tbuckley/cabot-search huggingface dataset:
Effect of Weight Loss and Continuous Positive Airway Pressure on Obstructive Sleep Apnea and Metabolic Profile Stratified by Craniofacial Phenotype: A Randomized Clinical Trial
Authors: Susanna S. S. Ng, Wilson W. S. Tam, Richard W. W. Lee, Tat-On Chan, Karen Yiu, Brian T. Y. Yuen, Ka-Tak Wong, Jean Woo, Ronald C. W. Ma, Ken K. P. Chan, Fanny W. S. Ko, Peter A. Cistulli, David S. Hui
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Craniofacial structure is believed to modulate the effect of weight loss on obstructive sleep apnea (OSA), but whether this affects metabolic profile after weight loss compared with continuous positive airway pressure (CPAP) is unknown among obese Chinese patients with OSA. Objectives: To compare the change in metabolic profile between a lifestyle modification program (LMP), stratified by craniofacial phenotype, and CPAP therapy for 6 months. Methods: We randomly assigned 194 patients with body mass index ⩾ 25 kg/m2 and moderate to severe OSA to participate in the LMP or receive CPAP therapy for 6 months in a 2:1 ratio. Assessments included computed tomography for assessing maxillomandibular volume (MMV), hsCRP (high-sensitivity C-reactive protein), and insulin sensitivity. Measurements and Main Results: Among 128 and 66 subjects in the LMP and CPAP groups, respectively, hsCRP was reduced more in the LMP group than the CPAP group (median [interquartile range], -0.7 [-1.4 to -0.0] vs. -0.3 [-0.9 to 0.4] mg/L; P = 0.012). More patients in the LMP group achieved low hsCRP (<1 mg/L) than the CPAP group (21.1% vs. 9.1%; P = 0.04). Insulin sensitivity improved only in the LMP group, with 3.1 (95% confidence interval, 1.5-6.6) times more patients with normal glucose regulation after intervention. The LMP group was stratified into LMP-small MMV (n = 64) and LMP-large MMV (n = 64) groups according to the median MMV value of 233.2 cm3. There was no significant difference in hsCRP (median [interquartile range], -0.7 [-1.3 to 0.1] vs. -0.7 [-1.5 to -0.2] mg/L; P = 0.884) and insulin sensitivity (median [interquartile range], 0.5 [-0.2 to 1.9] vs. 0.6 [0.1 to 2.0]; P = 0.4860) between the LMP-small MMV and LMP-large MMV groups. Conclusions: Weight reduction alleviated subclinical inflammation and improved insulin sensitivity more than CPAP among obese Chinese patients with moderate to severe OSA, and this effect was not influenced by craniofacial structure. Clinical trial registered with www.clinicaltrials.gov (NCT03287973).
Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Adam J. Luginbuhl, Jennifer M. Johnson, Larry A. Harshyne, Alban J. Linnenbach, Sanket K. Shukla, Angela Alnemri, Gaurav Kumar, David M. Cognetti, Joseph M. Curry, Nikita Kotlov, Zoya Antysheva, Sandrine Degryse, Kyle Mannion, Michael K. Gibson, James Netterville, Brandee Brown, Rita Axelrod, Ralph Zinner, Madalina Tuluc, Stacey Gargano, Benjamin E. Leiby, Ayako Shimada, My G. Mahoney, Ubaldo Martinez-Outschoorn, Ulrich Rodeck, Young J. Kim, Andrew P. South, Athanassios Argiris
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC). Patients and Methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis. Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery. Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.
Ratio-based perceptual foundations for rational numbers, and perhaps whole numbers, too?
Authors: Edward M. Hubbard, Percival G. Matthews
Journal: Behavioral and Brain Sciences (2021)

Abstract Clarke and Beck suggest that the ratio processing system (RPS) may be a component of the approximate number system (ANS), which they suggest represents rational numbers. We argue that available evidence is inconsistent with their account and advocate for a two-systems view. This implies that there may be many access points for numerical cognition – and that privileging the ANS may be a mistake.
Discovery of a genetic module essential for assigning left–right asymmetry in humans and ancestral vertebrates
Authors: Emmanuelle Szenker-Ravi, Tim Ott, Muznah Khatoo, Anne Moreau de Bellaing, Wei Xuan Goh, Yan Ling Chong, Anja Beckers, Darshini Kannesan, Guillaume Louvel, Priyanka Anujan, Vydianathan Ravi, Carine Bonnard, Sébastien Moutton, Patric Schoen, Mélanie Fradin, Estelle Colin, André Megarbane, Linda Daou, Ghassan Chehab, Sylvie Di Filippo, Caroline Rooryck, Jean-François Deleuze, Anne Boland, Nicolas Arribard, Rukiye Eker, Sumanty Tohari, Alvin Yu-Jin Ng, Marlène Rio, Chun Teck Lim, Birgit Eisenhaber, Frank Eisenhaber, Byrappa Venkatesh, Jeanne Amiel, Hugues Roest Crollius, Christopher T. Gordon, Achim Gossler, Sudipto Roy, Tania Attie-Bitach, Martin Blum, Patrice Bouvagnet, Bruno Reversade
Journal: Nature Genetics (2021)
Turning up the heat on the NHS: it’s not fair only to blame the government
Authors: Padmanabhan Badrinath
Journal: BMJ (2021)

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.
Abstract 12398: Cardiopulmonary Resuscitation Duration Determines Phenotype of Post-Arrest Brain Injury
Authors: Patrick J Coppler, Clifton W CALLAWAY, Jonathan Elmer
Journal: Circulation (2021)

Introduction: Patients resuscitated from out-of-hospital cardiac arrest (OHCA) have variable severity of brain injury. Signatures of severe injury on brain imaging and EEG including diffuse cerebral edema and burst suppression with identical bursts (BSIB). Current therapies for these patterns of injury are inadequate and patient outcomes are poor. Hypothesis: We hypothesize distinct phenotypes of brain injury are associated with increasing CPR duration. Methods: We identified from our prospective registry OHCA patients treated between January 2010 to July 2019. We abstracted CPR duration, best neurological examination &lt; 6 hours from OHCA, initial brain CT grey-to-white ratio (GWR), and initial EEG pattern. We defined cerebral edema as GWR &lt;1.20. We defined BSIB according to American Clinical Neurophysiology Society guidelines. We considered four phenotypes on presentation: awake; comatose with neither BSIB nor cerebral edema; BSIB; and cerebral edema. BSIB and cerebral edema were considered as non-mutually exclusive outcomes. We compared duration of CPR across groups using Kruskal-Wallis tests with Bonferroni correction for multiple hypothesis testing. We report the probability of presenting phenotype at the median CPR duration for each group using local regression. Results: We included 2,721 patients, of whom 582 (21%) were awake, 1,428 (52%) had coma without BSIB or edema, 372 (14%) had BSIB and 356 (13%) had cerebral edema. Only 47 (2%) had both BSIB and edema. Median CPR duration was 16 [IQR 8-28] minutes overall. Median CPR duration increased in a stepwise manner across groups: awake 6 [3-12] minutes; comatose without BSIB or edema 16 [9-27] minutes; BSIB 21 [14-30] minutes; cerebral edema 32 [22-46] minutes (all P &lt;0.001). The probability of observing each phenotype at the median CPR duration for each was: awake (0.42); comatose without BSIB or edema (0.72); BSIB (0.34); cerebral edema (0.29). Conclusions: The brain injury phenotype is related to CPR duration, which is a surrogate for severity of ischemic injury. The sequence of most likely brain injury phenotype with progressively longer CPR duration is awake, coma without BSIB or edema, BSIB, and finally cerebral edema.
A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma
Authors: Julie Westerlin Kjeldsen, Cathrine Lund Lorentzen, Evelina Martinenaite, Eva Ellebaek, Marco Donia, Rikke Boedker Holmstroem, Tobias Wirenfeldt Klausen, Cecilie Oelvang Madsen, Shamaila Munir Ahmed, Stine Emilie Weis-Banke, Morten Orebo Holmström, Helle Westergren Hendel, Eva Ehrnrooth, Mai-Britt Zocca, Ayako Wakatsuki Pedersen, Mads Hald Andersen, Inge Marie Svane
Journal: Nature Medicine (2021)

Abstract Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study ( https://clinicaltrials.gov/ , NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7–90.5%) was reached, with 43% (CI, 27.4–60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4–69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of &gt;93% of patients during vaccination. Vaccine-reactive T cells comprised CD4 + and CD8 + T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.
Myeloid-Derived Suppressive Cell Expansion Promotes Melanoma Growth and Autoimmunity by Inhibiting CD40/IL27 Regulation in Macrophages
Authors: Julio C. Valencia, Rebecca A. Erwin-Cohen, Paul E. Clavijo, Clint Allen, Michael E. Sanford, Chi-Ping Day, Megan M. Hess, Morgan Johnson, Jie Yin, John M. Fenimore, Ian A. Bettencourt, Koichi Tsuneyama, Maria E. Romero, Kimberly D. Klarmann, Peng Jiang, Heekyong R. Bae, Daniel W. McVicar, Glenn Merlino, Elijah F. Edmondson, Niroshana Anandasabapathy, Howard A. Young
Journal: Cancer Research (2021)

Abstract The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces de novo autoinflammation and exacerbates underlying AID, even without evident antitumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Cross-talk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pregenerated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL27. Moreover, low CD40/IL27 signaling in tumors correlated with high tumor-associated macrophage infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFNγ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes. Significance: Myeloid-derived suppressor cells induce macrophage reprogramming by suppressing CD40/IL27 signaling to drive melanoma progression, simultaneously affecting underlying autoimmune disease and facilitating resistance to immunotherapy within preexisting autoimmune landscapes.
FertilityOnline: A Straightforward Pipeline for Functional Gene Annotation and Disease Mutation Discovery
Authors: Jianing Gao, Huan Zhang, Xiaohua Jiang, Asim Ali, Daren Zhao, Jianqiang Bao, Long Jiang, Furhan Iqbal, Qinghua Shi, Yuanwei Zhang
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Exploring the genetic basis of human infertility is currently under intensive investigation. However, only a handful of genes have been validated in animal models as disease-causing genes in infertile men. Thus, to better understand the genetic basis of human spermatogenesis and bridge the knowledge gap between humans and other animal species, we construct the FertilityOnline, a database integrating the literature-curated functional genes during spermatogenesis into an existing spermatogenic database, SpermatogenesisOnline 1.0. Additional features, including the functional annotation and genetic variants of human genes, are also incorporated into FertilityOnline. By searching this database, users can browse the functional genes involved in spermatogenesis and instantly narrow down the number of candidates of genetic mutations underlying male infertility in a user-friendly web interface. Clinical application of this database was exampled by the identification of novel causative mutations in synaptonemal complex central element protein 1 (SYCE1) and stromal antigen 3 (STAG3) in azoospermic men. In conclusion, FertilityOnline is not only an integrated resource for spermatogenic genes but also a useful tool facilitating the exploration of the genetic basis of male infertility. FertilityOnline can be freely accessed at http://mcg.ustc.edu.cn/bsc/spermgenes2.0/index.html.
COVID-19 trends and severity among symptomatic children aged 0–17 years in 10 European Union countries, 3 August 2020 to 3 October 2021
Authors: Nick Bundle, Nishi Dave, Anastasia Pharris, Gianfranco Spiteri, Charlotte Deogan, Jonathan E Suk
Journal: Eurosurveillance (2021)

We estimated risks of severe outcomes in 820,404 symptomatic paediatric COVID-19 cases reported by 10 European Union countries between August 2020 and October 2021. Case and hospitalisation rates rose as transmission increased but severe outcomes were rare: 9,611 (1.2%) were hospitalised, 640 (0.08%) required intensive care and 84 (0.01%) died. Despite increased individual risk (adjusted odds ratio hospitalisation: 7.3; 95% confidence interval: 3.3–16.2; intensive care: 8.7; 6.2–12.3) in cases with comorbidities, most (83.7%) hospitalised children had no comorbidity.
Expert Evaluation of Strategies to Modernize Newborn Screening in the United States
Authors: Donald B. Bailey, Katherine Ackerman Porter, Sara M. Andrews, Melissa Raspa, Angela Y. Gwaltney, Holly L. Peay
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Novel therapies, including cell and gene therapies, can radically improve outcomes among patients with rare disorders, especially if provided early. Newborn screening (NBS) could support early access to novel therapies, but the speed of new therapy development is a disruptive event for which the public health NBS system and state newborn screening programs are unprepared. <h3>Objective</h3> To identify and evaluate possible solutions for modernizing NBS. <h3>Design, Setting, and Participants</h3> In this survey study, NBS experts representing clinical research, federal or state advisory boards, patient advocacy groups, industry, or state laboratories completed an online survey in which they considered 20 potential solutions for modernizing NBS and rated each. <h3>Exposures</h3> Participants considered 20 potential solutions in the 5 following domains: (1) timeliness of disorder review, (2) alternative mechanisms to offer screening for new disorders not currently part of NBS, (3) expanded data collection, (4) support for states, and (5) emerging methods of screening and their consequences. <h3>Main Outcomes and Measures</h3> Mean ratings for each solution on efficacy, acceptability, feasibility, and sustainability. <h3>Results</h3> The survey was completed by 40 NBS experts (median [range] age, 54 [37-73] years; 22 [55.0%] women). Participants acknowledged that substantial change is needed to prepare the NBS system for rapid expansion of novel therapies; on a scale of 0 (no change) to 10 (extensive change), the median (range) score was 8 (2-10), with 18 respondents (45.0%) believing that the NBS would need many new components or an entirely new system to accommodate the changes. All solutions for modernization were considered potentially efficacious by at least 23 respondents (57.5%). The 2 most strongly endorsed were to establish mechanisms for cross-state data coordination for provisional disorders (38 respondents [95.0%]) and create a network of regional screening laboratories (36 [90.0%]). These were closely followed by aligning programs across federal agencies (35 [87.5%]), expanding funding for research (34 [85.0%]), expanding funding to states (34 [85.0%]), building capacity to identify genetic variants and an associated clinical database (34 [85.0%]), and conducting surveillance to study long-term outcomes (34 [85.0%]). <h3>Conclusions and Relevance</h3> In this study, there was consensus among experts that NBS needs to change if the system is to be prepared for a rapid increase in transformative therapies. To our knowledge, this is the first systematic inventory of potential solutions for modernizing NBS and expert perceptions of each. The findings suggest that the modernization of NBS will require the integration of highly rated solutions, strategic planning, and coordination among multiple stakeholders.
Extramucosal Formation and Prognostic Value of Secretory Antibodies in Rheumatoid Arthritis
Authors: Klara Martinsson, Lovisa Lyttbacka Kling, Karin Roos‐Ljungberg, Irina Griazeva, Marina Samoylovich, Stephane Paul, Johan Rönnelid, Tomas Weitoft, Jonas Wetterö, Alf Kastbom
Journal: Arthritis & Rheumatology (2021)

To investigate levels and possible extramucosal formation of secretory Ig, including anti-citrullinated protein antibodies (ACPAs), in rheumatoid arthritis (RA). Three patient groups were studied: 1) ACPA-positive patients with musculoskeletal pain without clinical arthritis, 2) patients with recent-onset RA, and 3) patients with established RA. In baseline serum samples (groups 1 and 2) and paired synovial fluid samples (group 3), we analyzed total secretory IgA, total secretory IgM, free secretory component (SC), and SC-containing ACPA. Extramucosal formation of SC-containing ACPA was investigated by preincubating RA sera and affinity-purified ACPA with recombinant free SC. Compared to healthy controls, serum levels of total secretory IgA and total secretory IgM were increased both in patients with early RA and at-risk patients (P < 0.05). Patients with early RA with elevated total secretory Ig had significantly higher disease activity during the 3-year follow-up period compared to those without increased levels. At-risk patients who developed arthritis during follow-up (39 of 82) had higher baseline total secretory IgA levels compared to those who did not (P = 0.041). In established RA, total secretory IgA and total secretory IgM levels were higher in serum than in synovial fluid (P < 0.0001), but SC-containing ACPAs adjusted for total secretory Ig concentration were higher in synovial fluid (P < 0.0001). Preincubation with recombinant free SC yielded increased SC-containing ACPA reactivity in sera as well as in affinity-purified IgA and IgM ACPA preparations. Circulating secretory Ig are elevated before and at RA onset. In the presence of free SC, secretory Ig may form outside the mucosa, and SC-containing ACPAs are enriched in RA joints. These findings shed important new light on the mucosal connection in RA development.
A functional variant in the immune signalling receptor <scp>NKG2D</scp> alters skin cancer risk
Authors: Karin A. Vineretsky, Evidio Domingo‐Musibay, Margaret R. Karagas, DeAnn Lazovich, Jacquelyn K. Kuriger‐Laber, DeVon Hunter‐Schlichting, Heather H. Nelson
Journal: British Journal of Dermatology (2021)