Med最新文献

{"title":"Arab founder variants: Contributions to clinical genomics and precision medicine.","authors":"Lama AlAbdi, Sateesh Maddirevula, Bayan Aljamal, Halima Hamid, Aisha Almulhim, Mais O Hashem, Yusra Algoos, Mashael Alqahtani, Shahad Albaloshi, Mohammed Alghamdi, Mohammed Alduaylij, Hanan E Shamseldin, Seba Nadeef, Nisha Patel, Firdous Abdulwahab, Omar Abouyousef, Tarfa Alshidi, Amal Jaafar, Mohamed Abouelhoda, Adel Alhazzani, Ahmed Alfares, Ahmad Qudair, Ahood Alsulaiman, Amal Alhashem, Arif O Khan, Aziza Chedrawi, Basel Alebdi, Fahad AlAjlan, Fawaz Alotaibi, Hamad Alzaidan, Hanaa Banjar, Hanem Abdelraouf, Hisham Alkuraya, Iman Abumansour, Khowlah Alfayez, Maha Tulbah, Mohammed Alowain, Mohammed Alqahtani, Mohammed El-Kalioby, Mohammad Shboul, Raashda Sulaiman, Saed Al Tala, Sameena Khan, Serdar Coskun, Sobaihi Mrouge, Walaa Alenazi, Zuhair Rahbeeni, Fowzan S Alkuraya","doi":"10.1016/j.medj.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.005","url":null,"abstract":"<p><strong>Background: </strong>Founder variants are ancestral variants shared by individuals who are not closely related. The large effect size of some of these variants in the context of Mendelian disorders offers numerous precision medicine opportunities.</p><p><strong>Methods: </strong>Using one of the largest datasets on Mendelian disorders in the Middle East, we identified 2,908 medically relevant founder variants derived from 18,360 exomes and genomes and investigated their contribution to the clinical annotation of the human genome.</p><p><strong>Findings: </strong>Strikingly, ∼34% of Arab founder variants are absent in gnomAD. We found a strong contribution of Arab founder variants to the identification of novel gene-disease links (n = 224) and the support/dispute (n = 81 support, n = 101 dispute) of previously reported candidate gene-disease links. The powerful segregation evidence generated by Arab founder variants allowed many ClinVar and Human Gene Mutation Database variants to be reclassified. Overall, 39.5% of diagnostic reports from our clinical lab are based on founder variants, and 19.41% of tested individuals carry at least one pathogenic founder variant. The presumptive loss-of-function mechanism that typically underlies autosomal recessive diseases means that Arab founder variants also offer unique opportunities in \"druggable genome\" research. Arab founder variants were also informative of migration patterns in the Middle East consistent with documented historical accounts.</p><p><strong>Conclusions: </strong>We highlight the contribution of founder variants from an under-represented population group to precision medicine and inform future prevention programs. Our study also sheds light on the added value of these variants in supplementing other lines of research in tracing population history.</p><p><strong>Funding: </strong>There is no funding for this work.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent late-onset neutropenia following treatment with different B cell-depleting strategies in multiple sclerosis.","authors":"Maria Protopapa, Muriel Schraad, Katrin Pape, Falk Steffen, Livia Steenken, Frauke Zipp, Vinzenz Fleischer, Stefan Bittner","doi":"10.1016/j.medj.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.006","url":null,"abstract":"<p><strong>Background: </strong>As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment.</p><p><strong>Methods: </strong>Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab.</p><p><strong>Findings: </strong>In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity.</p><p><strong>Conclusions: </strong>This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment.</p><p><strong>Funding: </strong>This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of gut microbiota on immune checkpoint inhibitors in multi-cancer and as microbial biomarkers for predicting therapeutic response.","authors":"Yufeng Lin, Mingxu Xie, Harry Cheuk-Hay Lau, Ruijie Zeng, Ruyi Zhang, Luyao Wang, Qing Li, Yiwei Wang, Danyu Chen, Lanping Jiang, William Damsky, Jun Yu","doi":"10.1016/j.medj.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.007","url":null,"abstract":"<p><strong>Background: </strong>Gut bacteria are related to immune checkpoint inhibitors (ICIs). However, there is inconsistency in ICI-associated species, while the role of non-bacterial microbes in immunotherapy remains elusive. Here, we evaluated the association of trans-kingdom microbes with ICIs by multi-cohort multi-cancer analyses.</p><p><strong>Methods: </strong>We retrieved fecal metagenomes from 1,359 ICI recipients with four different cancers (metastatic melanoma [MM], non-small cell lung carcinoma [NSCLC], renal cell cancer [RCC], and hepatocellular carcinoma) from 12 published datasets. Microbiota composition was analyzed using the Wilcoxon rank test. The performance of microbial biomarkers in predicting ICI response was assessed by random forest. Key responder-associated microbes were functionally examined in vitro and in mice.</p><p><strong>Findings: </strong>Trans-kingdom gut microbiota (bacteria, eukaryotes, viruses, and archaea) was significantly different between ICI responders and non-responders in multi-cancer. Bacteria (Faecalibacterium prausnitzii, Coprococcus comes) and eukaryotes (Nemania serpens, Hyphopichia pseudoburtonii) were consistently enriched in responders of ≥2 cancer types or from ≥3 cohorts, contrasting with the depleted bacterium Hungatella hathewayi. Responder-associated species in each cancer were revealed, such as F. prausnitzii in MM and 6 species in NSCLC. These signature species influenced ICI efficacy by modulating CD8⁺ T cell activity in vitro and in mice. Moreover, bacterial and eukaryotic biomarkers showed great performance in predicting ICI response in patients from discovery and two validation cohorts (MM: area under the receiver operating characteristic curve [AUROC] = 72.27%-80.19%; NSCLC: AUROC = 72.70%-87.98%; RCC: AUROC = 83.33%-89.58%).</p><p><strong>Conclusions: </strong>This study identified trans-kingdom microbial signatures associated with ICI in multi-cancer and specific cancer types. Trans-kingdom microbial biomarkers are potential predictors of ICI response in patients with cancer.</p><p><strong>Funding: </strong>Funding information is shown in the acknowledgments.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine decreases cerebral hyperperfusion incidence following carotid stenting: A double-blind, randomized controlled trial.","authors":"Enqiang Chang, Lingzhi Wu, Xinyi Li, Jinpeng Zhou, Hui Zhi, Min Sun, Guanyu Chen, Jiaqi Bi, Li Li, Tianxiao Li, Daqing Ma, Jiaqiang Zhang","doi":"10.1016/j.medj.2024.09.012","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.012","url":null,"abstract":"<p><strong>Background: </strong>Cerebral hyperperfusion syndrome (CHS) is a severe complication after carotid artery stenting (CAS). Dexmedetomidine (Dex) is an α₂ adrenoceptor agonist with sedative, analgesic, and neuroprotective properties. This randomized, double-blind, placebo-controlled trial (ChiCTR1900024416) aims to investigate whether prophylactic low-dose Dex decreases CH-induced brain injury following CAS.</p><p><strong>Methods: </strong>After obtaining written informed consent, patients aged 18-80 who underwent CAS were enrolled between July 2019 and October 2022. Patients were randomly assigned to receive either intravenous Dex (0.1 μg/kg/h, until post-operative day 3) (n = 80) or placebo (normal saline) (n = 80). The primary endpoint was the incidence of CH and CHS assessed up to the third post-operative day. The secondary endpoints included National Institute of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) scores within 30 days of operation, extubation time, discharge from the hospital within 7 days post-operation, length of hospital stay post-operation, and all-cause 30-day mortality. Blood samples were collected before and after surgery for lipidomics, brain-derived neurotrophic factor (BDNF), and neurofilament light chain (Nfl) measurements. Acceptability, safety, and efficacy were evaluated by Cox model and logistic model.</p><p><strong>Findings: </strong>CH occurred in 30 (37.5%) of 80 patients who received a placebo compared to 9 (11.2%) of 80 patients given Dex (prevalence: odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.088-0.467; p < 0.001; incidence: hazard ratio [HR]: 0.27, 95% CI: 0.14-0.50; p < 0.001). CHS was significantly higher in the placebo group (13.75%) than in the Dex group (2.5%) (prevalence: [OR]: 0.161, 95% CI: 0.024-0.626; p = 0.020; incidence: [HR]: 0.17, 95% CI: 0.06-0.52; p = 0.009). Dex significantly upregulated BDNF, decreased Nfl, and uniquely increased lysophosphatidylethanolamine.</p><p><strong>Conclusions: </strong>A low prophylactic dose of Dex significantly reduced the incidence of CH and CHS up to 72 h after CAS.</p><p><strong>Funding: </strong>This work was funded by National Natural Science Foundation of China (no. 82271288) and the Henan Provincial Science and Technology Research Project (nos. 242300421192 and JQRC2023004).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor.","authors":"Michelle Sætersmoen, Ivan S Kotchetkov, Lamberto Torralba-Raga, Jorge Mansilla-Soto, Ebba Sohlberg, Silje Zandstra Krokeide, Quirin Hammer, Michel Sadelain, Karl-Johan Malmberg","doi":"10.1016/j.medj.2024.09.010","DOIUrl":"10.1016/j.medj.2024.09.010","url":null,"abstract":"<p><strong>Background: </strong>Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A⁺ CD8⁺ T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells.</p><p><strong>Methods: </strong>We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma.</p><p><strong>Findings: </strong>A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression.</p><p><strong>Conclusions: </strong>The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.</p><p><strong>Funding: </strong>This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.","authors":"Dimitrios C Ladakis, Kimystian L Harrison, Matthew D Smith, Krista Solem, Sachin Gadani, Larissa Jank, Soonmyung Hwang, Farzaneh Farhadi, Blake E Dewey, Kathryn C Fitzgerald, Elias S Sotirchos, Shiv Saidha, Peter A Calabresi, Pavan Bhargava","doi":"10.1016/j.medj.2024.09.011","DOIUrl":"10.1016/j.medj.2024.09.011","url":null,"abstract":"<p><strong>Background: </strong>Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.</p><p><strong>Methods: </strong>Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters.</p><p><strong>Findings: </strong>In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p = 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4⁺ and Th1/17 cells decreased, while CD4⁺ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups.</p><p><strong>Conclusions: </strong>Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.</p><p><strong>Funding: </strong>National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142509385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation of PSA and survival in metastatic hormone-sensitive prostate cancer treated with rezvilutamide plus ADT in the CHART trial.","authors":"Xiaojie Bian, Weijie Gu, Xuepei Zhang, Liping Xie, Shaogang Wang, Benkang Shi, Ting Sun, Shaozhong Wei, Zhiliang Weng, Shujie Xia, Bangmin Han, Zhuoqun Xu, Jinchun Xing, Dahong Zhang, Danfeng Xu, Chuanjun Du, Chaohong He, Qilin Wang, Xinfeng Yang, Jianpo Lian, Wenliang Wang, Dingwei Ye","doi":"10.1016/j.medj.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.009","url":null,"abstract":"<p><strong>Background: </strong>This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC).</p><p><strong>Methods: </strong>A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed.</p><p><strong>Findings: </strong>The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles.</p><p><strong>Conclusions: </strong>PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC.</p><p><strong>Funding: </strong>This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluid biomarkers in the context of amyloid-targeting disease-modifying treatments in Alzheimer's disease.","authors":"Yan Hu, Min Cho, Pallavi Sachdev, Jeffrey Dage, Suzanne Hendrix, Oskar Hansson, Randall J Bateman, Harald Hampel","doi":"10.1016/j.medj.2024.08.004","DOIUrl":"10.1016/j.medj.2024.08.004","url":null,"abstract":"<p><p>Clinical management and therapeutics development for Alzheimer's disease (AD) have entered a new era, with recent approvals of monoclonal antibody therapies targeting the underlying pathophysiology of the disease and modifying its trajectory. Imaging and fluid biomarkers are becoming increasingly important in the clinical development of AD therapeutics. This review focuses on the evidence of fluid biomarkers from recent amyloid-β-targeting clinical trials, summarizing biomarker data across 12 trials. It further proposes a simple framework to put biomarker guidance in the context of amyloid-pathway-targeted disease modification, delineates factors that impact biomarker data in clinical trials, and highlights knowledge gaps and future directions. Increased knowledge and data on biomarkers in the context of disease progression and disease modification will help to better design future AD trials and guide the clinical management of patients on AD-modifying therapies, bringing us closer to the implementation of precision medicine in AD.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1206-1226"},"PeriodicalIF":12.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global burden and management of women with epilepsy in pregnancy: A modeling study.","authors":"Leihao Sha, Ze Cao, Yutong Fu, Yifei Duan, Yilin Xia, Xiaoru Feng, Torbjörn Tomson, Xiaolei Xie, Lei Chen","doi":"10.1016/j.medj.2024.07.005","DOIUrl":"10.1016/j.medj.2024.07.005","url":null,"abstract":"<p><strong>Background: </strong>Most pregnant women with epilepsy do not receive proper medical care, which creates a special burden worldwide. We aimed to qualify this special global burden and assess the impact of different clinical management strategies to reduce it.</p><p><strong>Methods: </strong>The data used in this study were extracted from articles published between 2005 and 2022. We calculated the economic costs associated with major burdens experienced by pregnant women with epilepsy. We developed a microsimulation model to estimate the different effects of various interventions and their combinations as integrated strategies for pregnant women with epilepsy and related burden reduction. We also compared the regional differences in disease burden and interventions.</p><p><strong>Findings: </strong>The total economic burden for pregnant women with epilepsy is estimated to reach $1.8 billion globally annually, which is more than three times the burden for epilepsy alone. Folic acid supplementation is projected to be the most effective intervention, with a 9.1% reduction in major congenital malformations, a 14.9% reduction in autism spectrum disorder, and a 10.8% reduction in offspring-related economic burden globally annually. Integrated strategies are associated with a reduced economic burden of up to $37.7 million annually globally. Folic acid supplementation is the most effective intervention in high- and upper-middle-income countries, whereas changes in antiseizure medication prescriptions are more effective in lower-middle- and low-income countries.</p><p><strong>Conclusion: </strong>This study highlights the huge burden for pregnant women with epilepsy and actions that must be taken to improve their quality of life.</p><p><strong>Funding: </strong>This work was supported by the Sichuan Science and Technology Program (2023YFS0047).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1326-1333.e4"},"PeriodicalIF":12.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141761382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NanoRanger enables rapid single-base-pair resolution of genomic disorders.","authors":"Yingzi Zhang, Chongwei Bi, Seba Nadeef, Sateesh Maddirevula, Mashael Alqahtani, Fowzan S Alkuraya, Mo Li","doi":"10.1016/j.medj.2024.07.003","DOIUrl":"10.1016/j.medj.2024.07.003","url":null,"abstract":"<p><strong>Background: </strong>Delineating base-resolution breakpoints of complex rearrangements is crucial for an accurate clinical understanding of pathogenic variants and for carrier screening within family networks or the broader population. However, despite advances in genetic testing using short-read sequencing (SRS), this task remains costly and challenging.</p><p><strong>Methods: </strong>This study addresses the challenges of resolving missing disease-causing breakpoints in complex genomic disorders with suspected homozygous rearrangements by employing multiple long-read sequencing (LRS) strategies, including a novel and efficient strategy named nanopore-based rapid acquisition of neighboring genomic regions (NanoRanger). NanoRanger does not require large amounts of ultrahigh-molecular-weight DNA and stands out for its ease of use and rapid acquisition of large genomic regions of interest with deep coverage.</p><p><strong>Findings: </strong>We describe a cohort of 16 familial cases, each harboring homozygous rearrangements that defied breakpoint determination by SRS and optical genome mapping (OGM). NanoRanger identified the breakpoints with single-base-pair resolution, enabling accurate determination of the carrier status of unaffected family members as well as the founder nature of these genomic lesions and their frequency in the local population. The resolved breakpoints revealed that repetitive DNA, gene regulatory elements, and transcription activity contribute to genome instability in these novel recessive rearrangements.</p><p><strong>Conclusions: </strong>Our data suggest that NanoRanger greatly improves the success rate of resolving base-resolution breakpoints of complex genomic disorders and expands access to LRS for the benefit of patients with Mendelian disorders.</p><p><strong>Funding: </strong>M.L. is supported by KAUST Baseline Award no. BAS/1/1080-01-01 and KAUST Research Translation Fund Award no. REI/1/4742-01.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1307-1325.e3"},"PeriodicalIF":12.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141761384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}