ovarian carcinoma (HR 0.75, 95% CI 0.57-0.98, p = 0.034). Aspirin monotherapy was similarly associated with reduced incidence of HCC (HR 0.46, 95% CI 0.32-0.64, p < 0.001) and all obesity-related cancers (HR 0.71, 95% CI, 0.56-0.90, p = 0.004), with benefits observed in males (HR 0.71, 95% CI 0.56-0.90, p = 0.004), females (HR 0.77, 95% CI 0.67-0.88, p < 0.001) and in older (HR 0.72, 95% CI 0.63-0.82, p < 0.001) but not younger people (HR 0.78, 95% CI 0.60-1.03, p = 0.589).</p><p><strong>Conclusions: </strong>Aspirin/antiplatelet agents may have a role in primary cancer prevention in people living with NAFLD.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"574"},"PeriodicalIF":7.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766236","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 of melatonin for prolonged disorders of consciousness: a double-blind, randomized clinical trial.","authors":"Xinrui Wen, Jie Yu, Genying Zhu, Jinhua Wang, Yangyang Sun, Jiajia Zhou, Jiaye Cai, Fanxia Meng, Yi Ling, Yi Sun, Jiajia Zhao, Fangping He, Qisheng Cheng, Chuan Xu, Jian Gao, Jingqi Li, Benyan Luo","doi":"10.1186/s12916-024-03793-2","DOIUrl":"10.1186/s12916-024-03793-2","url":null,"abstract":"<p><strong>Background: </strong>Sleep is essential for the recovery of patients with disorders of consciousness (DoC). However, few approaches targeting sleep were applied. Melatonin has been shown to enhance sleep efficiency with virtually no side effects. This study explored melatonin's benefits for patients with prolonged DoC, as well as the underlying mechanisms involved.</p><p><strong>Methods: </strong>A cohort of 46 patients with prolonged DoC were randomly assigned to either the melatonin treatment group or the placebo group. Assessments were conducted using the Coma Recovery Scale-Revised (CRS-R), electroencephalography (EEG), and polysomnography (PSG) before and after the intervention, with follow-up CRS-R evaluations performed 6 months post-treatment.</p><p><strong>Results: </strong>Compared to the placebo, melatonin demonstrated a significant improvement in CRS-R scores after a 2-week period in patients with unresponsive wakefulness syndrome (UWS) (F_group*time = 6.86, P = 0.032; F_group = 4.03, P = 0.045) and this improvement was particularly pronounced in visual scores (F_group*time = 7.03, P = 0.030; F_group = 4.90, P = 0.027). Moreover, patients with UWS who received melatonin exhibited a higher relative spectral density of the alpha band in the frontal lobe compared to those who received placebo (F_time-mel = 4.55, P = 0.033) and benefited for their prognosis after 6 months (Pseudo R² = 0.370, F = 12.03, P = 0.034).</p><p><strong>Conclusions: </strong>Overall, melatonin intervention seems to have a better response in UWS patients with preserved sleep cycles. These positive effects may not be solely attributed to improvements in the patients' sleep quality.</p><p><strong>Trail registration: </strong>ClinicalTrials.gov: NCT05285124.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"576"},"PeriodicalIF":7.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766260","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":"Inequalities in the prevalence recording of 205 chronic conditions recorded in primary and secondary care for 12 million patients in the English National Health Service.","authors":"Shaolin Wang, Yiu-Shing Lau, Matt Sutton, Michael Anderson, Christodoulos Kypridemos, Anna Head, Ben Barr, Richard Cookson, Chris Bentley, Laura Anselmi","doi":"10.1186/s12916-024-03767-4","DOIUrl":"10.1186/s12916-024-03767-4","url":null,"abstract":"<p><strong>Background: </strong>Understanding the prevalence of diseases and where it is detected and recorded in healthcare settings is important for planning effective prevention and care provision. We examined inequalities in the prevalence of 205 chronic conditions and in the care setting where the related diagnoses were recorded in the English National Health Service.</p><p><strong>Methods: </strong>We used data from the Clinical Practice Research Datalink Aurum linked with Hospital Episode Statistics for 12.8 million patients registered with 1406 general practices in 2018. We mapped diagnoses recorded in primary and secondary care in the previous 12 years. We used linear regressions to assess associations of ethnicity, deprivation, and general practice with a diagnosis being recorded in primary care only, secondary care only, or both settings.</p><p><strong>Results: </strong>72.65% of patients had at least one diagnosis recorded in any care setting. Most diagnoses were reported only in primary care (62.56%) and a minority only in secondary care (15.24%) or in both settings (22.18%). Black (- 0.08 percentage points (pp)), Asian (- 0.08 pp), mixed (- 0.13 pp), and other ethnicity patients (- 0.31 pp) were less likely than White patients to have a condition recorded. Patients in most deprived areas were 0.27 pp more likely to have a condition recorded (+ 0.07 pp in secondary care only, + 0.10 pp in both primary and secondary care, and + 0.10 pp in primary care only). Differences in prevalence by ethnicity were driven by diagnostic recording in primary care. Higher recording of diagnoses in more deprived areas was consistent across care settings. There were large differences in prevalence and diagnostic recording between general practices after adjusting for patient characteristics.</p><p><strong>Conclusions: </strong>Linked primary and secondary care records support the identification of disease prevalence more comprehensively. There are inequalities in the prevalence and setting of diagnostic recording by ethnicity, deprivation, and providers on average across conditions. Further research should examine inequalities for each specific condition and whether they reflect also differences in access or recording as well as disease burden. Improving recording where needed and making national linked records accessible for research are key to understanding and reducing inequalities in disease prevention and management.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"570"},"PeriodicalIF":7.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766203","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":"Peripheral artery disease, antithrombotic treatment and outcomes in European and Asian patients with atrial fibrillation: analysis from two prospective observational registries.","authors":"Davide Antonio Mei, Giulio Francesco Romiti, Tommaso Bucci, Bernadette Corica, Jacopo Francesco Imberti, Niccolò Bonini, Marco Vitolo, Alena Shantsila, Hung-Fat Tse, Tze-Fan Chao, Giuseppe Boriani, Marco Proietti, Gregory Y H Lip","doi":"10.1186/s12916-024-03792-3","DOIUrl":"10.1186/s12916-024-03792-3","url":null,"abstract":"<p><strong>Background: </strong>In patients with atrial fibrillation (AF), the impact of peripheral artery disease (PAD) on oral anticoagulant (OAC) therapy use and the risk of outcomes remains unclear.</p><p><strong>Objective: </strong>To analyse the epidemiology of PAD in a large cohort of European and Asian AF patients, and the impact on treatment patterns and risks of adverse outcomes.</p><p><strong>Methods: </strong>We analysed AF patients from two large prospective observational registries. OAC prescription and risk of outcomes were analysed according to the presence of PAD, using adjusted Logistic and Cox regression analyses. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). Interaction analyses were also performed.</p><p><strong>Results: </strong>Fifteen-thousand-four-hundred-ninety-seven patients with AF (mean age 68.9, SD 11.6 years; 38.6% female, 30% from Asia) were included in the analysis. PAD was found in 941 patients (6.1%), with a higher prevalence among European individuals compared to Asian (8.1% vs 1.2%, p < 0.001). On logistic regression analysis, European patients had sixfold higher odds of presenting with PAD compared with Asians (OR 6.23, 95% CI 4.75-8.35). After adjustments, PAD was associated with lower use of OAC (OR: 0.59, 95% CI: 0.50-0.69). On Cox regression analysis, PAD was associated with a higher risk of the primary composite outcome (HR 1.28, 95% CI: 1.08-1.52) and all-cause death (HR 1.40, 95% CI: 1.16-1.69). A significant interaction was observed between PAD and age, with higher effects of PAD found in younger patients (< 65 years) for the risk of the primary outcome (p_int = 0.014).</p><p><strong>Conclusions: </strong>In patients with AF, PAD is associated with lower use of OAC and a higher risk of adverse outcomes, with a greater risk seen in younger patients.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"567"},"PeriodicalIF":7.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766290","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":"Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.","authors":"Charlotte Ling, Magdalena Vavakova, Bilal Ahmad Mir, Johanna Säll, Alexander Perfilyev, Melina Martin, Per-Anders Jansson, Cajsa Davegårdh, Olof Asplund, Ola Hansson, Allan Vaag, Emma Nilsson","doi":"10.1186/s12916-024-03789-y","DOIUrl":"10.1186/s12916-024-03789-y","url":null,"abstract":"<p><strong>Background: </strong>A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.</p><p><strong>Methods: </strong>By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.</p><p><strong>Results: </strong>Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.</p><p><strong>Conclusions: </strong>Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"572"},"PeriodicalIF":7.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766287","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":"Phenome-wide diagnostic comparison among suicide deaths and living individuals with chronic pain diagnoses.","authors":"Emily DiBlasi, Erin A Kaufman, Sam Webster, Emily E Hagn, Andrey A Shabalin, Danli Chen, Seonggyun Han, Rana Jawish, Eric T Monson, Michael J Staley, Brooks R Keeshin, Anna R Docherty, Amanda V Bakian, Akiko Okifuji, Hilary Coon","doi":"10.1186/s12916-024-03794-1","DOIUrl":"10.1186/s12916-024-03794-1","url":null,"abstract":"<p><strong>Background: </strong>Chronic pain, regardless of its type, is a significant risk factor for suicide. However, not all individuals with chronic pain also experience suicidal thoughts and behaviors. Better characterization of clinical risk profiles and comorbidities across the medical spectrum among people with chronic pain who die by suicide is urgently needed to aid treatment and prevention strategies.</p><p><strong>Methods: </strong>This case-control study leverages population-based data from the Utah Suicide Mortality Risk Study. Specifically, we identify clinical phenotypes from diagnostic data that differentiate between individuals that died by suicide with chronic pain diagnoses (N = 1,410) and living control individuals who also had chronic pain diagnoses (N = 4,664). Medical diagnostic codes were aggregated via phecodes to perform a phenotype-based phenome-wide association study. Using multivariable logistic regression analysis adjusting for covariates and multiple testing, differences in 1,727 common clinical phenotypes (phecodes) were assessed between suicide deaths and controls with chronic pain diagnoses. Models were also stratified by sex.</p><p><strong>Results: </strong>Chronic pain diagnoses were nearly three times more prevalent in individuals who died by suicide compared with those who did not. Sixty-five phecodes were significantly overrepresented among suicide deaths with chronic pain diagnoses compared with controls with chronic pain diagnoses. Utah suicide deaths with chronic pain had significantly more psychiatric diagnoses (mood disorders, anxiety disorders, attention deficit hyperactivity disorder, posttraumatic stress disorder, personality disorders, schizophrenia/psychosis, substance use related traits and prior overdoses, and diagnoses related to previous suicidal thoughts and behaviors) in addition to insomnia and specific pain related diagnoses compared to Utah controls with chronic pain (odds ratios ranged from 1.40-7.10). Twenty-five phecodes were overrepresented in controls with chronic pain compared to suicides. These were related to preventative care, cancer, obesity and other conditions (odds ratios ranged from 0.16-0.73). Sex-specific analyses largely replicated the combined analyses, yet the strength of the association was stronger for women with phecodes related to prior self-harm.</p><p><strong>Conclusions: </strong>Results identified multiple clinical comorbidities with chronic pain that differentiate suicide deaths from living control individuals with a history of diagnosed chronic pain. Our findings may help discern individuals with chronic pain who may be at greater risk for suicide death.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"568"},"PeriodicalIF":7.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766219","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":"Investigating pain-related medication use and contribution to polypharmacy in adults with intellectual disabilities: a systematic review.","authors":"Christine Pacitti, Deborah Cairns, Laura Ward, Barbara I Nicholl","doi":"10.1186/s12916-024-03770-9","DOIUrl":"10.1186/s12916-024-03770-9","url":null,"abstract":"<p><strong>Background: </strong>Adults with intellectual disability experience more pain than adults without and, despite a higher number of medications being prescribed, may be less likely to receive medication for pain. We conducted a systematic review of existing literature on medication for pain and painful conditions in adults with intellectual disability to explore if there is any association with polypharmacy, multimorbidity or demographic characteristics.</p><p><strong>Methods: </strong>This systematic review followed PRISMA guidelines. Medline, Embase, PubMed, PsycINFO, Web of Science, CINAHL, Cochrane Library and Scopus were searched from January 2000 to 21st October 2024. We included original, peer-reviewed observational, qualitative or mixed-method studies published in English with data on medication for pain or painful conditions in adults with intellectual disability. Two independent reviewers performed study selection, data extraction, and quality assessment; disagreements were resolved by a third reviewer. Adapted Newcastle-Ottawa Scale or the Critical Appraisal Skills Programme for qualitative studies was used for quality assessment of included studies and findings were reported via narrative synthesis. PROSPERO registration: CRD42023415051.</p><p><strong>Results: </strong>Twenty-seven of 26,170 articles met the eligibility criteria. Adults with intellectual disability were more likely to have simple analgesic medication than non-steroidal anti-inflammatory drugs, opioids or adjuvant pain medications than the general population. Psychotropic medications were more commonly prescribed in adults with intellectual disability than medication for pain or painful conditions. Adults with intellectual disability and caregivers reported under-recognition and most likely under-treatment of pain.</p><p><strong>Conclusions: </strong>Adults with intellectual disability may receive less pharmacological management of pain with analgesics and medication for painful conditions despite the high prevalence of polypharmacy, suggesting pain is under-treated. Better assessment and pharmacological treatment of pain and painful conditions is a key future research priority to address this health inequality and improve quality of life for this vulnerable group of people.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"22 1","pages":"565"},"PeriodicalIF":7.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766286","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}