tbuckley/cabot-search huggingface dataset:
Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes
Authors: Matteo Bersanelli, Erica Travaglino, Manja Meggendorfer, Tommaso Matteuzzi, Claudia Sala, Ettore Mosca, Chiara Chiereghin, Noemi Di Nanni, Matteo Gnocchi, Matteo Zampini, Marianna Rossi, Giulia Maggioni, Alberto Termanini, Emanuele Angelucci, Massimo Bernardi, Lorenza Borin, Benedetto Bruno, Francesca Bonifazi, Valeria Santini, Andrea Bacigalupo, Maria Teresa Voso, Esther Oliva, Marta Riva, Marta Ubezio, Lucio Morabito, Alessia Campagna, Claudia Saitta, Victor Savevski, Enrico Giampieri, Daniel Remondini, Francesco Passamonti, Fabio Ciceri, Niccolò Bolli, Alessandro Rambaldi, Wolfgang Kern, Shahram Kordasti, Francesc Sole, Laura Palomo, Guillermo Sanz, Armando Santoro, Uwe Platzbecker, Pierre Fenaux, Luciano Milanesi, Torsten Haferlach, Gastone Castellani, Matteo G. Della Porta
Journal: Journal of Clinical Oncology (2021)

Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
Abstract 16607: A Comparison Of Outcomes Between Patients At Low And Intermediate-risk With Aortic Stenosis Undergoing Transcatheter Or Surgical Valve Repair
Authors: Mahin R Khan, Waleed T Kayani, Malalai Manan, Ahmad Munir, Ihab Hamzeh, Salim S Virani, Yochai Birnbaum, Hani Jneid, Mahboob Alam
Journal: Circulation (2019)

Introduction: In view of paucity of robust data and to improve precision of effect size, we aim to compare safety and efficacy of transcatheter aortic valve replacement (TAVR) with surgical aortic ...
Extra-Aortic Identifiers to Guide Genetic Testing in Familial Thoracic Aortic Aneurysms and Dissections Syndromes: It Is All About the Company One Keeps⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Eloisa Arbustini, Nupoor Narula
Journal: Journal of the American College of Cardiology (2012)
Aerosol Transmission of SARS-CoV-2: Inhalation as well as Exhalation Matters for COVID-19
Authors: Keir E. J. Philip, Adam Lewis, Sara C. Buttery, Colm McCabe, Daisy Fancourt, Christopher M. Orton, Michael I. Polkey, Nicholas S. Hopkinson
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study
Authors: Daniel P. Petrylak, Yohann Loriot, David R. Shaffer, Fadi Braiteh, John Powderly, Lauren C. Harshman, Paul Conkling, Jean-Pierre Delord, Michael Gordon, Joseph W. Kim, Indrani Sarkar, Kobe Yuen, Edward E. Kadel, Sanjeev Mariathasan, Carol O'Hear, Sujata Narayanan, Marcella Fassò, Susheela Carroll, Thomas Powles
Journal: Clinical Cancer Research (2021)

Atezolizumab [anti-programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.All 35 evaluable patients [median age, 68 years (range, 45-83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9-not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.
Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis
Authors: Christopher G. Hughes, Patrick T. Mailloux, John W. Devlin, Joshua T. Swan, Robert D. Sanders, Antonio Anzueto, James C. Jackson, Aimee S. Hoskins, Brenda T. Pun, Onur M. Orun, Rameela Raman, Joanna L. Stollings, Amy L. Kiehl, Matthew S. Duprey, Lan N. Bui, Hollis R. O’Neal, Allison Snyder, Michael A. Gropper, Kalpalatha K. Guntupalli, Gregg J. Stashenko, Mayur B. Patel, Nathan E. Brummel, Timothy D. Girard, Robert S. Dittus, Gordon R. Bernard, E. Wesley Ely, Pratik P. Pandharipande
Journal: New England Journal of Medicine (2021)

Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months.Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups.Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).
Embracing Genetic Diversity to Improve Black Health
Authors: Akinyemi Oni-Orisan, Yusuph Mavura, Yambazi Banda, Timothy A. Thornton, Ronnie Sebro
Journal: New England Journal of Medicine (2021)

Embracing Genetic Diversity to Improve Black Health Ideally, race will be replaced with genetic ancestry as a variable in medical research and practice. But until more ancestry data are available, ...
Put to the test: use of rapid testing technologies for covid-19
Authors: Alex Crozier, Selina Rajan, Iain Buchan, Martin McKee
Journal: BMJ (2021)

Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety (SA), cognitive-behavioral interventions targeting SA might be adopted to reduce loneliness. However, whether SA and loneliness share the same underlying neurocognitive mechanisms is still an elusive question. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in SA are evident in loneliness. We used a prestratified approach involving 42 (21 females) participants with high loneliness (HL) and 40 (20 females) participants with low loneliness (LL) scores. During fMRI, participants completed a social gambling task to measure the subjective value of engaging in social situations and responses to social feedback. Univariate and multivariate analyses of behavioral and neural data replicated known task effects. However, although HL participants showed increased SA, loneliness was associated with a response pattern clearly distinct from SA. Specifically, contrary to expectations based on SA differences, Bayesian analyses revealed moderate evidence for equal subjective values of engaging in social situations and comparable amygdala responses to social decision-making and striatal responses to positive social feedback in both groups. Moreover, while explorative analyses revealed reduced pleasantness ratings, increased striatal activity, and decreased striatal-hippocampal connectivity in response to negative computer feedback in HL participants, these effects were diminished for negative social feedback. Our findings suggest that, unlike SA, loneliness is not associated with withdrawal from social interactions. Thus, established interventions for SA should be adjusted when targeting loneliness. <b>SIGNIFICANCE STATEMENT</b> Loneliness can cause serious health problems. Adapting well-established cognitive-behavioral therapies targeting social anxiety might be promising to reduce chronic loneliness given a close link between both constructs. However, a better understanding of behavioral and neurobiological factors associated with loneliness is needed to identify which specific mechanisms of social anxiety are shared by lonely individuals. We found that lonely individuals show a consistently distinct pattern of behavioral and neural responsiveness to social decision-making and social feedback compared with previous findings for social anxiety. Our results indicate that loneliness is associated with a biased emotional reactivity to negative events rather than social avoidance. Our findings thus emphasize the distinctiveness of loneliness from social anxiety and the need for adjusted psychotherapeutic protocols.
Spatial Evolution of Histologic and Endoscopic Healing in the Left and Right Colon in Patients With Ulcerative Colitis
Authors: Sushrut Jangi, Ariela K. Holmer, Parambir S. Dulai, Brigid Boland, Mark Valasek, Vipul Jairath, Brian G. Feagan, William J. Sandborn, Siddharth Singh
Journal: Clinical Gastroenterology and Hepatology (2021)
Internet search and medicaid prescription drug data as predictors of opioid emergency department visits
Authors: Sean D. Young, Qingpeng Zhang, Jiandong Zhou, Rosalie Liccardo Pacula
Journal: npj Digital Medicine (2021)

Abstract The primary contributors to the opioid crisis continue to rapidly evolve both geographically and temporally, hampering the ability to halt the growing epidemic. To address this issue, we evaluated whether integration of near real-time social/behavioral (i.e., Google Trends) and traditional health care (i.e., Medicaid prescription drug utilization) data might predict geographic and longitudinal trends in opioid-related Emergency Department (ED) visits. From January 2005 through December 2015, we collected quarterly State Drug Utilization Data; opioid-related internet search terms/phrases; and opioid-related ED visit data. Modeling was conducted using least absolute shrinkage and selection operator (LASSO) regression prediction. Models combining Google and Medicaid variables were a better fit and more accurate ( R 2 values from 0.913 to 0.960, across states) than models using either data source alone. The combined model predicted sharp and state-specific changes in ED visits during the post 2013 transition from heroin to fentanyl. Models integrating internet search and drug utilization data might inform policy efforts about regional medical treatment preferences and needs.
Association of Medical Stimulants With Mortality in the US From 2010 to 2017
Authors: Joshua C. Black, Gabrielle E. Bau, Janetta L. Iwanicki, Richard C. Dart
Journal: JAMA Internal Medicine (2021)

Discussion | During the COVID-19 pandemic in California, older adults, Black and Latino residents, and those without college degrees have experienced the highest per capita excess mortality.Following the statewide shelter-in-place, Latino residents and those without a high school degree/GED had the greatest increase in excess per capita mortality, with rates more than tripling after reopening.We hypothesize that this pattern reflects the risk of COVID-19 death faced by low-wage, essential workers and their social networks owing to occupational exposure, crowded housing, and inadequate access to testing or treatments. 6 Although a limitation of this study is that our analyses were not designed to determine the associations with particular policies, our results suggest that the policies adopted to date have had disparate outcomes across population subgroups.Our findings underscore the importance of examining the inequitable effects of policies during the pandemic,
Abstract 12630: Association Between Z-score for Birth Weight and Postoperative Outcomes in Neonates and Infants With Congenital Heart Disease
Authors: Martina A Steurer, Shabnam Peyvandi, John M Costello, Anita J Moon-Grady, Robert Habib, Kevin D Hill, Marshall L Jacobs, Laura Jelliffe-Pawlowski, Roberta Keller, Sara K Pasquali, Vadiyala M Reddy, Sarah Tabbutt, satish rajagopal
Journal: Circulation (2020)

Background: Neonates with congenital heart disease are more likely to be small for gestational age. Few studies have investigated the effect of birth weight Z-score on outcomes after congenital heart surgery. Methods: Patients from the Society of Thoracic Surgeons Congenital Heart Surgery Database (2010 to 2016) undergoing cardiac surgery at a corrected gestational age ≤ 44 weeks were included, and classified as severely (birth weight Z-score -4 to -2), moderately (Z-score between -2 and -1) and mildly growth restricted (Z-score -1.0 to -0.5) and compared to a reference (Z-score 0 to 0.5). Multivariable logistic regression clustering on center was used to evaluate the association of birth weight Z-score with operative mortality, postoperative complications and length of stay, adjusting for other patient characteristics. Interaction between Z-score for birth weight and gestational age was assessed. Results: In 25,244 patients, operative mortality was 8.6% and major complications occurred in 19.4%. Compared to the reference group with no growth restriction, the adjusted odds (AOR) of mortality was increased in infants with severe (AOR 2.4, CI 2.0-3.0), moderate (AOR 1.7, CI 1.4-2.0) and mild growth restriction (AOR 1.4, CI 1.2-1.6). The AOR for major postoperative complications was increased for infants with severe (AOR 1.4, CI 1.2-1.7) and moderate growth restriction (AOR 1.2, CI 1.1-1.4), but not in mildly growth restricted infants (AOR 1.0, CI 0.9-1.2). Length of stay was prolonged for all growth restricted cohorts (adjusted Hazard Ratio&lt;1, p&lt;0.05 for all). There was significant interaction between birth weight Z-score and gestational age (p=0.007) with the strongest association between birth weight Z-score and operative mortality in early-term (gestational age 37-38 weeks), followed by full-term (&gt;38 weeks) and then preterm infants (&lt;37 weeks). Conclusions: Even birth weight Z-scores that are slightly below average are independent risk factors for mortality and morbidity in neonates undergoing cardiac surgery. The strongest association between poor fetal growth and operative mortality exists in early-term neonates. These novel findings may account for some of the previously unexplained variation in cardiac surgical outcomes.
Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma
Authors: Thomas Powles, Jonathan E. Rosenberg, Guru P. Sonpavde, Yohann Loriot, Ignacio Durán, Jae-Lyun Lee, Nobuaki Matsubara, Christof Vulsteke, Daniel Castellano, Chunzhang Wu, Mary Campbell, Maria Matsangou, Daniel P. Petrylak
Journal: New England Journal of Medicine (2021)

Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment.We conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival.A total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively).Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).
BCL11B Regulates Arterial Stiffness and Related Target Organ Damage
Authors: Jeff Arni C. Valisno, Joel May, Kuldeep Singh, Eric Y. Helm, Lisia Venegas, Enkhjargal Budbazar, Jena B. Goodman, Christopher J. Nicholson, Dorina Avram, Richard A. Cohen, Gary F. Mitchell, Kathleen G. Morgan, Francesca Seta
Journal: Circulation Research (2021)

Rationale: BCL11B (B-cell leukemia 11b) is a transcription factor known as an essential regulator of T lymphocytes and neuronal development during embryogenesis. A genome-wide association study showed that a gene desert region downstream of BCL11B , known to function as a BCL11B enhancer, harbors single nucleotide polymorphisms associated with increased arterial stiffness. However, a role for BCL11B in the adult cardiovascular system is unknown. Objective: Based on these human findings, we sought to examine the relation between BCL11B and arterial function. Methods and Results: Here we report that BCL11B is expressed in the vascular smooth muscle where it regulates vascular stiffness. RNA sequencing of aortas from wild-type and Bcl11b null mice (BSMKO) identified the cGMP (cyclic guanosine monophosphate)-cGMP-dependent protein kinase G (PKG) as the most significant differentially regulated signaling pathway in BSMKO compared with wild-type mice. BSMKO aortas showed decreased levels of PKG1, increased levels of Ca ++ -calmodulin-dependent serine/threonine phosphatase calcineurin (PP2B) and decreased levels of their common phosphorylation target, phosphorylated vasodilator-stimulated phosphoprotein (pVASP S239 ), a regulator of cytoskelatal actin rearrangements. Decreased pVASP S239 in BSMKO aortas was associated with increased actin polymerization (filamentous/globular actin ratio). Functionally, aortic force, stress, wall tension, and stiffness, measured ex vivo in organ baths, were increased in BSMKO aortas, and BSMKO mice had increased pulse wave velocity, the in vivo index of arterial stiffness. Despite having no effect on blood pressure or microalbuminuria, increased arterial stiffness in BSMKO mice was associated with increased incidence of cerebral microbleeds compared with age-matched wild-type littermates. Conclusions: We have identified vascular smooth muscle BCL11B as a crucial regulator of aortic smooth muscle function and a potential therapeutic target for vascular stiffness.