tbuckley/cabot-search huggingface dataset:
Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19
Authors: Myron J. Levin, Andrew Ustianowski, Stéphane De Wit, Odile Launay, Miles Avila, Alison Templeton, Yuan Yuan, Seth Seegobin, Adam Ellery, Dennis J. Levinson, Philip Ambery, Rosalinda H. Arends, Rohini Beavon, Kanika Dey, Pedro Garbes, Elizabeth J. Kelly, Gavin C.K.W. Koh, Karen A. Near, Kelly W. Padilla, Konstantina Psachoulia, Audrey Sharbaugh, Katie Streicher, Menelas N. Pangalos, Mark T. Esser
Journal: New England Journal of Medicine (2022)

The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group.A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).
The human fear paradox: Affective origins of cooperative care
Authors: Tobias Grossmann
Journal: Behavioral and Brain Sciences (2022)

Abstract Already as infants humans are more fearful than our closest living primate relatives, the chimpanzees. Yet heightened fearfulness is mostly considered maladaptive, as it is thought to increase the risk of developing anxiety and depression. How can this human fear paradox be explained? The fearful ape hypothesis presented herein stipulates that, in the context of cooperative caregiving and provisioning unique to human great ape group life, heightened fearfulness was adaptive. This is because from early in ontogeny fearfulness expressed and perceived enhanced care-based responding and provisioning from, while concurrently increasing cooperation with, mothers and others. This explanation is based on a synthesis of existing research with human infants and children, demonstrating a link between fearfulness, greater sensitivity to and accuracy in detecting fear in others, and enhanced levels of cooperative behaviors. These insights critically advance current evolutionary theories of human cooperation by adding an early-developing affective component to the human cooperative makeup. Moreover, the current proposal has important cultural, societal, and health implications, as it challenges the predominant view in Western, educated, industrialized, rich, and democratic (WEIRD) societies that commonly construe fearfulness as a maladaptive trait, potentially ignoring its evolutionary adaptive functions.
Comparing quantitative and qualitative verbal and social autopsy tools for under-5 deaths in Uganda: a cross-sectional study
Authors: Amy Blasini, Peter Waiswa, Ann Wolski, Philip Wanduru, Chelsea Finkbeiner, Lucky Amutuhaire, Cheryl A Moyer
Journal: The Lancet Global Health (2022)

Understanding biological causes of death and sociocultural factors that influence survival outcomes is crucial to reducing mortality in low-resource settings. Verbal and Social Autopsy instruments (VASAs) query family members about events leading up to an individual's death, resulting in quantitative, categorical data. We aimed to determine the value of a supplemental in-depth interview (known as VASA-QUAL) that generated detailed qualitative data in understanding childhood deaths.This cross-sectional study was conducted in Kawaala and Nakulabye in Kampala, Uganda between Feb 6 and March 7, 2020, using 20 village health team members to assist in the identification and recruitment of families within which a children younger than 5 years had died within the preceding 6 months. Family members were interviewed by a trained, local researcher who conducted the quantitative VASA and the VASA-QUAL in-depth interview. Quantitative data were analysed using Stata (v16.0), and qualitative data were transcribed into English and analysed using NVivo (v12.0). Three coders compared quantitative variables from the VASA with qualitative variables from the VASA-QUAL using a rubric of eight key indicators related to symptom recognition, decision making, care seeking, and treatments given, derived from the Pathways to Survival framework. Agreement across sources and new insights from qualitative data were recorded.48 VASAs were conducted, reflecting 48 deaths of children between the ages of 1 month and 3 days to 52 months. Agreement on key indicators ranged from 77% (for illness recognition) to 100% (for following provider referral recommendations). The qualitative component added or clarified information about pediatric illness and care-seeking across all indicators, including information about recognition of illness (96% of cases), care-seeking decisions (81%), whether home care was provided (75%), and choice of outside care (92%). The qualitative interviews frequently included symptoms that were missing or denied in the quantitative VASA, and they often clarified the chronological order of symptoms identified via VASA. Many qualitative interviews described complicated mechanisms of decision making, involving multiple key players, which were not adequately captured in the quantitative survey.Supplementing quantitative VASA tools with an in-depth VASA-QUAL interview provided important additional information. Supplemental qualitative interviews are an important tool for understanding the complexity of events leading up to childhood deaths.The Northern Pacific Global Health Research Training Consortium, Fogarty International Center at the National Institutes of Health.
<i>TP53</i> copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia
Authors: Mehrnoosh Tashakori, Tapan Kadia, Sanam Loghavi, Naval Daver, Rashmi Kanagal-Shamanna, Sherry Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol A. Bivins, Elias J. Jabbour, L. Jeffrey Medeiros, Kapil Bhalla, Hagop M. Kantarjian, Farhad Ravandi, Joseph D. Khoury
Journal: Blood (2022)

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.
Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins
Authors: Hui-Hua Li, Monte S. Willis, Pamela Lockyer, Nathaniel Miller, Holly McDonough, David J. Glass, Cam Patterson
Journal: Journal of Clinical Investigation (2022)

The authors recently became aware that the image for the HA (Foxo3a) blot in Figure 5C was a duplicate of the image presented as the anti-Myc (atrogin-1) blot in the right panel of Figure 4E.The corresponding authors have reviewed the original data and determined that the image in Figure 5C was incorrect.The corrected figure panel appears below.Additional lanes of the His (ubiquitin) blot, which were cropped from the original figure, are also displayed.
Health inequity drives disease biology to create disparities in prostate cancer outcomes
Authors: William G. Nelson, Otis W. Brawley, William B. Isaacs, Elizabeth A. Platz, Srinivasan Yegnasubramanian, Karen S. Sfanos, Tamara L. Lotan, Angelo M. De Marzo
Journal: Journal of Clinical Investigation (2022)

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men.
Time-restricted feeding modulates the DNA methylation landscape, attenuates hallmark neuropathology and cognitive impairment in a mouse model of vascular dementia
Authors: Sharmelee Selvaraji, Motakis Efthymios, Roger Sik Yin Foo, David Y. Fann, Mitchell Kim Peng Lai, Christopher Li Hsian Chen, Kah Leong Lim, Thiruma V. Arumugam
Journal: Theranostics (2022)

Objective: Vascular dementia (VaD) is the second most common cause of dementia worldwide. The increasing contribution of lifestyle-associated risk factors to VaD has pointed towards gene-environment interactions (i.e. epigenetics). This study thus aims to investigate the DNA methylation landscape in a chronic cerebral hypoperfusion (CCH) mouse model of VaD. As a nexus between the gene-environment interaction, intermittent fasting (IF) was introduced as a prophylactic intervention. Methods: Bilateral common carotid artery stenosis (BCAS) was used to induce CCH by placing micro-coils of 0.18 mm in each common carotid artery of the mice. The coils were left in the mice for 7, 15 and 30 days to study temporal differences. IF was introduced for 16 h daily for 4 months prior to BCAS. Reduced Representation Bisulfite Sequencing (RRBS) was used to study the DNA methylation landscape. Cognitive impairment was measured using Barnes Maze Test. White matter lesions (WML) and neuronal loss were measured using Luxol fast blue staining and cresyl violet staining respectively. Results: IF mice subjected to CCH displayed significantly better cognitive learning ability and memory, improved neuropathological alterations with reduced WMLs and neuronal loss. Modulation of DNA methylation patterns in the cortex of AL CCH mice was re-modelled and signs of reversal was observed in IF CCH mice across all three timepoints. Conclusions: These findings provide an understanding of how IF may protect the brain against damage caused by CCH and show promise in offering potential beneficial effects in mitigating the neuropathology and cognitive deficits in VaD.
Abstract EP63: Recurrent Ischemic Stroke And Cigarette Smoking: A Secondary Analysis Of The Point Trial
Authors: Adam E Lang, Adam H De Havenon, Brian Mac Grory, Nils Henninger, Karen Furie, J D Easton, Anthony Kim, S. Claiborne Johnston, Shadi Yaghi
Journal: Circulation (2022)

Background: Conflicting data exists surrounding whether or not the effect of clopidogrel on risk reduction of cardiovascular outcomes, including stroke, is more pronounced in smokers. The aim of this study was to determine the effect of smoking status on subsequent stroke risk in all patients with minor ischemic stroke or TIA, as well as subgroups that may be particularly impacted by an effect, and determine whether smoking improves the effect of clopidogrel treatment on subsequent stroke risk reduction. Subgroup analysis included those of older age, black race, and female gender, as these groups may have higher risk of clopidogrel non-response and subsequently poor outcomes. Methods: This was a post-hoc analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial. The POINT trial compared clopidogrel plus aspirin (DAPT) to aspirin alone for prevention of recurrent stroke, myocardial infarction, or vascular death within 3 months of a high-risk TIA or minor ischemic stroke. We used multivariable cox-regression models to determine the effect of smoking on the efficacy of DAPT in reducing the risk of subsequent ischemic stroke in all patients and prespecified subgroups stratified based on age, sex, race, and diabetes. We also performed interaction analyses to determine whether the effect of clopidogrel on subsequent ischemic stroke differed with respect to smoking status. Results: Data from 4,877 participants enrolled in the POINT trial were analyzed. Among these, 1,004 were current smokers and 3,873 were non-smokers. Smoking was associated with a non-significantly increased risk of recurrent ischemic stroke during follow up (hazard ratio, 1.31 [95% CI, 0.97 - 1.78], P=0.076). The effect of clopidogrel on ischemic stroke was not significantly different in non-smokers (hazard ratio, 0.74 [95% CI, 0.56 - 0.98], P=0.03) compared to smokers (adjusted hazard ratio, 0.63 [95% CI, 0.37 - 1.05], P=0.078), P for interaction = 0.572. In addition, the effect of clopidogrel on major hemorrhage was not significantly different in current smokers (hazard ratio, 2.59 [95% CI, 1.08 - 6.21], P=0.032) compared to non-smokers (hazard ratio, 1.67 [95% CI, 0.40 - 7.00], P=0.481), P for interaction = 0.613. This finding was maintained across different subgroups: males, females, blacks, whites, those with and without diabetes, and those aged &lt; 60 and ≥ 60 years. Conclusions: Cigarette smoking was associated with a non-significantly higher risk of subsequent ischemic stroke and smoking did not modify the effect of clopidogrel-based dual antiplatelet therapy on subsequent ischemic stroke risk reduction, even in the subgroups of stratified based on age, sex, race, and diabetes, where greater likelihood of effect was theorized. Every effort should be made to encourage tobacco dependence treatment and cessation in patients with minor ischemic stroke and TIA.
Abstract MP23: Does Predictors Of Overweight/obesity Among Women Vary Based On The Residential Setting? A Multilevel Analysis Of Repeated Cross-sectional Data In Nigeria
Authors: Jason M Were, Emmanuel Kyeremeh, Bridget O Annor, M. K Campbell, Saverio Stranges
Journal: Circulation (2022)

Background: Overweight/obesity is increasingly becoming a major public health problem in Nigeria despite the persistence of underweight burden. A major contributor of this is the urban sprawl experienced in the country with approximately half of the Nigerian population living in urban areas. Evidence suggests that similar socio-demographic factors could have different influences on an individual’s nutrition status by virtue of their residential setting. Yet, little is known about this phenomenon in the Nigerian context. Objectives: This study aimed to explore the following objectives: 1) to determine whether the anticipated increase in overweight/obesity prevalence is subsequently paralleled by substantial decrease in undernutrition in the last decade; and 2) to examine both the individual and household predictors’ overweight/obesity among women of reproductive age in rural and urban Nigeria. Methods: We used data acquired from the 2008, 2013 and 2018 Nigeria Demographic and Health Surveys (DHS). Our outcome was defined using standard Body Mass Index (BMI) categories calculated from height and weight measurements of the study participants. The national and stratified (urban/rural) prevalence estimates of underweight (BMI &lt;18.5 Kg/m 2 ), overweight (BMI 25 - 29.9 Kg/m 2 ), and obese (BMI ≥ 30 Kg/m 2 ) were computed for each survey. Afterwards, the underweight subjects were excluded from the study. Two-level (individual and household) logistic regression models were applied to examine the influence of individual and household characteristics on women’s overweight/obese status. Results: Findings show a steady increase in both the prevalence of overweight and obesity from 16.1% and 6.1% in 2008 to 18.2% and 10.0% in 2018, respectively, while underweight prevalence was averagely 12% across each survey. Regardless of the residential setting, age, marital status, education, occupation, household wealth and survey year were consistently associated with increased risk of overweight/obesity, whereas breastfeeding showed a protective association with overweight/obesity. Having multiple children and living in female-headed homes were unique risk factors for overweight/obesity among urban women while ethnicity, media exposure and state of residence were unique risk factors for overweight/obesity among rural women. Conclusion: Public health interventions aimed at lowering the risk of overweight/obesity should embrace the differences in risk factors that exists between rural and urban dwellers.
Spatially Distinct Reprogramming of the Tumor Microenvironment Based On Tumor Invasion in Diffuse-Type Gastric Cancers
Authors: Hye Young Jeong, In-Hye Ham, Sung Hak Lee, Daeun Ryu, Sang-Yong Son, Sang-Uk Han, Tae-Min Kim, Hoon Hur
Journal: Clinical Cancer Research (2021)

Histologic features of diffuse-type gastric cancer indicate that the tumor microenvironment (TME) may substantially impact tumor invasiveness. However, cellular components and molecular features associated with cancer invasiveness in the TME of diffuse-type gastric cancers are poorly understood.We performed single-cell RNA-sequencing (scRNA-seq) using tissue samples from superficial and deep invasive layers of cancerous and paired normal tissues freshly harvested from five patients with diffuse-type gastric cancer. The scRNA-seq results were validated by immunohistochemistry (IHC) and duplex in situ hybridization (ISH) in formalin-fixed paraffin-embedded tissues.Seven major cell types were identified. Fibroblasts, endothelial cells, and myeloid cells were categorized as being enriched in the deep layers. Cell type-specific clustering further revealed that the superficial-to-deep layer transition is associated with enrichment in inflammatory endothelial cells and fibroblasts with upregulated CCL2 transcripts. IHC and duplex ISH revealed the distribution of the major cell types and CCL2-expressing endothelial cells and fibroblasts, indicating tumor invasion. Elevation of CCL2 levels along the superficial-to-deep layer axis revealed the immunosuppressive immune cell subtypes that may contribute to tumor cell aggressiveness in the deep invasive layers of diffuse-type gastric cancer. The analyses of public datasets revealed the high-level coexpression of stromal cell-specific genes and that CCL2 correlated with poor survival outcomes in patients with gastric cancer.This study reveals the spatial reprogramming of the TME that may underlie invasive tumor potential in diffuse-type gastric cancer. This TME profiling across tumor layers suggests new targets, such as CCL2, that can modify the TME to inhibit tumor progression in diffuse-type gastric cancer.See related commentary by Huang and Brekken, p. 6284.