Available COVID-19 mortality indices are limited to acute inpatient data. Using nationwide medical administrative data available prior to SARS-CoV-2 infection from the US Veterans Health ...Administration (VA), we developed the VA COVID-19 (VACO) 30-day mortality index and validated the index in two independent, prospective samples.
We reviewed SARS-CoV-2 testing results within the VA between February 8 and August 18, 2020. The sample was split into a development cohort (test positive between March 2 and April 15, 2020), an early validation cohort (test positive between April 16 and May 18, 2020), and a late validation cohort (test positive between May 19 and July 19, 2020). Our logistic regression model in the development cohort considered demographics (age, sex, race/ethnicity), and pre-existing medical conditions and the Charlson Comorbidity Index (CCI) derived from ICD-10 diagnosis codes. Weights were fixed to create the VACO Index that was then validated by comparing area under receiver operating characteristic curves (AUC) in the early and late validation cohorts and among important validation cohort subgroups defined by sex, race/ethnicity, and geographic region. We also evaluated calibration curves and the range of predictions generated within age categories. 13,323 individuals tested positive for SARS-CoV-2 (median age: 63 years; 91% male; 42% non-Hispanic Black). We observed 480/3,681 (13%) deaths in development, 253/2,151 (12%) deaths in the early validation cohort, and 403/7,491 (5%) deaths in the late validation cohort. Age, multimorbidity described with CCI, and a history of myocardial infarction or peripheral vascular disease were independently associated with mortality-no other individual comorbid diagnosis provided additional information. The VACO Index discriminated mortality in development (AUC = 0.79, 95% CI: 0.77-0.81), and in early (AUC = 0.81 95% CI: 0.78-0.83) and late (AUC = 0.84, 95% CI: 0.78-0.86) validation. The VACO Index allows personalized estimates of 30-day mortality after COVID-19 infection. For example, among those aged 60-64 years, overall mortality was estimated at 9% (95% CI: 6-11%). The Index further discriminated risk in this age stratum from 4% (95% CI: 3-7%) to 21% (95% CI: 12-31%), depending on sex and comorbid disease.
Prior to infection, demographics and comorbid conditions can discriminate COVID-19 mortality risk overall and within age strata. The VACO Index reproducibly identified individuals at substantial risk of COVID-19 mortality who might consider continuing social distancing, despite relaxed state and local guidelines.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breeding crops for high yield and superior adaptability to new and variable climates is imperative to ensure continued food security, biomass production, and ecosystem services. Advances in genomics ...and phenomics are delivering insights into the complex biological mechanisms that underlie plant functions in response to environmental perturbations. However, linking genotype to phenotype remains a huge challenge and is hampering the optimal application of high-throughput genomics and phenomics to advanced breeding. Critical to success is the need to assimilate large amounts of data into biologically meaningful interpretations. Here, we present the current state of genomics and field phenomics, explore emerging approaches and challenges for multiomics big data integration by means of next-generation (Next-Gen) artificial intelligence (AI), and propose a workable path to improvement.
The integration of genomics and phenomics will speed the development of climate resilient crops; however, these omics technologies are generating large, heterogeneous, and complex data much faster than currently can be analyzed.First-generation AI is being used in surveying and classifying omics data; however, it is designed to solve well-defined tasks of single-omics datasets that do not require integration of data across multiple modalities.Next-generation AI can change the dynamics of how experiments are planned, thus enabling better data integration, analysis, and interpretation.There is a critical need to develop means by which to open the black boxes prevalent in many current AI approaches so that they can be interpreted meaningfully from a complex biological perspective. AI decisions and outputs can be explained by breeders and researchers via human–computer interaction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
AbstractObjectiveTo evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital ...with coronavirus disease 2019 (covid-19) in the United States.DesignObservational cohort study.SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system.ParticipantsAll 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.Main outcome measuresThe main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.ResultsOf 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses.ConclusionsEarly initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.
The aim of this work was 2-fold: (1) to evaluate current knowledge and identify key directions in the study of sluggish cognitive tempo (SCT); and (2) to arrive at a consensus change in terminology ...for the construct that reflects the current science and may be more acceptable to researchers, clinicians, caregivers, and patients.
An international Work Group was convened that, in early 2021, compiled an online archive of all research studies on SCT and summarized the current state of knowledge, noted methodological issues, and highlighted future directions, and met virtually on 10 occasions in 2021 to discuss these topics and terminology.
Major progress has been made over the last decade in advancing our understanding of SCT across the following domains of inquiry: construct measurement and stability; genetic, environmental, pathophysiologic, and neuropsychological correlates; comorbid conditions; functional impairments; and psychosocial and medication interventions. Findings across these domains are summarized, and potential avenues to pursue in the next generation of SCT-related research are proposed. Following repeated discussions on terminology, the Work Group selected “cognitive disengagement syndrome” (CDS) to replace “SCT” as the name for this construct. This term was deemed to best satisfy considerations that should apply when selecting terms for a condition or syndrome, as it does not overlap with established terms for other constructs, is not offensive, and reflects the current state of the science.
It is evident that CDS (SCT) has reached the threshold of recognition as a distinct syndrome. Much work remains to further clarify its nature (eg, transdiagnostic factor, separate disorder, diagnostic specifier), etiologies, demographic factors, relations to other psychopathologies, and linkages to specific domains of functional impairment. Investigators are needed with interests and expertise spanning basic, clinical, and translational research to advance our understanding and to improve the lives of individuals with this unique syndrome.
Background Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but ...tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. Methods ODYSSEY ALTERNATIVE ( NCT01709513 ) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. Results Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 1.8 mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% 3.1%, P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38–0.99, P = .042). Conclusions Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, ...multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10
) and 1 (p = 3.69 × 10
). A strong pan-ancestry signal at the Dopamine Receptor D2 locus (p = 1.77 × 10
) was also identified and subsequently replicated in a large, independent international civilian cohort (p = 7.97 × 10
). Additionally, ancestry-specific genome-wide significant loci were also detected in African-Americans, European-Americans, Asian-Americans, and Hispanic-Americans. Pathway analyses suggested over-representation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. These findings confirm that the genetic architecture underlying suicide attempt risk is complex and includes both pan-ancestry and ancestry-specific risk loci. Moreover, pathway analyses suggested many commonly impacted biological pathways that could inform development of improved therapeutics for suicide prevention.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
CRISPR-Cas9 tools have transformed genetic manipulation capabilities in the laboratory. Empirical rules-of-thumb have been developed for only a narrow range of model organisms, and ...mechanistic underpinnings for sgRNA efficiency remain poorly understood. This work establishes a novel feature set and new public resource, produced with quantum chemical tensors, for interpreting and predicting sgRNA efficiency. Feature engineering for sgRNA efficiency is performed using an explainable-artificial intelligence model: iterative Random Forest (iRF). By encoding quantitative attributes of position-specific sequences for Escherichia coli sgRNAs, we identify important traits for sgRNA design in bacterial species. Additionally, we show that expanding positional encoding to quantum descriptors of base-pair, dimer, trimer, and tetramer sequences captures intricate interactions in local and neighboring nucleotides of the target DNA. These features highlight variation in CRISPR-Cas9 sgRNA dynamics between E. coli and H. sapiens genomes. These novel encodings of sgRNAs enhance our understanding of the elaborate quantum biological processes involved in CRISPR-Cas9 machinery.
Graphical Abstract
Graphical Abstract
Pseudomonas putida KT2440 (hereafter KT2440) is a well-studied platform bacterium for the production of industrially valuable chemicals from heterogeneous mixtures of aromatic compounds obtained from ...lignin depolymerization. KT2440 can grow on lignin-related monomers, such as ferulate (FA), 4-coumarate (4CA), vanillate (VA), 4-hydroxybenzoate (4HBA), and protocatechuate (PCA). Genes associated with their catabolism are known, but knowledge about the uptake systems remains limited. In this work, we studied the KT2440 transporters of lignin-related monomers and their substrate selectivity. Based on the inhibition by protonophores, we focused on five genes encoding aromatic acid/H+ symporter family transporters categorized into major facilitator superfamily that uses the proton motive force. The mutants of PP_1376 (pcaK) and PP_3349 (hcnK) exhibited significantly reduced growth on PCA/4HBA and FA/4CA, respectively, while no change was observed on VA for any of the five gene mutants. At pH 9.0, the conversion of these compounds by hcnK mutant (FA/4CA) and vanK mutant (VA) was dramatically reduced, revealing that these transporters are crucial for the uptake of the anionic substrates at high pH. Uptake assays using 14C-labeled substrates in Escherichia coli and biosensor-based assays confirmed that PcaK, HcnK, and VanK have ability to take up PCA, FA/4CA, and VA/PCA, respectively. Additionally, analyses of the predicted protein structures suggest that the size and hydropathic properties of the substrate-binding sites of these transporters determine their substrate preferences. Overall, this study reveals that at physiological pH, PcaK and HcnK have a major role in the uptake of PCA/4HBA and FA/4CA, respectively, and VanK is a VA/PCA transporter. This information can contribute to the engineering of strains for the efficient conversion of lignin-related monomers to value-added chemicals.
•Aromatic acid/H+ symporters from Pseudomonas putida KT2440 were identified and characterized.•PcaK, HcnK, and VanK mediate protocatechuate/4-hydroxybenzoate, ferulate/4-coumarate, and vanillate uptake, respectively.•Escherichia coli cells expressing the transporter genes display uptake for the corresponding substrate.•Size and hydropathic properties of the substrate-binding sites are suggested to determine transporter substrate preferences.•These transporters are useful targets for enhanced microbial production of valuable chemicals from lignin-related monomers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal ...recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1
mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1
oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1
oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1
mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.
Herbicide-resistant weeds are increasingly a problem in crop fields when exposed to similar chemistry over time. To avoid future yield losses, identifying herbicidal chemistry needs to be ...accelerated. We screened 50,000 small molecules using a liquid-handling robot and light microscopy focusing on pre-emergent herbicides in the family of cellulose biosynthesis inhibitors. Through phenotypic, chemical, genetic, and in silico methods we uncovered 6-{4-(2-fluorophenyl)-1-piperazinylmethyl}-N-(2-methoxy-5-methylphenyl)-1,3,5-triazine-2,4-diamine (fluopipamine). Symptomologies support fluopipamine as a putative antagonist of cellulose synthase enzyme 1 (CESA1) from Arabidopsis (Arabidopsis thaliana). Ectopic lignification, inhibition of etiolation, phenotypes including loss of anisotropic cellular expansion, swollen roots, and live cell imaging link fluopipamine to cellulose biosynthesis inhibition. Radiolabeled glucose incorporation of cellulose decreased in short-duration experiments when seedlings were incubated in fluopipamine. To elucidate the mechanism, ethylmethanesulfonate mutagenized M2 seedlings were screened for fluopipamine resistance. Two loci of genetic resistance were linked to CESA1. In silico docking of fluopipamine, quinoxyphen, and flupoxam against various CESA1 mutations suggests that an alternative binding site at the interface between CESA proteins is necessary to preserve cellulose polymerization in compound presence. These data uncovered potential fundamental mechanisms of cellulose biosynthesis in plants along with feasible leads for herbicidal uses.
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