medRxiv (Cold Spring Harbor Laboratory)最新文献

{"title":"Prognostic Implications of Right Ventricular Dysfunction in Degenerative Mitral Regurgitation","authors":"Yohann Bohbot, Benjamin Essayagh, Giovanni Benfari, Jeroen J. Bax, Thierry Le Tourneau, Yan Topilsky, Clemence Antoine, Dan Rusinaru, Francesco Grigioni, Nina Ajmone Marsan, Aniek L. van Wijngaarden, Aviram Hochstadt, Jean-Christian Roussel, Prabin Thapa, Hector I. Michelena, Maurice Enriquez-Sarano, Christophe Tribouilloy","doi":"10.1101/2023.11.10.23298404","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298404","url":null,"abstract":"Background: The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with survival in patients with DMR. Methods: We used data from the Mitral Regurgitation International DAtabase-Quantitative (MIDA-Q) which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 4,379 (mean age: 67 years, 64.6% males, follow-up:5.3[3.3-8.2]years) consecutive patients with significant (?moderate) DMR was included and long-term survival was analyzed. Results: RVD, identified in 584(13.3%) patients, was associated with reduced 10-year survival (49±3% vs. 67±1%, p<0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures and surgery (adjusted HR[95%CI]=1.55[1.31-1.84]; p<0.001). This excess mortality was observed under medical management (adjusted HR[95%CI]=1.39[1.12-1.72]; p=0.003) and after surgical correction of mitral regurgitation (adjusted HR[95%CI]=1.56[1.08-2.27]; p=0.019). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 10-year survival (73±4% vs. 38±4%, p<0.001), even after adjustment (adjusted HR[95%CI]=0.53[0.35-0.81]; p=0.003) despite an increase of 1-month post-operative mortality (5% vs 2.2% for patients without RVD; p<0.001). Conclusions: RVD is observed in 13.3% of significant DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision-making process.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"78 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135036862","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":"Sleep disturbance as a precursor to anxiety, depression, and PTSD among rural Kenyans: a cross-lagged panel analysis from a rural Kenyan interventional cohort","authors":"Michael L Goodman, Miryoung Lee, Andrew Springer, Elizabeth Vaughan, Vanessaa Schick, Christine Markham, Stanley Gitari, Fridah Mukiri","doi":"10.1101/2023.11.11.23298315","DOIUrl":"https://doi.org/10.1101/2023.11.11.23298315","url":null,"abstract":"Sleep quality is essential to biopsychosocial functioning, yet there remains limited longitudinal research on sleep and mental or social well-being within low- or middle-income countries. This study utilizes longitudinal cohort data from a community-based empowerment program in Meru County, Kenya to assess cross-lagged correlations between sleep disturbance, social support, symptoms of depression, anxiety, and posttraumatic stress, Participants (n=373; 92% women; age range 18-86 years) who reported more sleep disturbance at T1 reported significantly more symptoms of depression, anxiety and PTSD, and significantly less social support at T2 (average 11 weeks later), controlling for all within-time correlations across measures, within-measure correlations across time, and sociodemographic background characteristics. Findings are consistent with research across high-income countries, underscoring the need for more contextualized research into sleep behaviors across low- and middle-income countries. Findings may inform interventions to increase mental and social well-being within Kenya.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"16 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135037450","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":"Age is Associated with Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility and Aging (SOMMA)","authors":"Melissa L Erickson, Terri L Blackwell, Theresa Mau, Peggy M Cawthon, Nancy W Glynn, Yujia (Susanna) Qiao, Steven Cummings, Paul M Coen, Nancy E Lane, Stephen B Kritchevsky, Anne B Newman, Samaneh Farsijani,, Karyn A Esser","doi":"10.1101/2023.11.11.23298422","DOIUrl":"https://doi.org/10.1101/2023.11.11.23298422","url":null,"abstract":"Background: Aging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. We characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults, both overall, and in relation, to sociodemographic characteristics. Methods: We analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables. Results: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P <0.001). Compared to the latest decile of acrophase, those is the earliest and midrange categories had more total activity (P=0.02). RAR was associated with some sociodemographic variables. Conclusions: Older age was associated with dampened circadian behavior; and behaviors were sexually dimorphic. We identified a behavioral phenotype characterized by early time-of-day of peak activity, high rhythmic amplitude, and more total activity.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"31 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135038814","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":"A Systematic Review evaluating the role of the 7 T MRI in Neurosurgery: Unveiling Trends in the Literature during the First Four Years after Clinical Approval in 2017.","authors":"Arosh S Perera Molligoda Arachchige, Niccolo Stomeo","doi":"10.1101/2023.11.12.23298426","DOIUrl":"https://doi.org/10.1101/2023.11.12.23298426","url":null,"abstract":"Aims: (1) To assess the impact of 7-Tesla Magnetic Resonance Imaging (7T MRI) on neurosurgery, focusing on its applications in diagnosis, treatment planning, and post-operative assessment. (2) To systematically analyze and identify patterns and trends in the existing literature related to the utilization of 7T MRI in neurosurgical contexts. Methods: Systematic search of PubMed for studies published between January 1, 2017, and December 31, 2021, using MeSH terms related to 7T MRI and neurosurgery. Inclusion criteria: Studies involving patients of all ages, meta-analyses, systematic reviews, and original research. Exclusion criteria: Studies with insufficient data, non-English publications, and studies involving animal subjects. Data synthesis involved standardized extraction forms, and a narrative synthesis was performed. Results: Identified 83 records from PubMed, screened for inclusion criteria, resulting in 48 studies included in the systematic review. Most common neurosurgical procedures using 7T MRI: endoscopic neurosurgery, resective epilepsy surgery, and deep brain stimulation surgery. Commonly treated pathologies: cerebrovascular diseases, epilepsy, pituitary adenoma, and gliomas. USA, Netherlands, and Germany had the highest absolute number of publications, but the Netherlands showed the highest research productivity per 7T MRI available. A decline in research output in 2018 followed by an increase in subsequent years. Could not conduct a meta-analysis due to insufficient studies for each pathology. Conclusions: 7T MRI holds great potential in improving the characterization and understanding of various neurological and psychiatric conditions. Superiority of 7T MRI over lower field strengths demonstrated in terms of image quality, lesion detection, and tissue characterization. Applications in epilepsy, pituitary adenoma, Parkinson's disease, cerebrovascular diseases, trigeminal neuralgia, traumatic head injury, multiple sclerosis, glioma, and psychiatric disorders. Limitations include database selection, research productivity metrics, and study inclusion criteria. Findings suggest the need for accelerated global distribution of 7T MR systems and increased training for radiologists to ensure safe and effective integration into routine clinical practice.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"5 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135037631","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":"Phenotypic and genomic analysis of a large-scale Corynebacterium diphtheriae outbreak among migrant populations in Europe","authors":"Andreas Hoefer, Helena MB Seth-Smith, Federica Palma, Stefanie Schindler, Luca Freschi, Alexandra Dangel, Anja Berger, Joshua C D'Aeth, Alexander Indra, Norman K Fry, Daniel Palm, Andreas Sing, Sylvain Brisse, Adrian Egli","doi":"10.1101/2023.11.10.23297228","DOIUrl":"https://doi.org/10.1101/2023.11.10.23297228","url":null,"abstract":"Background. Increased numbers of cases of Corynebacterium diphtheriae infections were diagnosed in migrant-related facilities of Europe since summer 2022. Most cases involved cutaneous diphtheria, although some respiratory cases and fatalities were reported. A pan-European consortium was created to assess the clinical, epidemiological and microbiological features of this outbreak. Methods. All 363 toxigenic C. diphtheriae infection cases from ten European countries were included. Data from case interviews regarding countries of origin and transit routes of migrants were collected. Bacterial isolates underwent whole genome sequencing and antibiotic susceptibility testing. Phylogenetic relationships of outbreak isolates and their antimicrobial resistance genes were studied. Results. Four major genomic clusters were identified, revealing the multiclonal nature of the outbreak. Genes ermX, coding for erythromycin resistance, and genes pbp2m and blaOXA-2 for beta-lactam resistance, were detected in a subset of isolates. Isolates harboring ermX were resistant to erythromycin, and isolates carrying pbp2m were resistant to penicillin, but susceptible to amoxicillin, whereas those carrying blaOXA-2 remained susceptible to beta-lactams. Genomic variation within the four genomic clusters led to estimate their most recent common ancestors between 2017 and 2020. Conclusions. The multi-country distribution of each cluster demonstrated repeated cross-border spread. The increased number of C. diphtheriae cases among migrants is a cause for concern, particularly considering antimicrobial resistance phenotypes that threaten the efficacy of first-line treatments. This work provides important knowledge on modern C. diphtheriae infections, useful for addressing the reemergence of diphtheria in vulnerable populations and to guide clinical management and measures to control further dissemination.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"31 12","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135037649","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":"Prescription of nutritional interventions to HIV patients in Dar es Salaam, Tanzania","authors":"Ajibola Ibraheem Abioye, Hellen Siril, Aisa Mhalu, Nzovu Ulenga, Wafaie W Fawzi","doi":"10.1101/2023.11.12.23298397","DOIUrl":"https://doi.org/10.1101/2023.11.12.23298397","url":null,"abstract":"Background Anemia and micronutrient deficiencies are common among people living with HIV (PLHIV). There are no current guidelines from the World Health Organization (WHO) regarding whether supplements are recommended or not. We sought to assess the practices with respect to nutritional supplementation among clinicians providing care to people living with HIV in Dar es Salaam, Tanzania. Methods We conducted a cross-sectional survey at clinics providing care to PLHIV in Dar es Salaam, Tanzania. All healthcare workers with prescribing responsibility were invited. Self-administered questionnaires were used to collect information about participants demographic and professional characteristics, and their approach to making decisions regarding the prescription of nutritional interventions. Descriptive analyses regarding prescribing patterns and associated factors were done. Results Two hundred and fifty-four clinicians participated in the survey. They were clinical officers (65%), medical assistants (21%) or medical doctors (13%), and attended to 30 patients (IQR: 10, 100) on average, per week. While the majority usually prescribed iron and multivitamin supplements (79% and 76%, respectively), only 33% usually prescribed ready-to-use therapeutic foods (RUTF). The decision to prescribe nutritional supplements were typically guided by patients clinical condition and laboratory test results. Pallor was the most commonly considered clinical feature across patient subgroups. Most participants commenced supplementation when hemoglobin concentration was ≤10g/dl. Clinicians who attended to between 10 and <100 patients or believed in the need for universal iron supplementation for pregnant PLHIV were more likely to prescribe iron supplements compared to counterparts who attended to <10 patients weekly or who did not believe in the need for universal iron supplementation for pregnant PLHIV respectively. Conclusion Clinicians frequently prescribe nutritional supplements, with considerable variation in how they decide whether and how to.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135036928","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":"Maternal Mortality and Last Mile Challenges: Improved Perspective for Leapfrogging","authors":"Shabbir Ahmed, Fatema Akter Tanbi, Hossain Zillur Rahman","doi":"10.1101/2023.11.08.23298278","DOIUrl":"https://doi.org/10.1101/2023.11.08.23298278","url":null,"abstract":"Background: Reducing maternal mortality to zero is one of the 3 targeted agendas of the International Conference of Population and Development (ICPD). Though global improvements in align with SDGs commitment have witnessed comparative development but in the case of reaching zero agenda there are still much more improvements to make. Objectives: Understanding the bottom-level reality with field experiences while also paying attention to the policy voices to understand the last mile stumbling blocks. Methods: Reality check along with expert opinions working at the field level and beneficiary consultations were the primary components for this study. Three specific modalities (i) field-level consultations with the stakeholders, (ii) facility inspection and (iii) roundtable discussion were the specific tools used for this study. Results: Findings show that in Bangladesh, substantial inequities exist both in the use of facility-based maternal healthcare with scarce and the absence of competent birth attendants for home births. Moreover, socio-cultural norms and the socioeconomic status of the families contribute to maternal deaths. The poor family setting, the hospital referral system, and the familial understanding of the overall maternal healthcare are largely responsible for maternal deaths. Conclusion: All these issues related to maternal deaths need proper attention to leap forward to overcome the last mile challenges. Determined focus on defining and identifying the last mile population, breaking the pedagogical limitations and institutional barriers with an additional focus on the last mile research to reach the underserved population is imperative to reach the last mile.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"40 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135037032","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":"Application of the Fluctuation Test to the data of Morbidity and Mortality by COVID-19 in China 2020-2023","authors":"Anyi Y Lopez, Maria A Fernandez, Hilda C Grassi, Efren J Andrades, Jesus E Andrades","doi":"10.1101/2023.11.12.23298174","DOIUrl":"https://doi.org/10.1101/2023.11.12.23298174","url":null,"abstract":"In this work the Luria and Delbruck Fluctuation Test was applied to the data of Morbidity and Mortality by COVID-19 in China from January 2020 to August 2023. Three types of data were used: es.statista.com, datosmacro.expansion.com and larepublica.co without modification, but trying to avoid and justify the anomalies and inconsistencies observed. The methods originally used to establish the interactions of two populations were evaluated: the viral population with that of its host and the drift of both organisms. Only the fluctuations of the weekly Variance of daily increase of Cases (Morbidity) and of the weekly Variance of daily increase of Deaths (Mortality) were studied. The results showed that the Fluctuation Test is applicable to the selected data from China and other data from India, Japan and South Korea, used as controls. The study was separated into two periods: a first initial period from January 2020 to September 2021 and a second final period from October 2021 to August 2023. Results were obtained for Morbidity and Mortality that relate the fluctuations of the first with the fluctuations of the second. However, it was possible to detect some anomalies and uncertainties that were possibly derived from inconsistencies in the original data. A repeated fluctuation was observed in the boreal winter in January, February and March of each one of the year studied. A clear decrease in fluctuation was detected in that period in 2021 that could be attributed to the strict confinement during the quarantine in China between 2020 and 2021. Massive, extensive and intensive vaccinations failed to completely eliminate the most important fluctuations. In this work we tried to correlate the appearance of some virus variants with the fluctuations. The most relevant results of said correlation are presented. With the results of this work, the animal origin cannot be confirmed nor can the human or laboratory origin of the SARS CoV-2 virus that caused the initial emerging infection, be ruled out. However, it was concluded that this method could be used to search for clues about its origin. One of these keys is the comparison of the result of the first important fluctuation in the boreal winter of 2020 in each of the countries studied as controls: India, Japan and South Korea. The comparison of this result with the first fluctuation of China for that same period could give clues about the origin of the virus.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"8 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135036808","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":"Cardiometabolic Health in Asian American Children: a NHANES Study","authors":"Julian Sethna, Kristal Wong, Kevin Meyers","doi":"10.1101/2023.11.11.23298417","DOIUrl":"https://doi.org/10.1101/2023.11.11.23298417","url":null,"abstract":"Background The aim was to compare cardiometabolic health between Asian American children and Non-Hispanic White (NHW) children as well as to compare cardiometabolic health among Asian American children by birthplace. Methods Children aged 6-17 years enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2011-2018 who self-identified as non-Hispanic Asian and NHW were included. Among Asian Americans, place of birth was defined as foreign-born vs United States (US)-born. Regression models were adjusted for age, sex, household income, food insecurity, passive smoke exposure, and body mass index (BMI) z-score. Results Among 3369 children, 8.4% identified as Asian American (age 11.7 years) and 91.6% identified as NHW (age 11.7 years). Compared to NHW children, Asian American children had significantly lower BMI z-scores and odds of obesity. Asian American children had higher HOMA-IR and uric acid, and greater odds of dyslipidemia, microalbuminuria and glomerular hyperfiltration compared to NHW children. Among Asian Americans, 30.5% were foreign-born. Compared to foreign-born Asian American children, US-born Asian American children had significantly higher non-HDL, triglycerides, HOMA-IR and uric acid, lower HDL, and lower odds of hyperfiltration. There were no differences in blood pressure by racial group or place of birth. Conclusions Although Asian American children have lower odds of obesity, they have significantly worse glucose intolerance, higher serum uric acid levels, more dyslipidemia and more microalbuminuria compared to NHW children. US-born Asian American children have worse cardiometabolic health profiles compared to foreign-born Asian Americans.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"10 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135036933","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":"Single-cell spatial proteomics identifies the JAK/STAT pathway as an actionable therapeutic target in lethal cutaneous drug reactions","authors":"Thierry Nordmann, Holly Anderton, Akito Hasegawa, Lisa Schweizer, Peng Zhang, Pia-Charlotte Stadler, Ankit Sinha, Andreas Metousis, Florian A. Rosenberger, Maximillian Zwiebel, Takashi K. Satoh, Florian Anzengruber, Maria C. Tanzer, Yuki Saito, Ting Gong, Marvin Thielert, Haruna Kimura, Natasha Silke, Edwin H. Rodriguez, Restivo Gaetana, Hong Ha Nguyen, Annette Gross, Mitchell P. Levesque, Peter J. Murray, Saskia Ingen-Housz-Oro, Andreas Mund, Riichiro Abe, John Silke, Chao Ji, Lars E. French, Matthias Mann","doi":"10.1101/2023.11.11.23295492","DOIUrl":"https://doi.org/10.1101/2023.11.11.23295492","url":null,"abstract":"Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction and an emerging public health issue. Triggered by common medications, TEN patients undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms driving keratinocyte cell death have been proposed, the main drivers remain unknown and no effective therapy exists. To systematically map molecular changes that are associated with TEN and identify potential druggable targets, we employed the single-cell spatial proteomics technique Deep Visual Proteomics. We analyzed formalin-fixed paraffin-embedded archived skin-tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified over 5,000 proteins in keratinocytes and skin-infiltrating immune cells. Most strikingly, this revealed a robust enrichment of Type-I and -II interferon signature in the immune cell and keratinocyte compartment of TEN patients, along with a drastic activation of pSTAT1. Targeted inhibition with pan-JAK inhibitor (JAKi) tofacitinib reduced keratinocyte-directed cytotoxicity in a novel live-cell imaging assay, using patient-derived keratinocytes and peripheral blood mononuclear cells (PBMCs). Furthermore, oral administration of pan-JAKi tofacitinib or baricitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Lastly, JAKi treatment was safe and associated with rapid cutaneous re-epithelialization and recovery in four patients with TEN. This study uncovers the JAK-STAT and interferon signaling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAK inhibition as a curative therapy.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"20 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135037779","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}