tbuckley/cabot-search huggingface dataset:
20-Year Prospective, Sequential Follow-Up Study of Heterogeneity in Associations of Duration of Untreated Psychosis With Symptoms, Functioning, and Quality of Life Following First-Episode Psychosis
Authors: Donal O’Keeffe, Anthony Kinsella, John L. Waddington, Mary Clarke
Journal: American Journal of Psychiatry (2022)

Objective: Determining the extent to which relationships between duration of untreated psychosis (DUP) and outcome endure longitudinally across the lifetime course of psychotic illness requires prospective, systematic studies of epidemiologically representative incidence cohorts across decades. Transience, persistence, or heterogeneity in associations between DUP and distinct outcome domains are yet to be investigated over such time frames. Methods: Prospective, sequential follow-up studies of an epidemiologically representative first-episode psychosis incidence cohort in Ireland were conducted at 6 months and 4, 8, 12, and 20 years (N=171). Linear mixed-model analyses were applied to determine whether prospective associations of DUP with symptoms, functioning, and quality of life were consistent or varied across psychotic illness trajectory over a 20-year period. Evaluations included time, DUP quartile, and DUP quartile-by-time interaction effects. Results: Prospective, sequential follow-ups showed positive and negative symptoms, function, and quality of life to exhibit distinct trajectories of improvement in relation to shorter DUP. Despite heterogeneity in course and relationship to premorbid features, associations between shorter DUP and greater improvement were still evident 20 years after the first psychotic episode. Across the long-term course of psychotic illness, trajectories of association between shorter DUP and better outcome differed between domains of psychopathology, functionality, and quality of life. Nevertheless, such associations with shorter DUP were sustained for at least 20 years. Conclusions: These profiles indicate that while associations between DUP and long-term outcome can vary according to the domain of outcome, they are sustained across decades in a manner that could not be fully accounted for in terms of premorbid features or lead-time bias.
Daridorexant: First Approval
Authors: Anthony Markham
Journal: Drugs (2022)

Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. It was selected from a pool of drug candidates on the basis of an expected effect duration of ≈ 8 h at a dose of 25 mg, with a half-life intended to minimize residual effects that might impair daytime functioning. Based on the results of two pivotal phase III trials, daridorexant was recently approved in the USA for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. This article summarizes the milestones in the development of daridorexant leading to this first approval.
EFFICACY AND SAFETY OF TAFOLECIMAB IN CHINESE PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (CREDIT-2): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL
Authors: Yujie Zhou, Meng Chai, Yongming He, Wang Zhao, Xuebin Han, Guoyan Zhao, Xueping Ma, Ping Qiao, Pei An, Haoyu Li, Shuling Yan, Qingyang Ma, Huan Deng, Lei Qian
Journal: Journal of the American College of Cardiology (2022)
Measuring image distortions arising from age‐related macular degeneration: An Iterative Amsler Grid (IAG)
Authors: Inci Ayhan, Edward Doyle, Johannes Zanker
Journal: MedComm (2022)

Metamorphopsia, perceived as distortion of a shape, is experienced in age-related macular degeneration (AMD): straight lines appear to be curved and wavy to AMD patients and some other retinal pathologies. Conventional clinical assessment largely relies on asking patients to identify irregularities in Amsler Grids - a standardized set of equally spaced vertical and horizontal lines. Perceived distortions or gaps in the grid are a sign of macular pathology. Here, we developed an iterative Amsler Grid (IAG) procedure to obtain a quantifiable map of visual deformations. Horizontal and vertical line segments representing metamorphopsia are displayed on a computer screen. Line segments appearing distorted are adjusted by participants using the computer mouse to change their orientation in several iteratively such that they appear straight. Control participants are able to reliably correct deformations that simulate metamorphopsia while maintaining fixation in the center. In a pilot experiment, we attempted to obtain deformation maps from a small number of AMD patients. Whereas some patients with extensive scotomas found this procedure challenging, others were comfortable using the IAG and generating deformation maps corresponding to their subjective reports. This procedure may potentially be used to quantify local distortions and map them reliably in patients with early AMD.
Early chains of transmission of COVID-19 in France, January to March 2020
Authors: Juliette Paireau, Alexandra Mailles, Catherine Eisenhauer, Franck de Laval, François Delon, Paolo Bosetti, Henrik Salje, Valérie Pontiès, Simon Cauchemez
Journal: Eurosurveillance (2022)

Introduction SARS-CoV-2, the virus that causes COVID-19, has spread rapidly worldwide. In January 2020, a surveillance system was implemented in France for early detection of cases and their contacts to help limit secondary transmissions. Aim To use contact-tracing data collected during the initial phase of the COVID-19 pandemic to better characterise SARS-CoV-2 transmission. Methods We analysed data collected during contact tracing and retrospective epidemiological investigations in France from 24 January to 30 March 2020. We assessed the secondary clinical attack rate and characterised the risk of a contact becoming a case. We described chains of transmission and estimated key parameters of spread. Results During the study period, 6,082 contacts of 735 confirmed cases were traced. The overall secondary clinical attack rate was 4.1% (95% confidence interval (CI): 3.6–4.6), increasing with age of index case and contact. Compared with co-workers/friends, family contacts were at higher risk of becoming cases (adjusted odds ratio (AOR): 2.1, 95% CI: 1.4–3.0) and nosocomial contacts were at lower risk (AOR: 0.3, 95% CI: 0.1–0.7). Of 328 infector/infectee pairs, 49% were family members. The distribution of secondary cases was highly over-dispersed: 80% of secondary cases were caused by 10% of cases. The mean serial interval was 5.1 days (interquartile range (IQR): 2–8 days) in contact tracing pairs, where late transmission events may be censored, and 6.8 (3–8) days in pairs investigated retrospectively. Conclusion This study increases knowledge of SARS-CoV-2 transmission, including the importance of superspreading events during the onset of the pandemic.
NSCLC Subtyping in Conventional Cytology: Results of the International Association for the Study of Lung Cancer Cytology Working Group Survey to Determine Specific Cytomorphologic Criteria for Adenocarcinoma and Squamous Cell Carcinoma
Authors: Deepali Jain, Aruna Nambirajan, Gang Chen, Kim Geisinger, Kenzo Hiroshima, Lester Layfield, Yuko Minami, Andre L. Moreira, Noriko Motoi, Mauro Papotti, Natasha Rekhtman, Prudence A. Russell, Spasenija Savic Prince, Fernando Schmitt, Yasushi Yatabe, Serenella Eppenberger-Castori, Lukas Bubendorf, Mary Beth Beasley, Sabina Berezowska, Alain Borczuk, Elizabeth Brambilla, Teh-Ying Chou, Jin-Haeng Chung, Wendy Cooper, Sanja Dacic, Yuchen Chan, Fred R. Hirsch, David Hwang, Philippe Joubert, Keith Kerr, Sylvie Lantuejoul, Dongmei Lin, Fernando Lopez-Rios, Daisuke Matsubara, Mari Mino-Kenudson, Andrew Nicholson, Claudia Poleri, Anja Roden, Kurt Schalper, Lynette Sholl, Erik Thunnissen, William D. Travis, Ming Tsao, Ignacio Wistuba, Gang Chen
Journal: Journal of Thoracic Oncology (2022)
Covid-19: What do we know about the delta omicron recombinant variant?
Authors: Elisabeth Mahase
Journal: BMJ (2022)

A combination of the delta (AY.4) and BA.1 omicron variants has been named by the World Health Organization as the BA.1 x AY.4 recombinant. First detected in France in January 2022, it has since picked up the nickname "deltacron"1—<b>Elisabeth Mahase</b> finds out more
Pneumatosis Intestinalis in Necrotizing Enterocolitis
Authors: Lorraine Tong, Yu-Tang Chang
Journal: New England Journal of Medicine (2022)

An 11-day-old boy presented with diarrhea, emesis, abdominal distention, and shock. Abdominal radiography revealed pneumatosis intestinalis (gas within the bowel wall). During an exploratory laparotomy, gas bubbles were seen in the bowel walls, a finding consistent with necrotizing enterocolitis. He died intraoperatively from worsening symptoms associated with shock.
Association of Body Mass Index With Clinical Outcomes in Patients With Cystic Fibrosis
Authors: Rita Nagy, Noémi Gede, Klementina Ocskay, Bernadett-Miriam Dobai, Alan Abada, Zsófia Vereczkei, Piroska Pázmány, Dorottya Kató, Péter Hegyi, Andrea Párniczky
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The prevalence of overweight (body mass index [BMI] = 25-29.9 [calculated as weight in kilograms divided by height in meters squared]) and obesity (BMI ≥30) is increasing among patients with cystic fibrosis (CF). However, it is unclear whether there is a benefit associated with increasing weight compared with the reference range (ie, normal) in CF. <h3>Objective</h3> To evaluate the association of altered BMI or body composition and clinical outcomes in patients with CF. <h3>Data Sources</h3> For this systematic review and meta-analysis, the literature search was conducted November 2, 2020, of 3 databases: MEDLINE (via PubMed), Embase, and Cochrane Central Register of Controlled Trials. <h3>Study Selection</h3> Patients older than 2 years diagnosed with CF with altered body composition or BMI were compared with patients having the measured parameters within the reference ranges. Records were selected by title, abstract, and full text; disagreements were resolved by consensus. Cohort studies and conference abstracts were eligible; articles with no original data and case reports were excluded. <h3>Data Extraction and Synthesis</h3> Two authors independently extracted data, which were validated by a third author. Studies containing insufficient poolable numerical data were included in the qualitative analysis. A random-effects model was applied in all analyses. <h3>Main Outcomes and Measures</h3> Pulmonary function, exocrine pancreatic insufficiency (PI), and CF-related diabetes (CFRD) were investigated as primary outcomes. Odds ratios (ORs) or weighted mean differences (WMDs) with 95% CIs were calculated. The hypothesis was formulated before data collection. <h3>Results</h3> Of 10 524 records identified, 61 met the selection criteria and were included in the qualitative analysis. Of these, 17 studies were included in the quantitative synthesis. Altogether, 9114 patients were included in the systematic review and meta-analysis. Overweight (WMD, –8.36%; 95% CI, –12.74% to –3.97%) and obesity (WMD, –12.06%; 95% CI, –23.91% to –0.22%) were associated with higher forced expiratory volume in the first second of expiration compared with normal weight. The odds for CFRD and PI were more likely in patients of normal weight (OR, 1.49; 95% CI, 1.10 to 2.00) than in those who were overweight (OR, 4.40; 95% CI, 3.00 to 6.45). High heterogeneity was shown in the analysis of pulmonary function (<i>I</i><sup>2</sup> = 46.7%-85.9%). <h3>Conclusions and Relevance</h3> The findings of this systematic review and meta-analysis suggest that the currently recommended target BMI in patients with CF should be reconsidered. Studies with long-term follow-up are necessary to assess the possible adverse effects of higher BMI or higher fat mass in patients with CF.
Abstract P5-06-01: Spatiotemporal gene expression analysis to identify novel tumor-neural crosstalk in TNBC brain metastases
Authors: Hong Zhao, Xin Wang, Jianting Sheng, Shan Xu, Dongbing Gao, Stephen Wong
Journal: Cancer Research (2022)

Abstract Brain metastasis (BrM) occurs in 25-40% of TNBC metastatic patients while one-year survival remains a single digit. In contrast to other primary subtypes, TNBC usually spreads to the brain rapidly at early stages or even before the diagnosis of primary cancer. The shorter development time of BrM in TNBC and shorter survival time after BrM diagnosis may indicate a certain innate ability of TNBC cells in adapting to the brain. Recent seminal findings and our studies identified enriched and diverse expressions of neurotransmitters receptors, transporters, and key synthesis enzymes in brain metastatic TNBC cells. Since neurotransmitters, gliotransmitters, neurotrophic factors, and neural cytokines, called neuroactive substances (NSs), are the most abundant and key intercellular communication signals in the brain, we hypothesize that tumor cells leverage NSs to assimilate into the neural circuitry via communicating with various types of neural cells, including astrocytes, microglia/macrophages, oligodendrocytes and so on, to reinforce tumor-neural crosstalk in the development of BrM. By performing spatial transcriptomics experiments on mouse brain tissue sections bearing TNBC metastatic tumors, we found that brain regions, tumor lesions at different locations, and even tumor-surrounding areas were well separated into different clusters based on the spatial gene expressions and further predicted several novel paracrine and autocrine signalings between/within tumors and tumor-surrounding neural niches under different conditions, including tumor locations, tumor sizes, tumor center vs. edges, and stages of tumor development using the Cell-Cell Communication Explorer (CCCExplorer), a computational modeling tool for multi-cellular crosstalk and intracellular signaling developed by our lab. We conducted functional experiments to demonstrate that cell type-specific depletion of the secreted NSs deactivated the activities of corresponding receptor and downstream signaling using a cellular co-culture BrM system. The presented study indicates that the characterization and identification of spatiotemporal tumor-neural crosstalk in the BrM metastatic niche would open up a new vista for discovering novel therapeutics targets for devastating metastatic brain tumor. Citation Format: Hong Zhao, Xin Wang, Jianting Sheng, Shan Xu, Dongbing Gao, Stephen Wong. Spatiotemporal gene expression analysis to identify novel tumor-neural crosstalk in TNBC brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-01.
OUTCOMES AND RESOURCE UTILIZATION IN PATIENTS HOSPITALIZED WITH GASTROINTESTINAL BLEEDING COMPLICATED BY TYPES 1 AND 2 MYOCARDIAL INFARCTION
Authors: Ishan Kamat, Salik Nazir, Abdul Khan Minhas, Matthew Deshotels, Tayyab Cheema, Yochai Birnbaum, Hani Jneid
Journal: Journal of the American College of Cardiology (2022)
DURATION OF SYMPTOMS AND USE OF DIAGNOSTIC TESTING IN PATIENTS WITH ISCHEMIA AND NO OBSTRUCTIVE CORONARY ARTERY DISEASE
Authors: Alexandra N. Schwann, Steffne Kunnirickal, Natalija Odanovic, Leslie Yingzhijie Tseng, Erica Sarah Spatz, Steven E. Pfau, Samit Shah
Journal: Journal of the American College of Cardiology (2022)
Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia
Authors: Shanna Hamilton, Radmila Terentyeva, Vladimir Bogdanov, Tae Yun Kim, Fruzsina Perger, Jiajie Yan, Xun Ai, Cynthia A. Carnes, Andriy E. Belevych, Christopher H. George, Jonathan P. Davis, Sandor Gyorke, Bum-Rak Choi, Dmitry Terentyev
Journal: Circulation Research (2022)

Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca 2+ homeostasis, impairing luminal Ca 2+ regulation of the sarcoplasmic reticulum (SR) Ca 2+ release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process. Methods: A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca 2+ and reactive oxygen species imaging in isolated ventricular myocytes (VMs). Results: The SR-targeted reactive oxygen species biosensor ERroGFP showed increased intra-SR oxidation in TAB VMs that was associated with increased expression of Ero1α (endoplasmic reticulum oxidoreductase 1 alpha). Pharmacological (EN460) or genetic Ero1α inhibition normalized SR redox state, increased Ca 2+ transient amplitude and SR Ca 2+ content, and reduced proarrhythmic spontaneous Ca 2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca 2+ -dependent ventricular tachyarrhythmias in TAB hearts challenged with isoproterenol. Experiments in TAB VMs and human embryonic kidney 293 cells expressing human RyR2 revealed that an Ero1α-mediated increase in SR Ca 2+ -channel activity involves dissociation of intraluminal protein ERp44 (endoplasmic reticulum protein 44) from the RyR2 complex. Site-directed mutagenesis and molecular dynamics simulations demonstrated a novel redox-sensitive association of ERp44 with RyR2 mediated by intraluminal cysteine 4806. ERp44-RyR2 association in TAB VMs was restored by Ero1α inhibition, but not by reducing agent dithiothreitol, as hypo-oxidation precludes formation of covalent bond between RyR2 and ERp44. Conclusions: A novel axis of intraluminal interaction between RyR2, ERp44, and Ero1α has been identified. Ero1α inhibition exhibits promising therapeutic potential by stabilizing RyR2-ERp44 complex, thereby reducing spontaneous Ca 2+ release and Ca 2+ -dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.
Need for more focus on lipid species in studies of biological and model membranes
Authors: Tore Skotland, Kirsten Sandvig
Journal: Progress in Lipid Research (2022)

The lipid composition of cellular membranes can impact a number of physiological processes such as signaling, cell migration, endocytosis and intracellular transport. In this article we focus on some aspects concerning analysis of lipids and research on lipid structure and function in mammalian cells that in our opinion have not obtained sufficient attention. This includes interleaflet coupling between the two layers of the membrane, and the role of lipid species, i.e. the role of the complete structure of the lipids, including lipid chain length and the position of double bonds. We highlight the role of PS species for membrane function. We also discuss the large diversity of PS species in different biological samples and the possible functional consequences, and we provide an overview of PS species from 40 different samples. Furthermore, recent studies show that there seems to be a coregulation concerning the levels of sphingolipids and ether lipids. We review and discuss the published data indicating such a coregulation. Moreover, we point to some of the pitfalls in the field of lipidomics and present suggestions for improvement. Finally, we discuss the importance of using asymmetric membrane models with a composition of lipid species that are common in biological membranes.
STAT3 inhibitor Napabucasin abrogates MDSC immunosuppressive capacity and prolongs survival of melanoma-bearing mice
Authors: Rebekka Bitsch, Annina Kurzay, Feyza Özbay Kurt, Carolina De La Torre, Samantha Lasser, Alisa Lepper, Alina Siebenmorgen, Verena Müller, Peter Altevogt, Jochen Utikal, Viktor Umansky
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Myeloid-derived suppressor cells (MDSCs) represent a negative prognostic factor in malignant melanoma. These cells are generated under chronic inflammatory conditions typical of cancer. The transcription factor signal transducer and activator of transcription 3 (STAT3) orchestrates MDSC accumulation and acquisition of immunosuppressive properties. Here we studied STAT3 inhibition by Napabucasin as a way to block MDSC accumulation and activity and its potential to treat malignant melanoma. Methods In vitro generated murine MDSC and primary MDSC from melanoma-bearing mice were used to investigate the effects of Napabucasin on MDSC in vitro . The RET transgenic mouse model of malignant melanoma was used to examine Napabucasin therapy efficiency and its underlying mechanisms in vivo . Furthermore, STAT3 activation and its correlation with survival were explored in MDSC from 19 patients with malignant melanoma and human in vitro generated monocytic myeloid-derived suppressor cell (M-MDSC) were used to evaluate the effects of Napabucasin. Results Napabucasin was able to abrogate the capacity of murine MDSC to suppress CD8 + T-cell proliferation. The STAT3 inhibitor induced apoptosis in murine MDSC, significantly increased expression of molecules associated with antigen processing and presentation, as well as slightly decreased expression of immunosuppressive factors on these cells. RET transgenic mice treated with Napabucasin showed prolonged survival accompanied by a strong accumulation of tumor-infiltrating antigen-presenting cells and activation of CD8 + and CD4 + T cells. Interestingly, patients with malignant melanoma with high expression of activated STAT3 in circulating M-MDSC showed significantly worse progression-free survival (PFS) than patients with low levels of activated STAT3. In addition, Napabucasin was able to abrogate suppressive capacity of human in vitro generated M-MDSC. Conclusion Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.
When an Aortic Bioprosthesis Fails in a Low-risk Patient, Randomize
Authors: Matthias Raschpichler, Holger Thiele, Michael A. Borger
Journal: JAMA Cardiology (2022)

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EFFICACY AND SAFETY OF VITAMIN K ANTAGONISTS VERSUS DIRECT ORAL ANTICOAGULANTS FOR ATRIAL FIBRILLATION AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT: A META-ANALYSIS
Authors: Vijairam Selvaraj, Mohammad Saud Khan, Alexis Contos, Atin Jindal, Mohammed Kazimuddin, Mohammad Abdul-Waheed, Marwan Saad, Omar Hyder, Herbert D. Aronow, J. Dawn Abbott
Journal: Journal of the American College of Cardiology (2022)