Characterizing Long COVID: Deep Phenotype of a Complex Condition

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or long COVID ), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FINDINGS: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411

Light-directed writing of chemically tunable narrow-band holographic sensors

This tunable holographic sensor offers interrogation and a reporting transducer as well as an analyte-responsive hydrogel, rendering it label-free and reusable. A single 6 ns laser pulse is used to fabricate holographic sensors consisting of silver nanoparticles arranged periodically within a polymer film. The tunability of the sensor is demonstrated through pH sensing of artificial urine and validated through computational modeling. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Low-Level Laser Therapy Activates NF-kB via Generation of Reactive Oxygen Species in Mouse Embryonic Fibroblasts

Background Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear. Methodology/Principal Findings In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm2 and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration. Conclusion We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.National Institutes of Health (U.S.) (grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense (CDMRP Program in TBI, W81XWH-09-1-0514)United States. Air Force Office of Scientific Research (FA9950-04-1-0079

Characterizing Long COVID: Deep Phenotype of a Complex Condition.

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or long COVID ), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FINDINGS: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Exercise as an Augmentation Treatment for Nonremitted Major Depressive Disorder: A Randomized, Parallel Dose Comparison

OBJECTIVE: Most patients with major depressive disorder (MDD) require second-step treatments to achieve remission. The TReatment with Exercise Augmentation for Depression (TREAD) study was designed to test the efficacy of aerobic exercise as an augmentation treatment for MDD patients who had not remitted with antidepressant treatment. METHOD: Eligible participants in this randomized controlled trial were sedentary individuals (men and women aged 18–70 years) diagnosed with DSM-IV nonpsychotic MDD who had not remitted with selective serotonin reuptake inhibitor (SSRI) treatment. Participants were recruited through physician referrals and advertisements. A total of 126 participants were randomized to augmentation treatment with either 16 kcal per kg per week (KKW) or 4 KKW of exercise expenditure for 12 weeks while SSRI treatment was held constant. Supervised ses sions were conducted at The Cooper Institute, Dallas, Texas, with additional home-based sessions as needed to fulfill the weekly exercise prescription. The primary outcome was remission (as determined by a score ≤ 12 on the Inventory of Depressive Symptomatology, Clinician-Rated). The study took place between August 2003 and August 2007. RESULTS: There were significant improvements over time for both groups combined (F(1,121) = 39.9, P < .0001), without differential group effect (group effect: F(1,134) = 3.2, P = .07; group-by-time effect: F(1,119) = 3.8, P = .06). Adjusted remission rates at week 12 were 28.3% versus 15.5% for the 16-KKW and 4-KKW groups, respectively, leading to a number needed to treat (NNT) of 7.8 for 16 KKW versus 4 KKW. Men, regardless of family history of mental illness, and women without a family history of mental illness had higher remission rates by week 12 with higher-dose (women, 39.0%; men, 85.4%) than with lower-dose exercise (women, 5.6%; men, 0.1%) (women: t(95) = 2.1, P = .04; men: t(88) = 5.4, P < .0001) (NNT: women, 3.0; men, 1.2). CONCLUSIONS: There was a trend for higher remission rates in the higher-dose exercise group (P < .06), with a clinically meaningful NNT of 7.8 in favor of the high exercise dose. Significant differences between groups were found when the moderating effects of gender and family history of mental illness were taken into account and suggest that higher-dose exercise may be better for all men and for women without a family history of mental illness

Epsilon-aminocaproic acid has no association with thromboembolic complications, renal failure, or mortality after liver transplantation

Objectives: To examine the role of epsilon-aminocaproic acid (EACA) administered after reperfusion of the donor liver in the incidences of thromboembolic events and acute kidney injury within 30 days after orthotopic liver transplantation. One-year survival rates between the EACA-treated and EACA-nontreated groups also were examined.Design: Retrospective, observational, cohort study design.Setting: Single-center, university hospital.Participants: The study included 708 adult liver transplantations performed from 2008 to 2013.Interventions: None.Measurements and Main Results: EACA administration was not associated with incidences of intracardiac thrombosis/pulmonary embolism (1.3%) or intraoperative death (0.6%). Logistic regression (n = 708) revealed 2 independent risk factors associated with myocardial ischemia (age and pre-transplant vasopressor use) and 8 risk factors associated with the need for post-transplant dialysis (age, female sex, redo orthotopic liver transplantation, preoperative sodium level, pre-transplant acute kidney injury or dialysis, platelet transfusion, and re-exploration within the first week after transplant); EACA was not identified as a risk factor for either outcome. One-year survival rates were similar between groups: 92% in EACA-treated group versus 93% in the EACA-nontreated group.Conclusions: The antifibrinolytic, EACA, was not associated with an increased incidence of thromboembolic complications or postoperative acute kidney injury, and it did not alter 1-year survival after liver transplantation. (C) 2016 Elsevier Inc. All rights reserved