tbuckley/cabot-search huggingface dataset:
Why evolve consciousness? Neural credit and blame allocation as a core function of consciousness
Authors: W. Tecumseh Fitch
Journal: Behavioral and Brain Sciences (2022)

Abstract I concur with Merker and colleague's critiques, suggesting that hypotheses about the evolutionary function of consciousness can help address them. Brains are parallel systems that function to compute possible actions and predict outcomes. I hypothesize that a core function of consciousness per se is the global feedback of information about those actions actually executed, supporting local learning via neuronal updating.
Cost-effectiveness of Robotic-Assisted Prostatectomy in the UK—Are We Doing Enough?
Authors: Vishnukamal Golla, Stephen B. Williams
Journal: JAMA Network Open (2022)

Muhieddine Labban, MD; Prokar Dasgupta, MBBS; Chao Song, MPH; Russell Becker, MA; Yanli Li, PhD; Usha Seshadri Kreaden, MS; Quoc-Dien Trinh, MD
Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311)
Authors: Robert L. Ferris, Yael Flamand, Gregory S. Weinstein, Shuli Li, Harry Quon, Ranee Mehra, Joaquin J. Garcia, Christine H. Chung, Maura L. Gillison, Umamaheswar Duvvuri, Bert W. O'Malley, Enver Ozer, Giovana R. Thomas, Wayne M. Koch, Neil D. Gross, R. Bryan Bell, Nabil F. Saba, Miriam Lango, Eduardo Méndez, Barbara Burtness
Journal: Journal of Clinical Oncology (2021)

Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC.
Single-Cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells
Authors: Chen Zhang, Xueshuai Han, Jingkun Liu, Lei Chen, Ying Lei, Kunying Chen, Jia Si, Tian-yi Wang, Hui Zhou, Xiaoyun Zhao, Xiaohui Zhang, Yihua An, Yueying Li, Qian-Fei Wang
Journal: Genomics Proteomics & Bioinformatics (2022)

Ex vivo-expanded mesenchymal stem cells (MSCs) have been demonstrated to be a heterogeneous mixture of cells exhibiting varying proliferative, multipotential, and immunomodulatory capacities. However, the exact characteristics of MSCs remain largely unknown. By single-cell RNA sequencing of 61,296 MSCs derived from bone marrow and Wharton's jelly, we revealed five distinct subpopulations. The developmental trajectory of these five MSC subpopulations was mapped, revealing a differentiation path from stem-like active proliferative cells (APCs) to multipotent progenitor cells, followed by branching into two paths: 1) unipotent preadipocytes or 2) bipotent prechondro-osteoblasts that were subsequently differentiated into unipotent prechondrocytes. The stem-like APCs, expressing the perivascular mesodermal progenitor markers CSPG4/MCAM/NES, uniquely exhibited strong proliferation and stemness signatures. Remarkably, the prechondrocyte subpopulation specifically expressed immunomodulatory genes and was able to suppress activated CD3+ T cell proliferation in vitro, supporting the role of this population in immunoregulation. In summary, our analysis mapped the heterogeneous subpopulations of MSCs and identified two subpopulations with potential functions in self-renewal and immunoregulation. Our findings advance the definition of MSCs by identifying the specific functions of their heterogeneous cellular composition, allowing for more specific and effective MSC application through the purification of their functional subpopulations.
How to design high quality acupuncture trials—a consensus informed by evidence
Journal: BMJ (2022)

How to design high quality acupuncture trials-a consensus informed by evidenceIn box 5 of this article by Yu-Qing Zhang et al (BMJ 2022; 376:e067476; doi:) the study's method of analysis was incorrectly described as repeated-measure analysis of variance.The online version has been corrected to say that the study used the Expectation for Relief Scale to measure patients' expectations at baseline and analysed the effect of expectations as a continuous variable using ANCOVA.In addition, a sentence in the section "Consideration 4: who should perform the intervention?"that referred to the effect of practitioner training and experience on pain has been removed because of changes to the supporting reference.
Intracellular Cholesterol Pools Regulate Oncogenic Signaling and Epigenetic Circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia
Authors: Marissa Rashkovan, Robert Albero, Francesca Gianni, Pablo Perez-Duran, Hannah I. Miller, Adam L. Mackey, Elisabeth M. Paietta, Martin S. Tallman, Jacob M. Rowe, Mark R. Litzow, Peter H. Wiernik, Selina Luger, Maria Luisa Sulis, Rajesh K. Soni, Adolfo A. Ferrando
Journal: Cancer Discovery (2021)

Abstract Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP- and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell–specific long-range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival. Significance: Overtly distinct cell metabolic pathways operate in ETP- and T-ALL pointing to specific metabolic vulnerabilities. Inhibition of mevalonate biosynthesis selectively blocks oncogenic AKT–MYC signaling in ETP-ALL and suppresses leukemia cell growth. Ultimately, these results will inform the development of novel tailored and more effective treatments for patients with high-risk ETP-ALL. This article is highlighted in the In This Issue feature, p. 587
Autoantibodies in COVID‐19 correlate with antiviral humoral responses and distinct immune signatures
Authors: Patrick Taeschler, Carlo Cervia, Yves Zurbuchen, Sara Hasler, Christian Pou, Ziyang Tan, Sarah Adamo, Miro E. Raeber, Esther Bächli, Alain Rudiger, Melina Stüssi‐Helbling, Lars C. Huber, Petter Brodin, Jakob Nilsson, Elsbeth Probst‐Müller, Onur Boyman
Journal: Allergy (2022)

Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19.We performed highly sensitive indirect immunofluorescence assays to detect antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed up to 1 year after infection, eleven vaccinated individuals, and 41 unexposed controls.Compared with healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, the paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B-cell compartment after recovery.Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased antiviral humoral immune responses and inflammatory immune signatures.
Abstract 10242: Single versus Dual Antiplatelet Post Transcatheter Aortic Valve Replacement: An Updated Meta-Analysis
Authors: Muhammad Khalid, Mahmoud El Iskandarani, Allah Yar, Amina Tahir, Sidra Tahir, THOMAS HELTON
Journal: Circulation (2021)

Introduction: Perioperative use of dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) remains controversial. This meta-analysis compares the safety and efficacy of single anti-antiplatelet therapy (SAPT) versus DAPT after TAVR in patients with no indications for long-term anticoagulation. Hypothesis: The use of SAPT is safe and efficacious in TAVR patients. Methods: Electronic databases were queried for randomized controlled trials (RCTs) and observational studies matching the inclusion criteria. The safety endpoints included bleeding and major vascular complications. The efficacy outcomes included myocardial infarction (MI), stroke, short and long-term all-cause mortality. The ratio risk ratio (RR) with 95% confidence interval (CI) was computed using a random-effect model. Results: A total of 4 RCTs and 2 observational studies (n=1,417) were included in the final analysis. There were decreased rates of bleeding (life-threatening or major) (RR: 0.44; CI: 0.31-0.63) with aspirin only therapy. However, there was no difference of MI (RR: 0.73; CI: 0.28-1.87), stroke (RR: 0.92; CI: 0.55-1.54), major vascular complications (RR: 0.61; CI: 0.35-1.07), short-term mortality (&gt;30 days) (RR: 0.82; CI: 0.45-1.49), and long-term mortality (&gt;30 days) (RR: 1.13; CI: 0.73-1.76). Conclusions: This analysis showed lower rates of bleeding and composite of bleeding/thromboembolic events with aspirin only compared to dual antiplatelet amongst patients that underwent TAVR for aortic stenosis.
Activation of the Calcium Receptor by Calcimimetic Agents Is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia
Authors: William G. Goodman, Donald T. Ward, Kevin J. Martin, Debra Drayer, Carol Moore, Jiahong Xu, James Lai, Yun Chon, Edward. F. Nemeth
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Hyperphosphatemia may contribute to secondary hyperparathyroidism among patients with CKD, but the mechanism responsible remains uncertain. Recent in vitro studies indicate that high levels of phosphorus attenuate the level of calcium receptor activation, and this observation has led to speculation that hyperphosphatemia diminishes the efficacy of calcimimetic agents when used clinically. Using data from large, prospective clinical trials of the calcimimetic agents etelcalcetide and cinacalcet, the authors demonstrate that hyperphosphatemia modestly reduces the effect of these agents in lowering parathyroid hormone (PTH) levels among those with secondary hyperparathyroidism undergoing hemodialysis. These findings demonstrate a role for phosphate as a negative modulator of calcium receptor activation in vivo in humans, but overall, it does not modify the PTH-lowering effect of either agent in a therapeutically meaningful way. Background Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro . Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. Methods To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. Results Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. Conclusions These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.
Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury
Authors: Lauren Herl Martens, Jiasheng Zhang, Sami J. Barmada, Ping Zhou, Sherry Kamiya, Binggui Sun, Sang-Won Min, Li Gan, Steven Finkbeiner, Eric J. Huang, Robert V. Farese Jr
Journal: Journal of Clinical Investigation (2022)
Proteomic evaluation of Alternaria alternata spores, hyphae, and commercial allergen extracts
Authors: Aishwarya Saha, Michael Strader, Brett Green, Angela Lemons, Donald Beezhold
Journal: Journal of Allergy and Clinical Immunology (2022)

Alternaria alternata is associated with allergic respiratory diseases, which can be managed with allergen extract-based diagnostics and immunotherapy. It is not known how asexual spores or the vegetative hyphae contribute to patient allergen reactivity and commercial allergen extracts are manufactured by extracting proteins without separating these components. Immunotherapy and diagnosis with existing products, while safe and effective, could be improved with better characterization of these elements.
Guidelines on how to manage cutaneous lupus erythematosus
Journal: British Journal of Dermatology (2022)

Cutaneous lupus erythematous (CLE) refers to a range of skin conditions with common clinical and laboratory findings.CLE is caused by a combination of genetic factors, autoantibodies and the environment, and can occur alone or as a feature of systemic lupus erythematosus (SLE).The British Association of Dermatologists put together a group that included consultant dermatologists, a consultant rheumatologist and patient representatives to review published evidence on treating adults, young people and children with CLE.The UKbased group produced 53 recommendations, based on a review of the evidence, for the management of CLE in general practitioner clinics and in hospitals.They used an approach called the GRADE system (Grading of Recommendations Assessment, Development and Evaluation) for developing guidelines.General measures central to the management of CLE include sun protection and smoking avoidance.The possibility of druginduced CLE should be considered, and medications that might potentially be the culprit stopped.Where the psychological impact of CLE on a patient is significant, referral to psychological support services should be considered.Topical steroids are an appropriate first-line medication for localized CLE.However, in active or widespread CLE, oral medications should be introduced early, with antimalarial drugs (such as hydroxychloroquine) being the first choice in most cases.The recommended patient management pathway for CLE is presented as a flow diagram to guide clinicians through options for first-line, second-line and third-line treatments.Recommendations for future research and audit points (to help check the care of patients with CLE is meeting the right standards) are also included.
Cancer Therapy Doesn't Diminish Vaccine Efficacy
Journal: Cancer Discovery (2021)

Patients with cancer are at high risk for complications and death from COVID-19 infections, but vaccination offers patients with solid tumors strong protection against SARS-CoV-2, including the Delta variant. Patients with hematologic malignancies, however, are less likely to mount a strong immune response to vaccination, possibly due to the natural history of the disease and to B cell-depleting therapies that affect antibody responses.
Abstract 072: Statin Eligibility And Use For Primary Prevention Among US Adults Across Strata Of Atherosclerotic Cardiovascular Disease Risk
Authors: Michael M Hammond, Natalie Cameron, Imani Bah, Kaitlyn Beltrame, Sadiya Khan, Nilay S Shah
Journal: Circulation (2022)

Introduction: In 2019, primary prevention guidelines broadened consideration for statin eligibility among those at borderline to intermediate risk for atherosclerotic cardiovascular disease (ASCVD) in the presence of a risk-enhancing factor (REF). However, the proportion of US adults affected by these guidelines, particularly among those estimated to be at borderline to intermediate risk for ASCVD, is unclear. Objectives: To determine the contemporary prevalence of statin use and eligibility among US adults at low, borderline, intermediate, and high ten-year risk of ASCVD in the presence of ASCVD risk-enhancing factors. Methods: We included participants age ≥ 20 years from the National Health and Nutrition Examination Survey from 2015-2018. Ten-year ASCVD risk was classified based on the Pooled Cohort Equations as: low &lt;5%, borderline 5 - &lt;7.5%, intermediate ≥7.5 - &lt;20%, and high ≥20%. The weighted prevalence of statin use was calculated in each risk category. Weighted logistic regression assessed the association between presence of risk-enhancing factors (see Table) with statin use across strata of ASCVD risk. Results: Of 1350 participants (representing 37,705,137 US adults), 46% were female and mean (SE) age was 58 (0.6) years. Of these 39%, 15%, 31% and 15% were in the low, borderline, intermediate, and high ASCVD risk groups, respectively. Among adults at borderline and intermediate ASCVD risk, 89% and 90% had at least one risk-enhancing factor, respectively. Of these adults, 88% and 91% were not on a statin, respectively. Odds of statin use for individuals with risk-enhancing factors is shown in the Table. Conclusion: A large proportion of adults with borderline/intermediate ASCVD risk were not taking a statin despite a high prevalence of risk-enhancing factors.
Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia
Authors: Allegra A. Petti, Saad M. Khan, Ziheng Xu, Nichole Helton, Catrina C. Fronick, Robert Fulton, Sai M. Ramakrishnan, Sridhar Nonavinkere Srivatsan, Sharon E. Heath, Peter Westervelt, Jacqueline E. Payton, Matthew J. Walter, Daniel C. Link, John DiPersio, Christopher Miller, Timothy J. Ley
Journal: Blood Cancer Discovery (2021)

Abstract To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, these data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion. Significance: These data enabled us to identify a relapse-enriched leukemic cell state with distinct transcriptional properties. Detailed case-by-case analyses elucidated the complex ways in which the AML genome, transcriptome, and immune microenvironment interact to evade chemotherapy. These analyses provide a blueprint for evaluating these factors in larger cohorts. This article is highlighted in the In This Issue feature, p. 1
Conflict, extremism, resilience and peace in South Asia; can covid-19 provide a bridge for peace and rapprochement?
Authors: Zulfiqar A Bhutta, Arun Mitra, Afsah Salman, Fawad Akbari, Suraya Dalil, Fyezah Jehan, Mushtaque Chowdhury, Saroj Jayasinghe, Purnima Menon, Samiran Nundy, Firdausi Qadri, Md Taufiqul Islam, Kul Gautam
Journal: BMJ (2021)