tbuckley/cabot-search huggingface dataset:
Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals
Authors: Jessica N. Peel, Rui Yang, Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Paul Bastard, Anish Behere, Axel Cederholm, Aaron Bodansky, Yoann Seeleuthner, Clément Conil, Jing-Ya Ding, Wei-Te Lei, Lucy Bizien, Camille Soudee, Mélanie Migaud, Masato Ogishi, Ahmad Yatim, Danyel Lee, Jonathan Bohlen, Thomas Perpoint, Laura Perez, Fernando Messina, Roxana Genet, Ludovic Karkowski, Mathieu Blot, Emmanuel Lafont, Laurie Toullec, Claire Goulvestre, Souad Mehlal-Sedkaoui, Jérôme Sallette, Fernando Martin, Anne Puel, Emmanuelle Jouanguy, Mark S. Anderson, Nils Landegren, Pierre Tiberghien, Laurent Abel, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Cheng-Lung Ku, Jean-Laurent Casanova
Journal: Journal of Clinical Investigation (2024)

BACKGROUND. Weakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adult individuals harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGA in a general population are unknown as is the the penetrance of nAIGA in HLA-DRB1*15:02 or 16:02 individuals, and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs. METHODS. This study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM. RESULTS. We find that anti-IFN-γ autoantibodies detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype are not neutralizing. Moreover, we do not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02, including 71 individuals with detectable anti-IFN-g autoantibodies (27.6%). Additionally, nAIGA are absent in 1,063 patients with an autoimmune disease. Furthermore, we find only a few other autoantibodies in seven patients with nAIGAs tested. Finally, seven of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGA. Yet, nAIGA are absent in the remaining 41 patients who are HLA-DRB1*15:02 or 16:02, the 45 patients with IFN-g autoantibodies, and the five patients with HLA-DRB1*15:02 or 16:02 and IFN-g autoantibodies . CONCLUSION. These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are causal of EM disease. FUNDING. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), and partly by French National Research Agency (ANR).
Knife-assisted incision for restoring esophageal lumen after surgical exclusion
Authors: Francesco Azzolini, Ernesto Fasulo, Francesco Vito Mandarino, Alberto Barchi, Silvio Danese
Journal: Endoscopy (2024)

Surgical repair with esophageal exclusion is a life-saving surgery for patients with mediastinitis following mid-esophageal perforation [1]. This is followed by either spontaneous recanalization of the organ or subsequent surgery to restore lumen patency [2].
Plasmacytoma and Amyloid Lymphadenopathy, FDG, and Fluorocholine
Authors: Gursan Kaya, Serkan Akin, Murat Tuncel, Pinar Kiratli
Journal: Clinical Nuclear Medicine (2024)

Abstract A 56-year-old man with thoracal mass suspected of solitary plasmacytoma was referred for 18 F-FDG PET-CT scan. His PET-CT revealed FDG-avid rib mass and cervical lesion at level 2. He also underwent 18 F-fluorocholine (FCH) PET-CT to evaluate possible metastatic spread of the disease. FCH PET-CT showed increased uptake at the rib mass, while the cervical lesion was not FCH-avid. Biopsies confirmed rib lesion was a solitary plasmacytoma; however, the cervical lesion was an amyloid deposited lymph node. This case showed FCH PET-CT is a valuable companion of FDG scan for the evaluation of plasma cell dyscrasias with a better specificity.
AI-Drafted Responses to Patients Reduced Clinician Burnout
Authors: Emily Harris
Journal: JAMA (2024)

Patricia Garcia, MD; Stephen P. Ma, MD, PhD; Shreya Shah, MD; Margaret Smith, MBA; Yejin Jeong, BA; Anna Devon-Sand, MPH; Ming Tai-Seale, PhD, MPH; Kevin Takazawa, BBA; Danyelle Clutter, MBA; Kyle Vogt, BA; Carlene Lugtu, MCiM; Matthew Rojo, MS; Steven Lin, MD; Tait Shanafelt, MD; Michael A. Pfeffer, MD; Christopher Sharp, MD
Navigating the U.S. regulatory landscape for neurologic digital health technologies
Authors: Neil A. Busis, Dilshad Marolia, Robert Montgomery, Laura J. Balcer, Steven L. Galetta, Scott N. Grossman
Journal: npj Digital Medicine (2024)

Digital health technologies (DHTs) can transform neurological assessments, improving quality and continuity of care. In the United States, the Food & Drug Administration (FDA) oversees the safety and efficacy of these technologies, employing a detailed regulatory process that classifies devices based on risk and requires rigorous review and post-market surveillance. Following FDA approval, DHTs enter the Current Procedural Terminology, Relative Value Scale Update Committee, and Centers for Medicare & Medicaid Services coding and valuation processes leading to coverage and payment decisions. DHT adoption is challenged by rapid technologic advancements, an inconsistent evidence base, marketing discrepancies, ambiguous coding guidance, and variable health insurance coverage. Regulators, policymakers, and payers will need to develop better methods to evaluate these promising technologies and guide their deployment. This includes striking a balance between patient safety and clinical effectiveness versus promotion of innovation, especially as DHTs increasingly incorporate artificial intelligence. Data validity, cybersecurity, risk management, societal, and ethical responsibilities should be addressed. Regulatory advances can support adoption of these promising tools by ensuring DHTs are safe, effective, accessible, and equitable.
Correction: Cutting-edge novel device in the treatment of obesity
Authors: Jan Kral, Jana Selucka, Katerina Waloszkova, Marek Buzga, Julius Spicak, Evzen Machytka
Journal: Endoscopy (2024)

Correction to: Cutting-edge novel device in the treatment of obesityEndoscopy 2024; 56(02): 155-156DOI: 10.1055/a-2209-3374
Endoscopic vacuum therapy as a salvage treatment of a life-threatening esophageal perforation
Authors: Carlos Robles-Medranda, Domenica Cunto, Maria Egas-Izquierdo, Juan Alcívar-Vásquez, Martha Arevalo-Mora, Jorge Baquerizo-Burgos, Daniela Tabacelia
Journal: Endoscopy (2024)

The mortality rate of esophageal perforations is 31% [1]. In severe cases, surgery becomes its mainstay management. But what happens when they fail to resolve a life-threatening condition? Endoscopic therapies (stenting, suturing, clipping) become a salvage option showing favorable results [2]; sometimes, though, they are not enough and require exploration of alternatives [3] [4]. We present challenging cases successfully treated with rescue endoscopic vacuum therapy (EVT) ([Video 1]).
Cardiac delivery of modified mRNA using lipid nanoparticles: Cellular targets and biodistribution after intramyocardial administration
Authors: M.C.I. Labonia, M. Estapé Senti, P.H. van der Kraak, M.A.D. Brans, I. Dokter, T.J. Streef, A.M. Smits, A.K. Deshantri, S.C.A. de Jager, R.M. Schiffelers, J.P.G. Sluijter, P. Vader
Journal: Journal of Controlled Release (2024)

Despite research efforts being made towards preserving (or even regenerating) heart tissue after an ischemic event, there is a lack of resources in current clinical treatment modalities for patients with acute myocardial infarction that specifically address cardiac tissue impairment. Modified messenger RNA (modRNA) presents compelling properties that could allow new therapeutic strategies to tackle the underlying molecular pathways that ultimately lead to development of chronic heart failure. However, clinical application of modRNA for the heart is challenged by the lack of effective and safe delivery systems. Lipid nanoparticles (LNPs) represent a well characterized class of RNA delivery systems, which were recently approved for clinical usage in mRNA-based COVID-19 vaccines. In this study, we evaluated the potential of LNPs for cardiac delivery of modRNA. We tested how variations in C12–200 modRNA-LNP composition affect transfection levels and biodistribution after intramyocardial administration in both healthy and myocardial-infarcted mice, and determined the targeted cardiac cell types. Our data revealed that LNP-mediated modRNA delivery outperforms the current state of the art (modRNA in citrate buffer) upon intramyocardial administration in mice, with only minor differences among the formulations tested. Furthermore, we determined both in vitro and in vivo that the cardiac cells targeted by modRNA-LNPs include fibroblasts, endothelial cells and epicardial cells, suggesting that these cell types could represent targets for therapeutic interference with these LNP formulations. These outcomes may serve as a starting point for LNP development specifically for therapeutic mRNA cardiac delivery applications.
Injectable, Electroconductive, Free Radical Scavenging Silk Fibroin/Black Phosphorus/Glycyrrhizic Acid Nanocomposite Hydrogel for Enhancing Spinal Cord Repair
Authors: Beichen Zhang, Wanshun Wang, Peng Gao, Xiang Li, Lingling Chen, Zefeng Lin, Hu Chen, Wenhao Liang, Zhiyuan Kong, Dingkun Lin, Xiaona Wu, Tao Zhang
Journal: Advanced Healthcare Materials (2024)

Spinal cord injury (SCI) often leads to a severe permanent disability. A poor inflammatory microenvironment and nerve electric signal conduction block are the main reasons for difficulty in spinal cord nerve regeneration. In this study, black phosphorus (BP) and glycyrrhizic acid (GA) are integrated into methacrylate-modified silk fibroin (SF) to construct a bifunctional injectable hydrogel (SF/BP/GA) with appropriate conductivity and the ability to inhibit inflammation to promote neuronal regeneration after SCI. This work discovers that the SF/BP/GA hydrogel can reduce the oxidative damage mediated by oxygen free radicals, promote the polarization of macrophages toward the anti-inflammatory M2 phenotype, reduce the expression of inflammatory factors, and improve the inflammatory microenvironment. Moreover, it induces neural stem cell (NSC) differentiation and neurosphere formation, restores signal conduction at the SCI site in vivo, and ameliorates motor function in mice with spinal cord hemisection, revealing a significant neural repair effect. An injectable, electroconductive, free-radical-scavenging hydrogel is a promising therapeutic strategy for SCI repair.
Rare case of early squamous cell carcinoma extending from the cardia to the fundus cured by endoscopic submucosal dissection
Authors: Tingzhu Lan, Hui Xie, Xianzong Ma, Lang Yang, Peng Jin
Journal: Endoscopy (2024)

A 70-year-old asymptomatic man with a preference for hot food and chronic alcohol consumption presented to our hospital for screening esophagogastroduodenoscopy, which revealed squamous metaplasia extending from the cardia to the fundus of the stomach ([Fig. 1]). Narrow-band imaging and magnified endoscopy showed a brown area and abnormal intraepithelial papillary capillary loops of type B1 within the squamous metaplasia of the stomach mucosa ([Fig. 2]), suggestive of early squamous cell carcinoma (SCC) with a low risk of submucosal infiltration. Biopsy confirmed high-grade dysplasia of the squamous epithelium. Endoscopic submucosal dissection (ESD) was performed to resect the lesion ([Video 1]). Lugol's iodine staining was used to determine the margin of the neoplasm before ESD, revealing a clear unstained area within a large area of dark brown mucosa ([Fig. 3]). Some columnar epithelial islands remained within the squamous metaplasia of the mucosa, with some unstained areas located outside the lesion. The lesion was completely resected without complications ([Fig. 4]). Histopathology confirmed an intramucosal SCC infiltrating into the lamina propria (pT1a-M2) ([Fig. 5]).
Endoscopic outcomes using a novel through-the-scope tack and suture system for gastrointestinal defect closure: a systematic review and meta-analysis
Authors: Andrew Canakis, Smit S. Deliwala, Michael Frohlinger, Benjamin Twery, Justin P. Canakis, Mohammed Rifat Shaik, Erik Gunnarsson, Osman Ali, Dushyant Singh Dahiya, Emily Gorman, Shayan S. Irani, Todd H. Baron
Journal: Endoscopy (2024)

Closure of gastrointestinal defects can reduce postprocedural adverse events. Over-the-scope clips and an over-the-scope suturing system are widely available, yet their use may be limited by defect size, location, operator skill level, and need to reinsert the endoscope with the device attached. The introduction of a through-the-scope helix tack suture system (TTSS) allows for closure of large irregular defects using a gastroscope or colonoscope, without the need for endoscope withdrawal. Since its approval 3 years ago, only a handful of studies have explored outcomes using this novel device.
Letter to the Editor: Endoscopy for potential variceal bleeding within 12 hours—Not so fast!
Authors: Loren Laine, Alan N. Barkun, Grigorios I. Leontiadis
Journal: Hepatology (2024)

1Yale School of Medicine, New Haven, CT, USA and VA Connecticut Healthcare System, West Haven, CT, USA 2McGill University, Montreal, Quebec, Canada 3McMaster University, Hamilton, Ontario, Canada Abbreviations: UGIB, upper gastrointestinal bleeding Correspondence Loren Laine, Section of Digestive Diseases, P.O. Box 208019, Yale School of Medicine, New Haven, CT 06520-8019. Email: [email protected]
Alcohol-associated liver cancer
Authors: Yaojie Fu, Luca Maccioni, Xin Wei Wang, Tim F. Greten, Bin Gao
Journal: Hepatology (2024)

Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis–associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.
Disentangling the riddle of systemic lupus erythematosus with antiphospholipid syndrome: blood transcriptome analysis reveals a less-pronounced IFN-signature and distinct molecular profiles in venous versus arterial events
Authors: Dionysis Nikolopoulos, Catherine Loukogiannaki, George Sentis, Panagiotis Garantziotis, Theodora Manolakou, Noemin Kapsala, Myrto Nikoloudaki, Antigone Pieta, Sofia Flouda, Ioannis Parodis, George Bertsias, Antonis Fanouriakis, Anastasia Filia, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2024)

Systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS) represents a challenging SLE endotype whose molecular basis remains unknown.
Acute hepatic porphyrias – a guide for Hepatologists
Authors: Akshata Moghe, Brendan M. McGuire, Cynthia Levy
Journal: Hepatology (2024)

The acute hepatic porphyrias (AHPs) are a group of rare, inherited disorders of the heme biosynthesis pathway, usually manifesting with attacks of acute abdominal pain and other neurovisceral symptoms, with or without cutaneous manifestations. AHPs are characterized by the accumulation of porphyrin precursors, porphobilinogen, and/or aminolevulinic acid, in the blood. The diagnosis is often missed or delayed due to both inadequate testing and the improper use of available laboratory tests. In this review, we describe the various clinical presentations of the 4 AHPs, elucidate the approach to diagnosis, and provide recommendations for immediate and long-term management. We also describe the different complications that can occur with long-standing AHP, including the development of HCC. The AHPs are very treatable conditions, with excellent outcomes if diagnosed and treated early. A high index of suspicion for the presence of these disorders, along with accurate testing and timely treatment, will help reduce the burden of disease and prevent irreversible complications in patients with AHP.
<i>NF1</i> mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma
Authors: Corina Anastasaki, Jit Chatterjee, Joshua P Koleske, Yunqing Gao, Stephanie L Bozeman, Chloe M Kernan, Lara I Marco Y Marquez, Ji-Kang Chen, Caitlin E Kelly, Connor J Blair, Dennis J Dietzen, Robert A Kesterson, David H Gutmann
Journal: Neuro-Oncology (2024)

With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation.
A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study
Authors: Mai Shi, Aimin Yang, Eric S. H. Lau, Andrea O. Y. Luk, Ronald C. W. Ma, Alice P. S. Kong, Raymond S. M. Wong, Jones C. M. Chan, Juliana C. N. Chan, Elaine Chow
Journal: PLoS Medicine (2024)

Background Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. Methods and findings We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. Conclusions Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.
Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation
Authors: Ioanna Tiniakou, Pei-Feng Hsu, Lorena S. Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M. Adams, Geunhyo Jang, Chetna Soni, Colleen M. Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C. Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T. Bedford, Stephen D. Nimer, Vesa Kaartinen, Esteban O. Mazzoni, Boris Reizis
Journal: Science Immunology (2024)

The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3