tbuckley/cabot-search huggingface dataset:
Knowledge and the brain: Why the knowledge-centric theory of mind program needs neuroscience
Authors: Adam Michael Bricker
Journal: Behavioral and Brain Sciences (2021)

Abstract The knowledge-centric theory of mind research program suggested by Phillips et al. stands to gain significant value by embracing a neurocognitive approach that takes full advantage of techniques such as fMRI and EEG. This neurocognitive approach has already begun providing important insights into the mechanisms of knowledge attribution, insights which support the claim that it is more basic than belief attribution.
Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation
Authors: Christopher J. Gibson, Haesook T. Kim, Lin Zhao, H. Moses Murdock, Bryan Hambley, Alana Ogata, Rafael Madero-Marroquin, Shiyu Wang, Lisa Green, Mark Fleharty, Tyler Dougan, Chi-An Cheng, Brendan Blumenstiel, Carrie Cibulskis, Junko Tsuji, Madeleine Duran, Christopher D. Gocke, Joseph H. Antin, Sarah Nikiforow, Amy E. DeZern, Yi-Bin Chen, Vincent T. Ho, Richard J. Jones, Niall J. Lennon, David R. Walt, Jerome Ritz, Robert J. Soiffer, Lukasz P. Gondek, R. Coleman Lindsley
Journal: Journal of Clinical Oncology (2021)

Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.
TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes
Authors: Katherine Quiroz-Figueroa, Cecilia Vitali, Donna M. Conlon, John S. Millar, John W. Tobias, Robert C. Bauer, Nicholas J. Hand, Daniel J. Rader
Journal: Journal of Clinical Investigation (2021)

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Trib1 (Trib1Δhep) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of Trib1Δhep but not Trib1Δhep CebpaΔhep mice. ATF3 has been shown to directly bind to the CEBPα protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in Trib1Δhep mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBPα, which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C.
Raising the stakes for cortical visual prostheses
Authors: Michael S. Beauchamp, William H. Bosking, Denise Oswalt, Daniel Yoshor
Journal: Journal of Clinical Investigation (2021)

In this issue of the JCI, the dream of restoring useful vision to blind individuals with neurotechnology moves one step closer to realization. Fernández et al. implanted an electrode array with 96 penetrating electrodes in the visual cortex of a blind patient who had been without light perception for 16 years due to optic neuropathy. Remarkably, the patient was able to perceive visual patterns created by passing current through array electrodes. The use of a penetrating electrode array meant that action potentials from single neurons could be recorded to study the neural response to stimulation. Compared with electrodes resting on the cortical surface, penetrating electrodes require one-tenth the current to create a visual percept. However, patterned electrical stimulation often fails to produce the expected percept for penetrating and surface electrode arrays, highlighting the need for further research to untangle the relationship between stimulus and perception.
Safety and Antitumor Activity of α-PD-L1 Antibody as Monotherapy or in Combination with α-TIM-3 Antibody in Patients with Microsatellite Instability–High/Mismatch Repair–Deficient Tumors
Authors: Antoine Hollebecque, Hyun C. Chung, Maria J. de Miguel, Antoine Italiano, Jean-Pascal Machiels, Chia-Chi Lin, Neesha C. Dhani, Marc Peeters, Victor Moreno, Wu-Chou Su, Kay Hoong Chow, Violeta R. Galvao, Michelle Carlsen, Danni Yu, Anna M. Szpurka, Yumin Zhao, Shelly L. Schmidt, Leena Gandhi, Xiaojian Xu, Yung-Jue Bang
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) tumors. However, 50%–60% do not respond to single-agent anti–programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6–12 months. This phase Ib trial evaluated safety and antitumor activity of anti–PD-L1 antibody LY3300054 monotherapy or in combination with anti–TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. Patients and Methods: Eligible patients ≥18 years without prior anti–PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor–resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti–TIM-3 antibody (cycles 1–2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. Results: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. Conclusions: LY3300054 monotherapy and combined LY3300054/anti–TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor–naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor–resistant/refractory MSI-H/dMMR tumors.
Abstract P202: Optimism Moderates The Effects Of Neighborhood Disadvantage On Incident Heart Failure Among African-Americans In The Jackson Heart Study (JHS) And Atherosclerosis Risk In Communities (ARIC) Study
Authors: Ganga S Bey, Gerardo M Heiss, James R Pike, Priya Palta, Sharrelle Barber
Journal: Circulation (2022)

Background: African-Americans experience a disproportionate burden of heart failure. Although previous research has identified neighborhoods as an important contributor to these disparities, less is understood about how psychosocial resilience factors, such as optimism, may provide protection from the effects of neighborhood disadvantage on heart failure risk. We tested the hypothesis that higher levels of optimism will attenuate the associations between greater neighborhood disadvantage and higher incidence of heart failure. Methods: Among 1,448 African-Americans dually enrolled in two community-based cohorts in Jackson, Mississippi—JHS and the ARIC study—who were free of heart failure as of January 1, 2000, 459 failure events classified by reviewer panel accrued through December 31, 2019. Multi-level age- and sex-adjusted Cox regression models with interaction terms were used to examine whether individual-level optimism moderated the associations of four measures of census tract-level neighborhood socioeconomic and social environment characteristics (the national Area Deprivation Index (ADI), a JHS neighborhood disadvantage score, racial residential segregation, and perceived physical disorder) on individual-level incident hospitalized heart failure. Results: Optimism moderated the associations of some neighborhood disadvantage measures (ADI and JHS neighborhood disadvantage score) on hospitalized heart failure risk (Table). Compared to participants reporting the lowest level of optimism, those in the highest tertile had 12%, 6%, 16%, and 9% lower rates of heart failure associated with increasing neighborhood disadvantage, respectively for each exposure. Interaction estimates for racial residential segregation and perceived physical disorder did not reach statistical significance. Conclusions: Optimism may provide resilience to the detrimental effects of neighborhood disadvantage on risk for heart failure.
A Legacy of Scientific Racism: William Osler's “An Alabama Student”
Authors: Charles S. Bryan, Richard D. deShazo, Margaret W. Balch
Journal: Annals of Internal Medicine (2022)

William Osler's essay “An Alabama Student” made John Young Bassett (1804–1851) a widely admired avatar of idealism in medicine. However, Bassett fiercely attacked the idea that all humans are members of the same species (known as monogenesis) and asserted that Black inferiority was a justification for slavery. Antebellum physician–anthropologists bequeathed a legacy of scientific racism that in subtler forms still runs deep in American society, including in the field of medicine.
Confused about Confusion
Authors: Anne M. Spanjaart, Fleur M. van der Valk, Geeske van Rooijen, Matthijs C. Brouwer, Marie J. Kersten
Journal: New England Journal of Medicine (2022)

Confusion developed in a 49-year-old woman with relapsed diffuse large B-cell lymphoma within days after she received CAR-T therapy. She had difficulty putting words together and was disoriented but had no focal abnormalities noted during the neurologic examination.
Real-world data on immune responses following heterologous prime-boost COVID-19 vaccination schedule with Pfizer and AstraZeneca vaccines in England
Authors: Samantha J Westrop, Heather J Whitaker, Annabel A Powell, Linda Power, Corinne Whillock, Helen Campbell, Ruth Simmons, Lenesha Warrener, Mary E Ramsay, Shamez N Ladhani, Kevin E Brown, Gayatri Amirthalingam
Journal: Journal of Infection (2022)

There are limited data on immune responses to heterologous COVID-19 immunisation schedules, especially following an extended ≥12-week interval between doses.SARS-CoV-2 infection-naïve and previously-infected adults receiving ChAd-BNT (ChAdOx1 nCoV-19, AstraZeneca followed by BNT162b2, Pfizer-BioNTech) or BNT-ChAd as part of the UK national immunisation programme provided blood samples at 30 days and 12 weeks after their second dose. Geometric mean concentrations (GMC) of anti-SARS-CoV-2 spike (S-antibody) and nucleoprotein (N-antibody) IgG antibodies and geometric mean ratios (GMR) were compared with a contemporaneous cohort receiving homologous ChAd-ChAd or BNT-BNT.During March-October 2021, 75,827 individuals were identified as having received heterologous vaccination, 9,489 invited to participate, 1,836 responded (19.3%) and 656 were eligible. In previously-uninfected adults, S-antibody GMC at 30 days post-second dose were lowest for ChAd-ChAd (862 [95% CI, 694 - 1069]) and significantly higher for ChAd-BNT (6233 [5522-7035]; GMR 6.29; [5.04-7.85]; p<0.001), BNT-ChAd (4776 [4066-5610]; GMR 4.55 [3.56-5.81]; p<0.001) and BNT-BNT (5377 [4596-6289]; GMR 5.66 [4.49-7.15]; p<0.001). By 12 weeks after dose two, S-antibody GMC had declined in all groups and remained significantly lower for ChAd-ChAd compared to ChAd-BNT (GMR 5.12 [3.79-6.92]; p<0.001), BNT-ChAd (GMR 4.1 [2.96-5.69]; p<0.001) and BNT-BNT (GMR 6.06 [4.32-8.50]; p<0.001). Previously infected adults had higher S-antibody GMC compared to infection-naïve adults at all time-points and with all vaccine schedules.These real-world findings demonstrate heterologous schedules with adenoviral-vector and mRNA vaccines are highly immunogenic and may be recommended after a serious adverse reaction to one vaccine product, or to increase programmatic flexibility where vaccine supplies are constrained.
Abstract P033: Higher Ambulatory Sbp Is Associated With Increasing Number Of Target Organ Abnormalities In Youth: The Ship Ahoy Study
Authors: Elaine Urbina, Gilad Hamdani, Michael A Ferguson, Joseph T Flynn, Marc B Lande, Kevin Meyers, Joshua A Samuels, Mark Mitsnefes
Journal: Circulation (2022)

Hypertension is associated with elevated left ventricular mass index (LVMI), cardiac dysfunction and increased arterial stiffness in adults which predict cardiovascular (CV) events. The extent to which elevated BP in youth is associated with subclinical CV target organ damage (TOD) is not known. We explored the relation between BP level and number of TOD abnormalities (nTOD). We measured clinic and ambulatory BP (ABP), anthropometrics, and nTOD in 244 adolescents (mean 15.5 + 1.8 years, 67% white, 60% male). Subjects were recruited as low-risk (L=98, SBP%&lt;80 th %), mid-risk (Mid=60, SBP% 80-&lt;90 th %); and high-risk (H=86, SBP% &gt;=90 th %) based on mean of 6 aneroid clinic BPs by age-, sex- and height-specific cut-points. 24-hour ABP was measured with an oscillometric device per pediatric guidelines. Four measures of TOD were: LVMI &gt; 38.6 g/m 2.7 ; LV systolic strain (Strain %) &gt; -18; LV diastolic function (E/e’) &gt; 8; pulse wave velocity (PWV) &gt; 5.8 m/sec. ANOVA was used to evaluate differences in CV risk factors and chi square for differences in nTOD across groups. Logistic regression models were used to determine if clinic and/or ABP was an independent predictor of nTOD after adjustment for age, sex, race, and BMI z-score. BP groups did not differ in BMI z-score. Clinic and ABP systolic and diastolic BP increased across BP groups. The distribution of nTOD was shifted towards higher BP group with most nTOD= 0 (47%) in the L and all (100%) nTOD = 4 in the H group (X 2 = 0.08) and became significant when L (clinic SBP&lt;75 th %) was compared to M+H (clinic SBP &gt; 80 th %; X 2 =0.04). Daytime ABP index (subject daytime systolic ABP/95 th % for daytime systolic ABP) and BMI z-score (both p &lt; 0.003) were significantly associated with nTOD in a model containing clinic SBP, age, sex and race (other covariates NS; full model p &lt; 0.0001, R 2 =0.22). We conclude that higher ABP is associated with a greater number of cardiac and vascular abnormalities in youth. ABP should be applied in youth with elevated BP to evaluate need for intensification of therapy to prevent CV TOD.
89Zr-PSMA-617 PET/CT May Reveal Local Recurrence of Prostate Cancer Unidentified by 68Ga-PSMA-11 PET/CT
Authors: Florian Rosar, Mark Bartholomä, Stephan Maus, Bastiaan M. Privé, Fadi Khreish, Gerben M. Franssen, Yvonne H.W. Derks, James Nagarajah, Samer Ezziddin
Journal: Clinical Nuclear Medicine (2022)

Abstract For localization of biochemical recurrence of prostate cancer, 68 Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89 Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89 Zr-labeled PSMA ligands, for example, 89 Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT.
Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study
Authors: Michael E Wechsler, Andrew Menzies-Gow, Christopher E Brightling, Piotr Kuna, Stephanie Korn, Tobias Welte, Janet M Griffiths, Kinga Sałapa, Åsa Hellqvist, Gun Almqvist, Harbans Lal, Primal Kaur, Tor Skärby, Gene Colice
Journal: The Lancet Respiratory Medicine (2022)
Inflammation and oxidative stress as mediators of the impacts of environmental exposures on human pregnancy: Evidence from oxylipins
Authors: Barrett M. Welch, Erin E. McNell, Matthew L. Edin, Kelly K. Ferguson
Journal: Pharmacology & Therapeutics (2022)

Inflammation and oxidative stress play major roles in healthy and pathological pregnancy. Environmental exposure to chemical pollutants may adversely affect maternal and fetal health in pregnancy by dysregulating these critical underlying processes of inflammation and oxidative stress. Oxylipins are bioactive lipids that play a major role in regulating inflammation and increasing lines of evidence point towards an importance in pregnancy. The biosynthetic production of oxylipins requires oxygenation of polyunsaturated fatty acids, which can occur through several well-characterized enzymatic and nonenzymatic pathways. This review describes the state of the science of epidemiologic evidence on oxylipin production in pregnancy and its association with 1) key pregnancy outcomes and 2) environmental exposures. We searched PubMed for studies of pregnancy that measured one or more oxylipin analytes during pregnancy or delivery. We evaluated oxylipin associations with three categories of adverse pregnancy outcomes, including preeclampsia, preterm birth, and fetal growth restriction, along with several categories of environmental pollutants. The majority of studies evaluated one to two oxylipins, most of which focused on oxylipins produced from nonenzymatic processes of oxidative stress. However, an increasing number of recent studies have leveraged technological advancements to profile a large number of oxylipins produced from distinct biosynthetic pathways. Although the literature indicated robust evidence that oxylipins produced via nonenzymatic pathways are associated with pregnancy outcomes and environmental exposures, evidence for enzymatically produced oxylipins showed that associations may differ between biosynthetic pathways. Along with summarizing this evidence, we review promising therapeutic options to regulate oxylipin production and provide a set of recommendations for future epidemiologic studies in these research areas. Further evidence is needed to improve our understanding of how oxylipins may act as key biological mediators for the adverse effects of environmental pollutants on pregnancy outcomes.
Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis
Authors: Humphrey Mulenga, Munyaradzi Musvosvi, Simon C. Mendelsohn, Adam Penn-Nicholson, Stanley Kimbung Mbandi, Andrew Fiore-Gartland, Michèle Tameris, Simbarashe Mabwe, Hadn Africa, Nicole Bilek, Fazlin Kafaar, Shabaana A. Khader, Balie Carstens, Katie Hadley, Chris Hikuam, Mzwandile Erasmus, Lungisa Jaxa, Rodney Raphela, Onke Nombida, Masooda Kaskar, Mark P. Nicol, Slindile Mbhele, Judi Van Heerden, Craig Innes, William Brumskine, Andriëtte Hiemstra, Stephanus T. Malherbe, Razia Hassan-Moosa, Gerhard Walzl, Kogieleum Naidoo, Gavin Churchyard, Mark Hatherill, Thomas J. Scriba
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Performance of blood transcriptomic tuberculosis (TB) signatures in longitudinal studies and effects of TB-preventive therapy and coinfection with HIV or respiratory organisms on transcriptomic signatures has not been systematically studied. Objectives: We evaluated longitudinal kinetics of an 11-gene blood transcriptomic TB signature, RISK11, and effects of TB-preventive therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. Methods: RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort, or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomized to TPT or no TPT; RISK11- participants received no TPT. PLHIV received standard-of-care antiretroviral therapy and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by real-time quantitative PCR. Measurements and Main Results: RISK11+ status was transient in most of the 128 HIV-negative participants with longitudinal samples; more than 70% of RISK11+ participants reverted to RISK11- by 3 months, irrespective of TPT. By comparison, reversion from a RISK11+ state was less common in 645 PLHIV (42.1%). Non-HIV viral and nontuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%) than those with bacterial organisms other than TB (13.4%) or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Conclusions: Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control.
18F-FDG PET/CT May Predict Tumor Type and Risk Score in Gestational Trophoblastic Disease
Authors: Carolina Bezzi, Lavinia Monaco, Samuele Ghezzo, Gregory Mathoux, Alice Bergamini, Enrica Zambella, Federico Fallanca, Ana Maria Samanes Gajate, Luca Presotto, Giulia Sabetta, Giorgia Mangili, Raffaella Cioffi, Valentino Bettinardi, Luigi Gianolli, Paola Mapelli, Maria Picchio
Journal: Clinical Nuclear Medicine (2022)

Purpose The aim of this study was to investigate the role of 18 F-FDG PET/CT in predicting pathological prognostic factors, including tumor type and International Federation of Gynecology and Obstetrics (FIGO) score, in gestational trophoblastic disease (GTD). Methods Retrospective monocentric study including 24 consecutive patients who underwent to 18 F-FDG PET/CT from May 2005 to March 2021 for GTD staging purpose. The following semiquantitative PET parameters were measured from the primary tumor and used for the analysis: maximum standardized uptake value (SUV max ), SUV mean , metabolic tumor volume (MTV) and total lesion glycolisis (TLG). Statistical analysis included Spearman correlation coefficient to evaluate the correlations between imaging parameters and tumor type (nonmolar trophoblastic vs postmolar trophoblastic tumors) and risk groups (high vs low, defined according to the FIGO score), whereas area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to assess the predictive value of the PET parameters. Mann-Whitney U test was used to further describe the parameter’s potential in differentiating the populations. Results SUV max and SUV mean resulted fair (AUC, 0.783; 95% confidence interval [CI], 0.56–0.95) and good (AUC, 0.811; 95% CI, 0.59–0.97) predictors of tumor type, respectively, showing a low (ρ = 0.489, adjusted P = 0.030) and moderate (ρ = 0.538, adjusted P = 0.027) correlation. According to FIGO score, TLG was instead a fair predictor (AUC, 0.770; 95% CI, 0.50–0.99) for patient risk stratification. Conclusions 18 F-FDG PET parameters have a role in predicting GTD pathological prognostic factors, with SUV max and SUV mean being predictive for tumor type and TLG for risk stratification.
Editor's Note: Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis
Authors: Danielle M. Gilkes, Pallavi Chaturvedi, Saumendra Bajpai, Carmen C. Wong, Hong Wei, Stephen Pitcairn, Maimon E. Hubbi, Denis Wirtz, Gregg L. Semenza
Journal: Cancer Research (2022)

The editors are publishing this note to alert readers to a concern about this article (1).In Fig. 1B, the Western blot bands representing HIF-1a, HIF-2a, and actin were inadvertently also used in Fig. 1A of a 2012 Oncogene publication by the authors (2).The blots were presented to demonstrate knockdown efficiency in subclones that were used for studies in both papers.