Homotopical resolutions associated to deformable adjunctions

Given an adjunction connecting reasonable categories with weak equivalences, we define a new derived bar and cobar construction associated to the adjunction. This yields homotopical models of the completion and cocompletion associated to the monad and comonad of the adjunction. We discuss applications of these resolutions to spectral sequences for derived completions and Goodwillie calculus in general model categories.Comment: 22 pages; v2 is the final journal version, with expository improvements suggested by the refere

A universal characterization of higher algebraic K-theory

In this paper we establish a universal characterization of higher algebraic K-theory in the setting of small stable infinity categories. Specifically, we prove that connective algebraic K-theory is the universal additive invariant, i.e., the universal functor with values in spectra which inverts Morita equivalences, preserves filtered colimits, and satisfies Waldhausen's additivity theorem. Similarly, we prove that non-connective algebraic K-theory is the universal localizing invariant, i.e., the universal functor that moreover satisfies the "Thomason-Trobaugh-Neeman" localization theorem. To prove these results, we construct and study two stable infinity categories of "noncommutative motives"; one associated to additivity and another to localization. In these stable infinity categories, Waldhausen's S. construction corresponds to the suspension functor and connective and non-connective algebraic K-theory spectra become corepresentable by the noncommutative motive of the sphere spectrum. In particular, the algebraic K-theory of every scheme, stack, and ring spectrum can be recovered from these categories of noncommutative motives. In order to work with these categories of noncommutative motives, we establish comparison theorems between the category of spectral categories localized at the Morita equivalences and the category of small idempotent-complete stable infinity categories. We also explain in detail the comparison between the infinity categorical version of Waldhausen K-theory and the classical definition. As an application of our theory, we obtain a complete classification of the natural transformations from higher algebraic K-theory to topological Hochschild homology (THH) and topological cyclic homology (TC). Notably, we obtain an elegant conceptual description of the cyclotomic trace map.Comment: Various revisions and correction

Identification of SKOR2 IgG as a novel biomarker of paraneoplastic neurologic syndrome

IntroductionThe development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples.MethodsStored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization.ResultsPhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2–specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative.DiscussionSKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy

Assessment of Disparities Associated with a Crisis Standards of Care Resource Allocation Algorithm for Patients in 2 US Hospitals during the COVID-19 Pandemic

Importance: Significant concern has been raised that crisis standards of care policies aimed at guiding resource allocation may be biased against people based on race/ethnicity. Objective: To evaluate whether unanticipated disparities by race or ethnicity arise from a single institution\u27s resource allocation policy. Design, Setting, and Participants: This cohort study included adults (aged ≥18 years) who were cared for on a coronavirus disease 2019 (COVID-19) ward or in a monitored unit requiring invasive or noninvasive ventilation or high-flow nasal cannula between May 26 and July 14, 2020, at 2 academic hospitals in Miami, Florida. Exposures: Race (ie, White, Black, Asian, multiracial) and ethnicity (ie, non-Hispanic, Hispanic). Main Outcomes and Measures: The primary outcome was based on a resource allocation priority score (range, 1-8, with 1 indicating highest and 8 indicating lowest priority) that was assigned daily based on both estimated short-term (using Sequential Organ Failure Assessment score) and longer-term (using comorbidities) mortality. There were 2 coprimary outcomes: maximum and minimum score for each patient over all eligible patient-days. Standard summary statistics were used to describe the cohort, and multivariable Poisson regression was used to identify associations of race and ethnicity with each outcome. Results: The cohort consisted of 5613 patient-days of data from 1127 patients (median [interquartile range {IQR}] age, 62.7 [51.7-73.7]; 607 [53.9%] men). Of these, 711 (63.1%) were White patients, 323 (28.7%) were Black patients, 8 (0.7%) were Asian patients, and 31 (2.8%) were multiracial patients; 480 (42.6%) were non-Hispanic patients, and 611 (54.2%) were Hispanic patients. The median (IQR) maximum priority score for the cohort was 3 (1-4); the median (IQR) minimum score was 2 (1-3). After adjustment, there was no association of race with maximum priority score using White patients as the reference group (Black patients: incidence rate ratio [IRR], 1.00; 95% CI, 0.89-1.12; Asian patients: IRR, 0.95; 95% CI. 0.62-1.45; multiracial patients: IRR, 0.93; 95% CI, 0.72-1.19) or of ethnicity using non-Hispanic patients as the reference group (Hispanic patients: IRR, 0.98; 95% CI, 0.88-1.10); similarly, no association was found with minimum score for race, again with White patients as the reference group (Black patients: IRR, 1.01; 95% CI, 0.90-1.14; Asian patients: IRR, 0.96; 95% CI, 0.62-1.49; multiracial patients: IRR, 0.81; 95% CI, 0.61-1.07) or ethnicity, again with non-Hispanic patients as the reference group (Hispanic patients: IRR, 1.00; 95% CI, 0.89-1.13). Conclusions and Relevance: In this cohort study of adult patients admitted to a COVID-19 unit at 2 US hospitals, there was no association of race or ethnicity with the priority score underpinning the resource allocation policy. Despite this finding, any policy to guide altered standards of care during a crisis should be monitored to ensure equitable distribution of resources

Revisiting the Effect of Acute P. falciparum Malaria on Epstein-Barr Virus: Host Balance in the Setting of Reduced Malaria Endemicity

Burkitt's lymphoma (BL), an EBV-associated tumour, occurs at high incidence in populations where malaria is holoendemic. Previous studies in one such population suggested that acute P.falciparum infection impairs EBV-specific T-cell surveillance, allowing expansion of EBV infected B-cells from which BL derives. We re-examined the situation in the same area, The Gambia, after a reduction in malaria endemicity. Cellular immune responses to EBV were measured in children with uncomplicated malaria before (day 0) and after treatment (day 28), comparing EBV genome loads in blood and EBV-specific CD8+ T-cell numbers (assayed by MHC Class I tetramers and IFNγ ELISPOTS) with those seen in age- and sex-matched healthy controls. No significant changes were seen in EBV genome loads, percentage of EBV-specific CD8+ T-cells and IFNγ producing T-cells in acute versus convalescent samples, nor any difference versus controls. Regression assays performed also no longer detected any impairment of EBV-specific T-cell surveillance. Acute uncomplicated malaria infection no longer alters EBV-specific immune responses in children in The Gambia. Given the recent decline in malaria incidence in that country, we hypothesise that gross disturbance of the EBV-host balance may be a specific effect of acute malaria only in children with a history of chronic/recurrent malaria challenge

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease