tbuckley/cabot-search huggingface dataset:
Implications of genetic variation in the complement system in age-related macular degeneration
Authors: Sarah de Jong, Giuliana Gagliardi, Alejandro Garanto, Anita de Breuk, Yara T.E. Lechanteur, Suresh Katti, Lambert P. van den Heuvel, Elena B. Volokhina, Anneke I. den Hollander
Journal: Progress in Retinal and Eye Research (2021)

Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.
Injectable conductive hydrogel can reduce pacing threshold and enhance efficacy of cardiac pacemaker
Authors: Zhao An, Jun Wu, Shu-Hong Li, Shanglin Chen, Fang-Lin Lu, Zhi-Yun Xu, Hsing-Wen Sung, Ren-Ke Li
Journal: Theranostics (2021)

Background: Pacemaker implantation is currently used in patients with symptomatic bradycardia. Since a pacemaker is a lifetime therapeutic device, its energy consumption contributes to battery exhaustion, along with its voltage stimulation resulting in local fibrosis and greater resistance, which are all detrimental to patients. The possible resolution for those clinical issues is an injection of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to reduce the myocardial threshold voltage for pacemaker stimulation. Methods: PAMB-G is synthesized by covalently linking PAMB to gelatin, and its conductivity is measured using two-point resistivity. Rat hearts are injected with gelatin or PAMB-G, and pacing threshold is evaluated using electrocardiogram and cardiac optical mapping. Results: PAMB-G conductivity is 13 times greater than in gelatin. The ex vivo model shows that PAMB-G significantly enhances cardiac tissue stimulation. Injection of PAMB-G into the stimulating electrode location at the myocardium has a 4 times greater reduction of pacing threshold voltage, compared with electrode-only or gelatin-injected tissues. Multi-electrode array mapping reveals that the cardiac conduction velocity of PAMB-G group is significantly faster than the non- or gelatin-injection groups. PAMB-G also reduces pacing threshold voltage in an adenosine-induced atrial-ventricular block rat model. Conclusion: PAMB-G hydrogel reduces cardiac pacing threshold voltage, which is able to enhance pacemaker efficacy.
Recalibration of deep learning models for abnormality detection in smartphone-captured chest radiograph
Authors: Po-Chih Kuo, Cheng Che Tsai, Diego M. López, Alexandros Karargyris, Tom J. Pollard, Alistair E. W. Johnson, Leo Anthony Celi
Journal: npj Digital Medicine (2021)

Abstract Image-based teleconsultation using smartphones has become increasingly popular. In parallel, deep learning algorithms have been developed to detect radiological findings in chest X-rays (CXRs). However, the feasibility of using smartphones to automate this process has yet to be evaluated. This study developed a recalibration method to build deep learning models to detect radiological findings on CXR photographs. Two publicly available databases (MIMIC-CXR and CheXpert) were used to build the models, and four derivative datasets containing 6453 CXR photographs were collected to evaluate model performance. After recalibration, the model achieved areas under the receiver operating characteristic curve of 0.80 (95% confidence interval: 0.78–0.82), 0.88 (0.86–0.90), 0.81 (0.79–0.84), 0.79 (0.77–0.81), 0.84 (0.80–0.88), and 0.90 (0.88–0.92), respectively, for detecting cardiomegaly, edema, consolidation, atelectasis, pneumothorax, and pleural effusion. The recalibration strategy, respectively, recovered 84.9%, 83.5%, 53.2%, 57.8%, 69.9%, and 83.0% of performance losses of the uncalibrated model. We conclude that the recalibration method can transfer models from digital CXRs to CXR photographs, which is expected to help physicians’ clinical works.
Sambadrome marks Brazil’s covid deaths
Authors: Alison Shepherd
Journal: BMJ (2021)

For decades the Marquês de Sapucaí Sambadrome has been the home of Rio de Janeiro's carnival celebrations, with as many as 90 000 spectators paying to watch the parades.This year, with the pandemic forcing the cancellation of the carnival, the site became a blaze of colour to commemorate the more than 241 000 people who have died in Brazil with covid-19-the second highest total in the world, behind the US.Brazil has recorded almost 10 million cases.
Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
Authors: Priyanka Sharma, Vandana G. Abramson, Anne O'Dea, Lauren Nye, Ingrid Mayer, Harsh B. Pathak, Marc Hoffmann, Shane R. Stecklein, Manana Elia, Sharon Lewis, Jecinta Scott, Jilliann A. De Jong, Yen Y. Wang, Rachel Yoder, Kelsey Schwensen, Karissa Finke, Jaimie Heldstab, Stephanie LaFaver, Stephen K. Williamson, Milind A. Phadnis, Gregory A. Reed, Bruce F. Kimler, Qamar J. Khan, Andrew K. Godwin
Journal: Clinical Cancer Research (2021)

Abstract Purpose: PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Patients and Methods: Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes. Results: A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting &amp;gt;12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected. Conclusions: The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
A CD22–Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity
Authors: Romain Ballet, Martin Brennan, Carolin Brandl, Ningguo Feng, Jeremy Berri, Julian Cheng, Borja Ocón, Amin Alborzian Deh Sheikh, Alex Marki, Yuhan Bi, Clare L. Abram, Clifford A. Lowell, Takeshi Tsubata, Harry B. Greenberg, Matthew S. Macauley, Klaus Ley, Lars Nitschke, Eugene C. Butcher
Journal: Nature Immunology (2021)
Recommendations for the diagnosis and treatment of paroxysmal kinesigenic dyskinesia: an expert consensus in China
Authors: Li Cao, Xiaojun Huang, Ning Wang, Zhiying Wu, Cheng Zhang, Weihong Gu, Shuyan Cong, Jianhua Ma, Ling Wei, Yanchun Deng, Qi Fang, Qi Niu, Jin Wang, Zhaoxia Wang, You Yin, Jinyong Tian, Shufen Tian, Hongyan Bi, Hong Jiang, Xiaorong Liu, Yang Lü, Meizhen Sun, Jianjun Wu, Erhe Xu, Tao Chen, Tao Chen, Xu Chen, Wei Li, Shujian Li, Qinghua Li, Xiaonan Song, Ying Tang, Ping Yang, Yun Yang, Min Zhang, Xiong Zhang, Yuhu Zhang, Ruxu Zhang, Yi Ouyang, Jintai Yu, Quanzhong Hu, Qing Ke, Yuanrong Yao, Zhe Zhao, Xiuhe Zhao, Guohua Zhao, Furu Liang, Nan Cheng, Jianhong Han, Rong Peng, Shengdi Chen, Beisha Tang
Journal: Translational Neurodegeneration (2021)

Abstract Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes. Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology. Clinically, PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action. The major cause of primary PKD is genetic abnormalities, and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance. The proline-rich transmembrane protein 2 ( PRRT2 ) was the first identified causative gene of PKD, accounting for the majority of PKD cases worldwide. An increasing number of studies has revealed the clinical and genetic characteristics, as well as the underlying mechanisms of PKD. By seeking the views of domestic experts, we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD. In this consensus, we review the clinical manifestations, etiology, clinical diagnostic criteria and therapeutic recommendations for PKD, and results of genetic analyses in PKD patients performed in domestic hospitals.
Predictors of Mortality in Critically Ill Covid-19 Patients - A Multicenter Prospective Analysis of 159 Patients
Authors: R. Ip, Z. Q. Baloch, M. Boumegouas, A. Al Abcha, S. Do, J. Arnautovic, K. Meka, C. Jacob, M. Wilcox, J. Ip
Journal: Circulation (2020)
Abstract 10110: Exercise Induced Pulmonary Capillary Wedge Pressure Elevation Impairs Lung Diffusion Capacity for Oxygen in Mitral Regurgitation
Authors: Takayuki Hidaka, Hitoshi Susawa, Kiho Itakura, Yu Harada, Hiroto Utsunomiya, Kanako Izumi, Mirai Kinoshita, Yusuke Ueda, Yasuki Kihara
Journal: Circulation (2019)

Introduction: Exercise-induced abnormal elevation of left ventricular filling pressure is thought to impair external respiration during exercise in cardiovascular diseases (CVD). However, precise r...
Immunoglobulin G4–Related Sclerosing Cholangitis Revealed by 68Ga-FAPI PET/MR
Authors: Chunxia Qin, Ling Yang, Weiwei Ruan, Fuqiang Shao, Xiaoli Lan
Journal: Clinical Nuclear Medicine (2021)

A 60-year-old woman with surgically confirmed immunoglobulin G4-related sclerosing cholangitis underwent 18F-FDG PET/CT due to significantly elevated serum CA-19-9 level, which revealed a hypermetabolic lesion in the residual liver. 68Ga-FAPI PET/MR was performed to further evaluate whether the FDG-avid lesion is a malignant tumor. Astonishingly, diffuse intense radioactivity was revealed throughout the liver, suggesting involvement of active immunoglobulin G4-related sclerosing cholangitis, but nonfocal elevated 68Ga-FAPI accumulation in the FDG-avid lesion indicated postoperative change. From this case, we speculated that FAPI imaging could be used for evaluation of chronic liver disease because fibroblast activation protein has a profibrogenic role in chronic liver injury.
FlsnRNA-seq: protoplasting-free full-length single-nucleus RNA profiling in plants
Authors: Yanping Long, Zhijian Liu, Jinbu Jia, Weipeng Mo, Liang Fang, Dongdong Lu, Bo Liu, Hong Zhang, Wei Chen, Jixian Zhai
Journal: Genome biology (2021)

Abstract The broad application of single-cell RNA profiling in plants has been hindered by the prerequisite of protoplasting that requires digesting the cell walls from different types of plant tissues. Here, we present a protoplasting-free approach, flsnRNA-seq, for large-scale full-length RNA profiling at a single-nucleus level in plants using isolated nuclei. Combined with 10x Genomics and Nanopore long-read sequencing, we validate the robustness of this approach in Arabidopsis root cells and the developing endosperm. Sequencing results demonstrate that it allows for uncovering alternative splicing and polyadenylation-related RNA isoform information at the single-cell level, which facilitates characterizing cell identities.
Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma
Authors: Robert Motzer, Boris Alekseev, Sun-Young Rha, Camillo Porta, Masatoshi Eto, Thomas Powles, Viktor Grünwald, Thomas E. Hutson, Evgeny Kopyltsov, María J. Méndez-Vidal, Vadim Kozlov, Anna Alyasova, Sung-Hoo Hong, Anil Kapoor, Teresa Alonso Gordoa, Jaime R. Merchan, Eric Winquist, Pablo Maroto, Jeffrey C. Goh, Miso Kim, Howard Gurney, Vijay Patel, Avivit Peer, Giuseppe Procopio, Toshio Takagi, Bohuslav Melichar, Frederic Rolland, Ugo De Giorgi, Shirley Wong, Jens Bedke, Manuela Schmidinger, Corina E. Dutcus, Alan D. Smith, Lea Dutta, Kalgi Mody, Rodolfo F. Perini, Dongyuan Xing, Toni K. Choueiri
Journal: New England Journal of Medicine (2021)

Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
Changes in Suicide Rates — United States, 2018–2019
Authors: Deborah M. Stone, Christopher M. Jones, Karin A. Mack
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Suicide is the 10th leading cause of death in the United States overall, and the second and fourth leading cause among persons aged 10-34 and 35-44 years, respectively (1).In just over 2 decades , approximately 800,000 deaths were attributed to suicide, with a 33% increase in the suicide rate over the period (1).In 2019, a total of 12 million adults reported serious thoughts of suicide during the past year, 3.5 million planned a suicide, and 1.4 million attempted suicide (2).Suicides and suicide attempts in 2019 led to a lifetime combined medical and work-loss cost (i.e., the costs that accrue from the time of the injury through the course of a person's expected lifetime) of approximately $70 billion (https://wisqars.cdc.gov:8443/costT/).From 2018 to 2019, the overall suicide rate declined for the first time in over a decade (1).To understand how the decline varied among different subpopulations by demographic and other characteristics, CDC analyzed changes in counts and age-adjusted suicide rates from 2018 to 2019 by demographic characteristics, county urbanicity, mechanism of injury, and state.Z-tests and 95% confidence intervals were used to assess statistical significance.Suicide rates declined by 2.1% overall, by 3.2% among females, and by 1.8% among males.Significant declines occurred, overall, in five states.Other significant declines were noted among subgroups defined by race/ethnicity, age, urbanicity, and suicide mechanism.These declines, although encouraging, were not uniform, and several states experienced significant rate increases.A comprehensive approach to prevention that uses data to drive decision-making, implements prevention strategies from CDC's Preventing Suicide: A Technical Package of Policy, Programs, and Practices with the best available evidence, and targets the multiple risk factors associated with suicide, especially in populations disproportionately affected, is needed to build on initial progress from 2018 to 2019 (3).Data from the 2018-2019 National Vital Statistics System multiple cause-of-death mortality files were analyzed.Suicide deaths were identified by using International Classification of Diseases, Tenth Revision underlying cause-of-death codes U03, X60-X84, and Y87.0.Two-digit age-adjusted death rates (per 100,000 population) and confidence intervals were calculated by using the direct method and the 2000 U.S. standard population, rounded to one digit.Data for persons aged <10 years are not shown in results by age group because determining suicidal intent in younger children is difficult and case counts were <20, indicating unstable rates (4).Urbanization level of the decedent's county of residence was categorized by using the 2013 National Center for Health Statistics Urban-Rural
Building resilient medical technology supply chains with a software bill of materials
Authors: Seth Carmody, Andrea Coravos, Ginny Fahs, Audra Hatch, Janine Medina, Beau Woods, Joshua Corman
Journal: npj Digital Medicine (2021)

Abstract An exploited vulnerability in a single software component of healthcare technology can affect patient care. The risk of including third-party software components in healthcare technologies can be managed, in part, by leveraging a software bill of materials (SBOM). Analogous to an ingredients list on food packaging, an SBOM is a list of all included software components. SBOMs provide a transparency mechanism for securing software product supply chains by enabling faster identification and remediation of vulnerabilities, towards the goal of reducing the feasibility of attacks. SBOMs have the potential to benefit all supply chain stakeholders of medical technologies without significantly increasing software production costs. Increasing transparency unlocks and enables trustworthy, resilient, and safer healthcare technologies for all.
Abstract 16385: Cardiac Catheterizations Among Cocaine Users: An Analysis From the VA CART Program
Authors: Ateka Gunja, Mladen VIdovich, Maggie Stanislawski, Anna Barón, Thomas Maddox, Steven Bradley
Journal: Circulation (2017)

Introduction: Cocaine use has been associated with adverse cardiovascular outcomes. Methods: The Department of Veterans Affairs Clinical Assessment Reporting and Tracking Program database was used ...
Abnormal Splicing Patterns and Novel Intron Retentions Affect Genes Regulating Splicing, NF-Kb, ERK1/2, and TP53 in Waldenstrom's Macroglobulinemia
Authors: Zachary Hunter, Nickolas Tsakmaklis, Lian Xu, Maria Demos, Amanda Kofides, Jiaji Chen, Gloria Chan, Manit Munshi, Xia Liu, Joshua Gustine, Kirsten Meid, Christopher Patterson, Toni Dubeau, Patricia Severns, Jorge J. Castillo, Guang Yang, Nikhil Munshi, Kenneth C Anderson, Steven P Treon
Journal: Blood (2017)
Eligibility in Cancer Clinical Research: The Intersection of Discovery, Generalizability, Beneficence, and Justice
Authors: Bruce J. Giantonio
Journal: Clinical Cancer Research (2021)

Abstract Eligibility criteria in clinical trials limit the study population for safety and scientific purposes. The American Society of Clinical Oncology and The Friends of Cancer Research collaboration reconsidered common eligibility criteria in cancer trials and found many to be unnecessarily restrictive. The current recommendations further their efforts to facilitate accrual and improve the generalizability of research results to practice. See related articles, p. 2394, 2400, 2408, 2416, 2424, and 2430
The Effects of Modifying Dysfunctional Appraisals in Posttraumatic Stress Disorder Using a Form of Cognitive Bias Modification: Results of a Randomized Controlled Trial in an Inpatient Setting
Authors: Marcella L. Woud, Simon E. Blackwell, Lorika Shkreli, Felix Würtz, Jan Christopher Cwik, Jürgen Margraf, Emily A. Holmes, Susann Steudte-Schmiedgen, Stephan Herpertz, Henrik Kessler
Journal: Psychotherapy and Psychosomatics (2021)

Introduction: Dysfunctional appraisals about traumatic events and their sequelae are a key mechanism in posttraumatic stress disorder (PTSD). Experimental studies have shown that a computerized cognitive training, cognitive bias modification for appraisals (CBM-APP), can modify dysfunctional appraisals and reduce analogue trauma symptoms amongst healthy and subclinical volunteers. Objective: We aimed to test whether CBM-APP could reduce dysfunctional appraisals related to trauma reactions in PTSD patients, and whether this would lead to improvements in PTSD symptoms. Methods: We compared CBM-APP to sham training in a parallel-arm proof-of-principle double-blind randomized controlled trial amongst 80 PTSD patients admitted to an inpatient clinic. Both arms comprised a training schedule of 8 sessions over a 2-week period and were completed as an adjunct to the standard treatment programme. Results: In intention-to-treat analyses, participants receiving CBM-APP showed a greater reduction in dysfunctional appraisals on a scenario task from pre- to posttraining (primary outcome) assessments, compared to those receiving sham training (d = 1.30, 95% CI 0.82–1.80), with between-group differences also found on the Posttraumatic Cognitions Inventory (PTCI; d = 0.92, 95% CI 0.46–1.39) and the PTSD Checklist for DSM-5 (PCL-5; d = 0.63, 95% CI 0.18–1.08), but not for long-term cortisol concentrations (d = 0.25, 95% CI –0.28 to 0.78). Reductions in dysfunctional appraisals assessed via the scenario task correlated with reductions on the PTCI, PCL-5, and hair cortisol concentrations from pre- to posttraining time points. Conclusions: Results support dysfunctional appraisals as a modifiable cognitive mechanism, and that their proximal modification transfers to downstream PTSD symptoms. These findings could open new avenues for improving present therapeutic approaches.
Abstract 17258: Mitochondrial Redox Protein Thioredoxin 2 Is Essential for Preserving Cardiac Function
Authors: Qunhua Huang, Luyao (Kevin) Xu, Yan Huang, Haifeng Zhang, Frank J Giordano, Wang Min
Journal: Circulation (2010)

There is increasing support for the idea that excessive production of reactive oxygen species (ROS) contribute to the pathogenesis of cardiac dysfunction. Mitochondrial redox protein thioredoxin (T...