tbuckley/cabot-search huggingface dataset:
γδ T cells suppress Plasmodium falciparum blood-stage infection by direct killing and phagocytosis
Authors: Caroline Junqueira, Rafael B. Polidoro, Guilherme Castro, Sabrina Absalon, Zhitao Liang, Sumit Sen Santara, Ângela Crespo, Dhelio B. Pereira, Ricardo T. Gazzinelli, Jeffrey D. Dvorin, Judy Lieberman
Journal: Nature Immunology (2021)
Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells
Authors: Simon J. Dovedi, Matthew J. Elder, Chunning Yang, Suzanne I. Sitnikova, Lorraine Irving, Anna Hansen, James Hair, Des C. Jones, Sumati Hasani, Bo Wang, Seock-Ah Im, Ben Tran, Deepa S. Subramaniam, Shelby D. Gainer, Kapil Vashisht, Arthur Lewis, Xiaofang Jin, Stacy Kentner, Kathy Mulgrew, Yaya Wang, Michael G. Overstreet, James Dodgson, Yanli Wu, Asis Palazon, Michelle Morrow, Godfrey J. Rainey, Gareth J. Browne, Frances Neal, Thomas V. Murray, Aleksandra D. Toloczko, William Dall'Acqua, Ikbel Achour, Daniel J. Freeman, Robert W. Wilkinson, Yariv Mazor
Journal: Cancer Discovery (2021)

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1- T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.See related commentary by Burton and Tawbi, p. 1008.This article is highlighted in the In This Issue feature, p. 995.
Endoscopic features of Cronkhite–Canada syndrome
Authors: Ravishankar Asokkumar, Steven Mesenas, Roy Soetikno
Journal: Endoscopy (2021)

Cronkhite–Canada syndrome (CCS) is a rare protein-losing enteropathy and profound malnutrition disease with high mortality [1] [2] [3]. CCS can be challenging to differentiate from other polyposis syndromes [4]. We describe the endoscopic features of CCS before and after treatment.
Outcomes After Elective Inguinal Hernia Repair Performed by Associate Clinicians vs Medical Doctors in Sierra Leone
Authors: Thomas Ashley, Hannah Ashley, Andreas Wladis, Håkon A. Bolkan, Alex J. van Duinen, Jessica H. Beard, Hertta Kalsi, Juuli Palmu, Pär Nordin, Kristina Holm, Michael Ohene-Yeboah, Jenny Löfgren
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Task sharing of surgical duties with medical doctors (MDs) without formal surgical training and associate clinicians (ACs; health care workers corresponding to an educational level between that of a nurse and an MD) is practiced to provide surgical services to people in low-resource settings. The safety and effectiveness of this has not been fully evaluated through a randomized clinical trial. <h3>Objective</h3> To determine whether task sharing with MDs and ACs is safe and effective in mesh hernia repair in Sierra Leone. <h3>Design, Setting, and Participants</h3> This single-blind, noninferiority randomized clinical trial included adult, healthy men with primary inguinal hernia randomized to receiving surgical treatment from an MD or an AC. In Sierra Leone, ACs practicing surgery have received 2 years of surgical training and completed a 1-year internship. The study was conducted between October 2017 and February 2019. Patients were followed up at 2 weeks and 1 year after operations. Observers were blinded to the study arm of the patients. The study was carried out in a first-level hospital in rural Sierra Leone. Data were analyzed from March to June 2019. <h3>Interventions</h3> All patients received an open mesh inguinal hernia repair under local anesthesia. The control group underwent operations performed by MDs, and the intervention group underwent operations performed by ACs. <h3>Main Outcomes and Measures</h3> The primary end point was hernia recurrence at 1 year. Outcomes were assessed by blinded observers at 2 weeks and 1 year after operations. <h3>Results</h3> A total of 230 patients were recruited (mean [SD] age, 43.0 [13.5] years), and all but 1 patient underwent inguinal hernia repair between October 23, 2017, and February 2, 2018, performed by 5 MDs and 6 ACs. A total of 114 patients were operated on by MDs, and 115 patients were operated on by ACs. There were no crossovers between the study arms. The follow-up rate was 100% at 2 weeks and 94.1% at 1 year. At 1 year, hernia recurrence occurred in 7 patients (6.9%) operated on by MDs and 1 patient (0.9%) operated on by ACs (absolute difference, −6.0 [95% CI, −11.2 to 0.7] percentage points;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> These findings demonstrate that task sharing of elective mesh inguinal hernia repair with ACs was safe and effective. The task sharing debate should progress to focus on optimizing surgical training programs for nonsurgeons and building capacity for elective surgical care in low- and middle-income countries. <h3>Trial Registration</h3> isrctn.org Identifier:ISRCTN63478884
Abstract 13760: Resting Heart Rate Variability Parameters are Similar in Chronic Electronic Cigarette Users and Chronic Tobacco Cigarette Smokers
Authors: Sara Arastoo, Kacey P Haptonstall, Roya Moheimani, Yasmine Choroomi, Elizabeth Tran, Kevin Nguyen, Karishma Lakhani, Isabelle Ruedisueli, Jeffrey Gornbein, Holly R Middlekauff
Journal: Circulation (2019)

Introduction: Abnormal heart rate variability (HRV) is associated with increased cardiovascular risk. HRV has been reported to be abnormal in chronic tobacco cigarette (TC) smokers and chronic elec...
Neuroimaging Biomarkers in Schizophrenia
Authors: Nina V. Kraguljac, William M. McDonald, Alik S. Widge, Carolyn I. Rodriguez, Mauricio Tohen, Charles B. Nemeroff
Journal: American Journal of Psychiatry (2021)

Schizophrenia is a complex neuropsychiatric syndrome with a heterogeneous genetic, neurobiological, and phenotypic profile. Currently, no objective biological measures—that is, biomarkers—are available to inform diagnostic or treatment decisions. Neuroimaging is well positioned for biomarker development in schizophrenia, as it may capture phenotypic variations in molecular and cellular disease targets, or in brain circuits. These mechanistically based biomarkers may represent a direct measure of the pathophysiological underpinnings of the disease process and thus could serve as true intermediate or surrogate endpoints. Effective biomarkers could validate new treatment targets or pathways, predict response, aid in selection of patients for therapy, determine treatment regimens, and provide a rationale for personalized treatments. In this review, the authors discuss a range of mechanistically plausible neuroimaging biomarker candidates, including dopamine hyperactivity, N-methyl-d-aspartate receptor hypofunction, hippocampal hyperactivity, immune dysregulation, dysconnectivity, and cortical gray matter volume loss. They then focus on the putative neuroimaging biomarkers for disease risk, diagnosis, target engagement, and treatment response in schizophrenia. Finally, they highlight areas of unmet need and discuss strategies to advance biomarker development.
TS01.06 High-Plex Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)
Authors: A. Kulasinghe, J. Monkman, T. Taheri, M. Warkiani, C. O’leary, R. Ladwa, D. Richard, K. O'Byrne
Journal: Journal of Thoracic Oncology (2021)
Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas
Authors: Nivea Dias Amoedo, Saharnaz Sarlak, Emilie Obre, Pauline Esteves, Hugues Bégueret, Yann Kieffer, Benoît Rousseau, Alexis Dupis, Julien Izotte, Nadège Bellance, Laetitia Dard, Isabelle Redonnet-Vernhet, Giuseppe Punzi, Mariana Figueiredo Rodrigues, Elodie Dumon, Walid Mafhouf, Véronique Guyonnet-Dupérat, Lara Gales, Tony Palama, Floriant Bellvert, Nathalie Dugot-Senan, Stéphane Claverol, Jean-Marc Baste, Didier Lacombe, Hamid Reza Rezvani, Ciro Leonardo Pierri, Fatima Mechta-Grigoriou, Matthieu Thumerel, Rodrigue Rossignol
Journal: Journal of Clinical Investigation (2021)

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.
Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts
Authors: Xing Yi Woo, Jessica Giordano, Anuj Srivastava, Zi-Ming Zhao, Michael W. Lloyd, Roebi de Bruijn, Yun-Suhk Suh, Rajesh Patidar, Li Chen, Sandra Scherer, Matthew H. Bailey, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Yuanxin Xi, Jing Wang, Jayamanna Wickramasinghe, Andrew V. Kossenkov, Vito W. Rebecca, Hua Sun, R. Jay Mashl, Sherri R. Davies, Ryan Jeon, Christian Frech, Jelena Randjelovic, Jacqueline Rosains, Francesco Galimi, Andrea Bertotti, Adam Lafferty, Alice C. O’Farrell, Elodie Modave, Diether Lambrechts, Petra ter Brugge, Violeta Serra, Elisabetta Marangoni, Rania El Botty, Hyunsoo Kim, Jong-Il Kim, Han-Kwang Yang, Charles Lee, Dennis A. Dean, Brandi Davis-Dusenbery, Yvonne A. Evrard, James H. Doroshow, Alana L. Welm, Bryan E. Welm, Michael T. Lewis, Bingliang Fang, Jack A. Roth, Funda Meric-Bernstam, Meenhard Herlyn, Michael A. Davies, Li Ding, Shunqiang Li, Ramaswamy Govindan, Claudio Isella, Jeffrey A. Moscow, Livio Trusolino, Annette T. Byrne, Jos Jonkers, Carol J. Bult, Enzo Medico, Jeffrey H. Chuang
Journal: Nature Genetics (2021)

Abstract Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.
THU0205 Comparison of self-reporting measures of functional disability and clinical variables in rheumatoid arthritis in a turkish population
Authors: P Borman, L Yilmaz, H Gunduz, N Barca, MT Duruoz
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To assess the relationship between the clinical variables and the functional disability of patients with rheumatoid arthritis (RA) in a Turkish population and to determine whether simple self-reporting questionnaires provide information as accurate as traditional measurements of RA. <h3>Methods</h3> Subjects with rheumatoid arthritis according to ACR criteria were recruited consecutively. Clinical and radiological parameters were correlated with Turkish versions of the disability scales (HAQ, AIMS and Duruöz?s Hand Index-DHI) to obtain the relationship between disease activity and the functional disability status of each patient. Pearson?s correlation coefficient and Student?s t test were used to assess the relationship between two quantitative variables and two groups (early and established RA), respectively. p &lt; 0.05 was accepted as significant. <h3>Results</h3> Fifty patients (40 women) with a mean age of 47.7 (SD: 11.1) completed the study. The HAQ and DHI were best correlated with clinical activity parameters of RA, such as the Ritchie articular index (RAI), pain (VAS) and erythrocyte sedimentation rate. Radiological scores were best correlated with disease duration. Sex and rheumatoid factor were not significantly correlated with DHI, whereas RF was correlated with functional disability assessed by HAQ. The psychological scales of AIMS correlated well with RAI and swollen joint counts. We found no association between the mean disease duration and scores of functional status. Disability was slightly but not significantly higher in sero (+) than in sero (-) patients. The functional disability scores in patients with long and short disease duration were not significantly different. <h3>Conclusion</h3> Self-reporting functional disability questionnaires can provide accurate information about clinical and functional status in a cost-effective way for Turkish RA patients, as for those in other countries.
Lack of Evidence of Angiotensin-Converting Enzyme 2 Expression and Replicative Infection by SARS-CoV-2 in Human Endothelial Cells
Authors: Ian R. McCracken, Gaye Saginc, Liqun He, Alik Huseynov, Alison Daniels, Sarah Fletcher, Claire Peghaire, Viktoria Kalna, Maarja Andaloussi-Mäe, Lars Muhl, Nicky M. Craig, Samantha J. Griffiths, Jürgen G. Haas, Christine Tait-Burkard, Urban Lendahl, Graeme M. Birdsey, Christer Betsholtz, Michela Noseda, Andrew H. Baker, Anna M. Randi
Journal: Circulation (2021)
FDG PET/CT in Disseminated Intracranial and Intramedullary Spinal Cord Tuberculomas
Authors: Mingyuan Liu, Lingdan Lu, Qianyun Liu, Yushu Bai, Aisheng Dong
Journal: Clinical Nuclear Medicine (2021)

A 54-year-old woman was referred because of dizziness with fatigue for 2 months. MRI of the head and spinal cord revealed multiple ring or homogeneous enhancing nodules in the brain and spinal cord, concerning for metastases. FDG PET/CT showed multiple hypermetabolic nodules in the brain and spinal cord corresponding to the gadolinium-enhanced nodules and diffuse FDG uptake in the bilateral lower lobes of the lungs. Chest high-resolution CT showed diffuse, bilateral miliary opacities, most predominant in the lower lobes. The imaging findings and results of cerebrospinal fluid analysis were consistent with disseminated central nervous system tuberculomas with miliary pulmonary tuberculosis.
Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease
Authors: Jessica K. Dennis, Julia M. Sealock, Peter Straub, Younga H. Lee, Donald Hucks, Ky’Era Actkins, Annika Faucon, Yen-Chen Anne Feng, Tian Ge, Slavina B. Goleva, Maria Niarchou, Kritika Singh, Theodore Morley, Jordan W. Smoller, Douglas M. Ruderfer, Jonathan D. Mosley, Guanhua Chen, Lea K. Davis
Journal: Genome Medicine (2021)

Abstract Background Clinical laboratory (lab) tests are used in clinical practice to diagnose, treat, and monitor disease conditions. Test results are stored in electronic health records (EHRs), and a growing number of EHRs are linked to patient DNA, offering unprecedented opportunities to query relationships between genetic risk for complex disease and quantitative physiological measurements collected on large populations. Methods A total of 3075 quantitative lab tests were extracted from Vanderbilt University Medical Center’s (VUMC) EHR system and cleaned for population-level analysis according to our QualityLab protocol. Lab values extracted from BioVU were compared with previous population studies using heritability and genetic correlation analyses. We then tested the hypothesis that polygenic risk scores for biomarkers and complex disease are associated with biomarkers of disease extracted from the EHR. In a proof of concept analyses, we focused on lipids and coronary artery disease (CAD). We cleaned lab traits extracted from the EHR performed lab-wide association scans (LabWAS) of the lipids and CAD polygenic risk scores across 315 heritable lab tests then replicated the pipeline and analyses in the Massachusetts General Brigham Biobank. Results Heritability estimates of lipid values (after cleaning with QualityLab) were comparable to previous reports and polygenic scores for lipids were strongly associated with their referent lipid in a LabWAS. LabWAS of the polygenic score for CAD recapitulated canonical heart disease biomarker profiles including decreased HDL, increased pre-medication LDL, triglycerides, blood glucose, and glycated hemoglobin (HgbA1C) in European and African descent populations. Notably, many of these associations remained even after adjusting for the presence of cardiovascular disease and were replicated in the MGBB. Conclusions Polygenic risk scores can be used to identify biomarkers of complex disease in large-scale EHR-based genomic analyses, providing new avenues for discovery of novel biomarkers and deeper understanding of disease trajectories in pre-symptomatic individuals. We present two methods and associated software, QualityLab and LabWAS, to clean and analyze EHR labs at scale and perform a Lab-Wide Association Scan.
Ways to Support Low-Income, At-Risk Young Children During and After Coronavirus Disease 2019—Reply
Authors: Danielle G. Dooley, Asad Bandealy, Megan M. Tschudy
Journal: JAMA Pediatrics (2021)

equipment, and/or therapy services to learn best are not well served by exclusively remote education.Second, individual education plans are important tools for equity.To assure that children with disabilities receive quality education and are appropriately accommodated, individual education plans should proactively account for limitations on class sizes, minimization of group activities, and truncation of the school day.Education in the least restrictive environment, the legal standard, is the goal while assuring safety and mitigating risk.Third, retention of therapy and paraprofessional support in schools has to be prioritized as budget cuts tighten operating margins for school districts.A largescale exodus of these professionals from the education sector would be catastrophic for children with disabilities.In addition to those operational realities, 2 truisms should drive planning to reopen schools.First, keeping children with disabilities safe in schools will necessitate effort.Schools should plan for those who require specialized transportation, those who cannot wear a mask, and those who need cleaning of specialized equipment.Next, there should be creative approaches to replace the socialization and integration that children with disabilities receive in mainstream group academic activities such as art, physical education, and field trips, which are slated to be minimized as schools reopen.Children with disabilities are more isolated than their peers, 4 and reopening plans must not exacerbate that reality.Even before the pandemic, budget cuts made it difficult for schools to implement adaptations critical to optimize learning for children with disabilities.However, these children are not disposable and future legislative and operational efforts should focus on child health and well-being 5 for all children.
Abstract 16125: Impact of COVID-19 on Echocardiography Volume at a Large Academic Medical Center
Authors: Merilyn S Varghese, Jordan B Strom, Sarah Fostello, Warren J Manning
Journal: Circulation (2020)

Introduction: COVID-19 has significantly impacted hospital systems worldwide. The impact of statewide stay-at-home mandates on echocardiography volumes is unclear. Methods: We queried our institutional echocardiography database from 6/1/2018 to 6/13/2020 to examine rates of transthoracic (TTE), stress (SE), and transesophageal echocardiograms (TEE) prior to and following the COVID-19 Massachusetts stay-at-home order on March 15, 2020. Results: Among 36,377 total studies performed during the study period, mean weekly study volume dropped from 332 + 3 TTEs/week, 30 + 1 SEs/week, and 21 + 1 TEEs/week prior to the stay-at-home order (6/1/2018-3/15/2020) to 158 + 13 TTEs/week, 8 + 2 SEs/week, and 8 + 1 TEEs/week after (% change, -52%, -73%, and -62% respectively, all p &lt; 0.001 when comparing volume prior to March 15 versus after). Weekly TTEs correlated strongly with hospital admissions throughout the study period (r = 0.93, 95% CI 0.89-0.95, p &lt; 0.001) ( Figure ). Outpatient TTEs declined more than inpatient TTEs (% change, -74% vs. -39%, p &lt;0.001). As of 3 weeks following the cessation of the stay-at-home order, TTE, SE, and TEE weekly volumes have increased to 73%, 66%, and 81% of pre-pandemic levels, respectively. Conclusions: Echocardiography volumes fell precipitously following the Massachusetts stay-at-home order, strongly paralleling declines in overall hospitalizations. Outpatient TTEs declined more than inpatient TTEs. Despite lifting of the order, echocardiography volumes remain substantially below pre-pandemic levels. The impact of the decreased use of echocardiographic services on patient outcomes remains to be determined.
David Oliver: Could we do better on hospital acquired covid-19 in a future wave?
Authors: David Oliver
Journal: BMJ (2021)

Hospitals are currently in the eye of a covid-19 storm, driven by a rapid rise in community infection rates and more new emergency cases presenting daily. But before the current surge there were concerns about covid infection acquired or identified during a hospital stay.

In October the Healthcare Safety Investigation Branch (HSIB) issued a report on the factors behind hospital acquired covid-19 infections in England last spring.1 We now have better access to testing and personal protective equipment (PPE). We have better knowledge from research and guidelines. But the rates of covid infection officially classified as “hospital acquired” have yet to fall.

NHS hospitals are fielding formal complaints from people angry and distressed that they, or a family member, may have contracted infection in what they expect to be a place of safety. Teams battling to deliver clinical care in a highly pressurised environment and at some personal risk will be sent down a distracting, demoralising warren of complaint handling and root cause …