tbuckley/cabot-search huggingface dataset:
Learning from patient safety incidents involving acutely sick adults in hospital assessment units in England and Wales: a mixed methods analysis for quality improvement
Authors: Alexandra Urquhart, Sarah Yardley, Elin Thomas, Liam Donaldson, Andrew Carson-Stevens
Journal: Journal of the Royal Society of Medicine (2021)

Six per cent of hospital patients experience a patient safety incident, of which 12% result in severe/fatal outcomes. Acutely sick patients are at heightened risk. Our aim was to identify the most frequently reported incidents in acute medical units and their characteristics.Retrospective mixed methods methodology: (1) an a priori coding process, applying a multi-axial coding framework to incident reports; and, (2) a thematic interpretative analysis of reports.Patient safety incident reports (10 years, 2005-2015) collected from the National Reporting and Learning System, which receives reports from hospitals and other care settings across England and Wales.Reports describing severe harm/death in acute medical unit were identified.Incident type, contributory factors, outcomes and level of harm were identified in the included reports. During thematic analysis, themes and metathemes were synthesised to inform priorities for quality improvement.A total of 377 reports of severe harm or death were confirmed. The most common incident types were diagnostic errors (n = 79), medication-related errors (n = 61), and failures monitoring patients (n = 57). Incidents commonly stemmed from lack of active decision-making during patient admissions and communication failures between teams. Patients were at heightened risk of unsafe care during handovers and transfers of care. Metathemes included the necessity of patient self-advocacy and a lack of care coordination.This 10-year national analysis of incident reports provides recommendations to improve patient safety including: introduction of electronic prescribing and monitoring systems; forcing checklists to reduce diagnostic errors; and increased senior presence overnight and at weekends.
Designing Clinical Trials in Wilson’s Disease
Authors: Peter Ott, Aftab Ala, Frederick K. Askari, Anna Czlonkowska, Ralf‐Dieter Hilgers, Aurélia Poujois, Eve A. Roberts, Thomas Damgaard Sandahl, Karl Heinz Weiss, Peter Ferenci, Michael L. Schilsky
Journal: Hepatology (2021)

Background and Aims Wilson's disease (WD) is an autosomal-recessive disorder caused by ATP7B gene mutations leading to pathological accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empirical observations. These therapies are effective, but there are still unmet needs for which treatment modalities are being developed. An increase of therapeutical trials is anticipated. Approach and Results The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial design. The authors of the article were organizers or presented during this workshop, and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria, and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naïve patients. Conclusions The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.
DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma
Authors: Katharina Filipski, Michael Scherer, Kim N. Zeiner, Andreas Bucher, Johannes Kleemann, Philipp Jurmeister, Tabea I. Hartung, Markus Meissner, Karl H. Plate, Tim R. Fenton, Jörn Walter, Sascha Tierling, Bastian Schilling, Pia S. Zeiner, Patrick N. Harter
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
A Yeast BiFC-Seq Method for Genome-Wide Interactome Mapping
Authors: Limin Shang, Yuehui Zhang, Yuchen Liu, Chaozhi Jin, Yanzhi Yuan, Chunyan Tian, Ming Ni, Xiaochen Bo, Li Zhang, Dong Li, Fuchu He, Jian Wang
Journal: Genomics Proteomics & Bioinformatics (2021)

Genome-wide physical protein-protein interaction (PPI) mapping remains a major challenge for current technologies. Here, we reported a high-efficiency BiFC-seq method, yeast-enhanced green fluorescent protein-based bimolecular fluorescence complementation (yEGFP-BiFC) coupled with next-generation DNA sequencing, for interactome mapping. We first applied yEGFP-BiFC method to systematically investigate an intraviral network of the Ebola virus. Two-thirds (9/14) of known interactions of EBOV were recaptured, and five novel interactions were discovered. Next, we used the BiFC-seq method to map the interactome of the tumor protein p53. We identified 97 interactors of p53, more than three-quarters of which were novel. Furthermore, in a more complex background, we screened potential interactors by pooling two BiFC libraries together and revealed a network of 229 interactions among 205 proteins. These results show that BiFC-seq is a highly sensitive, rapid, and economical method for genome-wide interactome mapping.
Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis
Authors: Léa Sureau, Corentin Orvain, Jean-Christophe Ianotto, Valérie Ugo, Jean-Jacques Kiladjian, Damien Luque Paz, Jérémie Riou
Journal: Blood Cancer Journal (2021)

Abstract Myelofibrosis is a myeloproliferative neoplasm associated with constitutional symptoms, increasing splenomegaly, and worsening cytopenias. Janus kinase (JAK) inhibitors have been used for the treatment of myelofibrosis for several years, but there is a lack of comparative information between those treatments. A systematic review and network meta-analysis was performed on randomized controlled trials in patients with myelofibrosis receiving JAK inhibitor or placebo or control. Primary outcomes were efficacy on spleen volume reduction and total symptom score reduction. Additional analyses were conducted on anemia and thrombopenia events. Seven studies were included in the network meta-analysis including 1953 patients randomly assigned to four JAK inhibitors—ruxolitinib, fedratinib, pacritinib, momelotinib—or control. In first-line therapy, momelotinib and fedratinib were associated with comparable efficacy to ruxolitinib, and with less toxicity on erythrocytes and platelets, respectively. Pacritinib was less effective on splenomegaly than ruxolitinib as a first-line treatment but seemed effective in second line, after ruxolitinib exposure. Fedratinib and ruxolitinib that are FDA approved in myelofibrosis have both confirmed being valuable option to treat splenomegaly and constitutional symptoms, and their slightly different tolerance-profiles can guide therapeutic choice for first-line treatment, according to patient profile. Momelotinib could be another option especially due to its positive effect on anemia.
Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models
Authors: Nathan D. Winters, Gaurav Bedse, Anastasia A. Astafyev, Toni A. Patrick, Megan Altemus, Amanda J. Morgan, Snigdha Mukerjee, Keenan D. Johnson, Vikrant R. Mahajan, Md Jashim Uddin, Philip J. Kingsley, Samuel W. Centanni, Cody A. Siciliano, David C. Samuels, Lawrence J. Marnett, Danny G. Winder, Sachin Patel
Journal: Journal of Clinical Investigation (2021)

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.
Stool microRNA profiles reflect different dietary and gut microbiome patterns in healthy individuals
Authors: Sonia Tarallo, Giulio Ferrero, Francesca De Filippis, Antonio Francavilla, Edoardo Pasolli, Valentina Panero, Francesca Cordero, Nicola Segata, Sara Grioni, Ruggero Gaetano Pensa, Barbara Pardini, Danilo Ercolini, Alessio Naccarati
Journal: Gut (2021)

MicroRNA (miRNA) profiles have been evaluated in several biospecimens in relation to common diseases for which diet may have a considerable impact. We aimed at characterising how specific diets are associated with the miRNome in stool of vegans, vegetarians and omnivores and how this is reflected in the gut microbial composition, as this is still poorly explored.We performed small RNA and shotgun metagenomic sequencing in faecal samples and dietary recording from 120 healthy volunteers, equally distributed for the different diets and matched for sex and age.We found 49 miRNAs differentially expressed among vegans, vegetarians and omnivores (adj. p <0.05) and confirmed trends of expression levels of such miRNAs in vegans and vegetarians compared with an independent cohort of 45 omnivores. Two miRNAs related to lipid metabolism, miR-636 and miR-4739, were inversely correlated to the non-omnivorous diet duration, independently of subject age. Seventeen miRNAs correlated (|rho|>0.22, adj. p <0.05) with the estimated intake of nutrients, particularly animal proteins, phosphorus and, interestingly, lipids. In omnivores, higher Prevotella and Roseburia and lower Bacteroides abundances than in vegans and vegetarians were observed. Lipid metabolism-related miR-425-3p and miR-638 expression levels were associated with increased abundances of microbial species, such as Roseburia sp. CAG 182 and Akkermansia muciniphila, specific of different diets. An integrated analysis identified 25 miRNAs, 25 taxa and 7 dietary nutrients that clearly discriminated (area under the receiver operating characteristic curve=0.89) the three diets.Stool miRNA profiles are associated with specific diets and support the role of lipids as a driver of epigenetic changes and host-microbial molecular interactions in the gut.
Sodium–Glucose Cotransporter 2 Inhibitors and Risk of Retinal Vein Occlusion Among Patients With Type 2 Diabetes: A Propensity Score–Matched Cohort Study
Authors: Min-Kyung Lee, Bongsung Kim, Kyungdo Han, Jae-Hyuk Lee, Minhee Kim, Mee Kyoung Kim, Ki-Hyun Baek, Ki-Ho Song, Hyuk-Sang Kwon, Young-Jung Roh
Journal: Diabetes Care (2021)

OBJECTIVE To assess the association between use of sodium–glucose cotransporter 2 (SGLT2) inhibitors and retinal vein occlusion (RVO) using data from the National Health Insurance Service in South Korea. RESEARCH DESIGN AND METHODS We used an active comparator, new user design, and nationwide data from 2014 to 2017. Based on a 1:1 propensity score match, we included 47,369 new users of SGLT2 inhibitors and 47,369 users of other glucose-lowering drugs (oGLDs). In the matched sample, we used the Cox proportional hazards model to estimate hazard ratios (HRs) with 95% CIs for developing RVO. Based on the main outcome, exploratory subgroup analyses were undertaken. RESULTS During a follow-up of 2.57 years, the incidence rate of RVO was 2.19 and 1.79 per 1,000 person-years in patients treated with SGLT2 inhibitors and oGLDs, respectively. The new use of SGLT2 inhibitors was associated with an increased risk of RVO compared with oGLD use (HR 1.264 [95% CI 1.056, 1.513]). In the subgroup analyses, a significant interaction with SGLT2 inhibitors was observed for age and estimated glomerular filtration rate (eGFR); the HR for RVO was higher in patients aged ≥60 years and those with eGFR &amp;lt;60 mL/min/1.73 m2 than in others. CONCLUSIONS In a matched cohort study, we found that SGLT2 inhibitors were associated with a significantly increased risk of RVO. Older patients and those with chronic kidney disease were at higher risk for RVO.
Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort
Authors: Rafal Dziadziuszko, Tony Mok, Solange Peters, Ji-Youn Han, Jorge Alatorre-Alexander, Natasha Leighl, Virote Sriuranpong, Maurice Pérol, Gilberto de Castro Junior, Ernest Nadal, Filippo de Marinis, Osvaldo Arén Frontera, Daniel S.W. Tan, Dae Ho Lee, Hye Ryun Kim, Mark Yan, Todd Riehl, Erica Schleifman, Sarah M. Paul, Simonetta Mocci, Rajesh Patel, Zoe June Assaf, David S. Shames, Michael S. Mathisen, Shirish M. Gadgeel
Journal: Journal of Thoracic Oncology (2021)

The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort.Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response.In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6-18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5-93.5) by investigator and 92.0% (95% CI: 84.1-96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6-88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9-98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1-87.7). Safety data were consistent with the known tolerability profile of alectinib.These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.
Subcutaneous Soft Tissue Metastases in Lung Adenocarcinoma
Authors: David Lubin, Abtin Jafroodifar, Rahul Seth, Daniel Zaccarini
Journal: Clinical Nuclear Medicine (2021)

Initial disease presentations are often surprising compared with expected clinical trajectories. We present a case of metastatic lung adenocarcinoma where the initial presentation was masquerading as a musculoskeletal soft tissue mass. Initial concern was for a hematoma after light trauma, but due to a pacemaker, MRI was contraindicated. Workup included a 99mTc-MDP bone scan where the lesion demonstrated activity. Further workup imaging was serendipitous, revealing a left upper lobe mass. Biopsy demonstrated poorly differentiated adenocarcinoma of lung origin. Soft tissue metastasis can occur with lung adenocarcinoma, and although it constitutes a less frequent metastatic route, it is nevertheless clinically important.
The PROTACtable genome
Authors: Melanie Schneider, Chris J. Radoux, Andrew Hercules, David Ochoa, Ian Dunham, Lykourgos-Panagiotis Zalmas, Gerhard Hessler, Sven Ruf, Veerabahu Shanmugasundaram, Michael M. Hann, Pam J. Thomas, Markus A. Queisser, Andrew B. Benowitz, Kris Brown, Andrew R. Leach
Journal: Nature Reviews Drug Discovery (2021)
Adoptive cellular therapy in solid tumor malignancies: review of the literature and challenges ahead
Authors: Kedar Kirtane, Hany Elmariah, Christine H Chung, Daniel Abate-Daga
Journal: Journal for ImmunoTherapy of Cancer (2021)

While immune checkpoint inhibitors (ICIs) have ushered in major changes in standards of care for many solid tumor malignancies, primary and acquired resistance is common. Insufficient antitumor T cells, inadequate function of these cells, and impaired formation of memory T cells all contribute to resistance mechanisms to ICI. Adoptive cellular therapy (ACT) is a form of immunotherapy that is rapidly growing in clinical investigation and has the potential to overcome these limitations by its ability to augment the number, specificity, and reactivity of T cells against tumor tissue. ACT has revolutionized the treatment of hematologic malignancies, though the use of ACT in solid tumor malignancies is still in its early stages. There are currently three major modalities of ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. TIL therapy involves expansion of a heterogeneous population of endogenous T cells found in a harvested tumor, while TCRs and CAR T cells involve expansion of a genetically engineered T-cell directed toward specific antigen targets. In this review, we explore the potential of ACT as a treatment modality against solid tumors, discuss their advantages and limitations against solid tumor malignancies, discuss the promising therapies under active investigation, and examine future directions for this rapidly growing field.
MO34-3 Evaluation for penetration and usage of Japanese guidelines on febrile neutropenia among hematology-oncology physicians
Authors: Nobu Akiyama, Takuho Okamura, Shun-ichi Kimura, Shingo Yano, Isao Yoshida, Hitoshi Kusaba, Hiroyuki Fujita, Kosuke Takahashi, Keitaro Fukushima, Hiromichi Iwasaki, Minoru Yoshida, Toshiaki Saeki, Kazuo Tamura, Sadamoto Zenda
Journal: Annals of Oncology (2021)
Abstract 16865: Severe Physical and Sexual Abuse in Childhood and Adolescence Predicts Cardiovascular Events in Women
Authors: Janet Rich-Edwards, Susan Mason, Kathryn Rexrode, Donna Spiegelman, Eileen Hibert, Ichiro Kawachi, Hee-Jin Jun, Rosalind Wright
Journal: Circulation (2011)

Context: Although physical and sexual abuse of girls is widespread and has been associated with increased risks of obesity, hypertension, and diabetes, no study has investigated the extent to which early abuse increases risk of confirmed cardiovascular disease (CVD) events in women. Hypothesis: Child and adolescent abuse has a dose-response association with risk of CVD events. Design, Setting, and Participants: We examined associations of child and adolescent abuse reported in 2001 with confirmed CVD events from 1989-2007 among 67,102 women in the Nurses' Health Study II. Main Outcome Measures: Proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for myocardial infarction (MI, n=263), stroke (n=251), and total CVD events (n=514). Results: Nine percent of participants reported severe physical abuse and 11% reported forced sex during childhood or adolescence. With adjustment for age, race, body type at age five, parental education and family history, the hazards ratio (HR) for cardiovascular events was 0.91 (95% confidence interval: 0.70-1.17) for mild physical abuse, 1.03 (0.83-1.27) for moderate physical abuse, and 1.45 (1.10-1.90) for severe physical abuse compared to no physical abuse in childhood or adolescence. Compared with women reporting no sexual abuse in childhood or adolescence, the HR was 1.10 (0.89-1.36) for unwanted sexual touching, 1.56 (1.14-2.15) for one episode of forced sexual activity, and 1.62 (1.17-2.22) for repeated forced sex in childhood or adolescence. Associations of severe abuse with stroke were somewhat stronger for stroke than for MI. Adult body mass index, smoking, alcohol use, hypertension, and diabetes accounted for 41% (21% - 66%) of the association of severe physical abuse and 37% (22% - 55%) of the association of forced sex with CVD events. Conclusions: Severe physical and sexual abuse in childhood and adolescence are prevalent risk factors for heightened CVD risk in adult women. Mild and moderate abuse were not associated with increased CVD risk. The excess risk associated with severe abuse is mediated by elevated adult CVD risk factors in women with a history of early abuse.
Reconsideration of Clinicopathologic Prognostic Factors in Pancreatic Neuroendocrine Tumors for Better Determination of Adverse Prognosis
Authors: Anil Aysal, Cihan Agalar, Tufan Egeli, Tarkan Unek, Ilhan Oztop, Funda Obuz, Ozgul Sagol
Journal: Endocrine Pathology (2021)
Effect of Targeted Behavioral Science Messages on COVID-19 Vaccination Registration Among Employees of a Large Health System
Authors: Henri C. Santos, Amir Goren, Christopher F. Chabris, Michelle N. Meyer
Journal: JAMA Network Open (2021)

The first opportunities to field test interventions to increase COVID-19 vaccination were among health care workers (HCWs), who were among the first to be offered COVID-19 vaccines. After 1 large Pennsylvania health system sent 36 vaccine-related mass emails to employees over 5 weeks (eAppendix in Supplement 1), 9723 of 23 700 HCWs (41%) had still not scheduled their vaccination. We sought to determine whether individually addressed emails designed with behaviorally informed features1,2,3,4,5 could increase vaccination registration compared with a delayed control group.