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

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

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

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 hospitalization2,3,4 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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Przyczyny obciazenia wod zeutrofizowanego jeziora Jagielek zwiazkami azotu i fosforu na tle warunkow meteorologicznych Pojezierza Olsztynskiego

The causes of the eutrophication of Lake Jagiełek, situated around 6 km south-west of Olsztyn, were investigated in the hydrological years 1998-2004. The catchment area of this water body is situated in the watershed zone of the Łyna and Pasłęka rivers. The lake is subject to advanced eutrophication. As regards precipitation amount, the analysed period consisted of three dry years, two normal years and one wet year. Due to the occurrence of three successive dry years and higher evaporation resulting from increased air temperatures (by 0.5°C on average), the lake shallowed with periodic exposure of bottom sediments in the shoreline zone. The periodic exposure and inundation of sections of the lake bottom has led to intense mineralization of bottom sediments. This process contributes to secondary contamination of surface water with mineral substances, mainly nitrogen and phosphorus compounds. The investigated water body is situated in a watershed zone and is characterised by low and stable electrolytic conductivity (113 µS·cm-1 on average) and low pH of water (6.72 on average) which periodically reaches 4.70. The concentration levels of biogenic elements (nitrogen and phosphorus compounds) are subject to seasonal fluctuation. Relatively high concentrations of N-NO3 (1.25 mg dm-3 on average) were observed in the winter and spring, while low levels of this compound (0.18 mg·dm-3 on average) were reported in the summer and autumn. P-PO4 concentrations were marked by a growing trend from 0.26 mg· dm-3 on average in the spring to 0.70 mg·dm-3 on average in the summer. A high water load with biogenic elements, whose concentrations significantly exceeded the allowable and dangerous levels of N and P according to Vollenweider’s criteria, speeded up the eutrophication process and stimulated the gradual self-decline of the entire ecosystem. The restoration of ecological balance in the surveyed.Przyczyny eutrofizacji jeziora Jagiełek, położonego ok. 6 km na południowy zachód od Olsztyna, badano w latach hydrologicznych 1998-2004. Zlewnia zbiornika jest położona w strefie wododziałowej rzek Łyny i Pasłęki. W zbiorniku stwierdzono zaawansowany stopień eutrofizacji wód. Pod względem ilości opadów, w analizowanym okresie wyróżniono 3 lata suche, 2 normalne i jeden rok wilgotny. Wystąpienie w krótkim okresie kilku lat suchych oraz wzrost parowania w wyniku podwyższenia temperatury powietrza (średnio o 0,5 st.C) spowodowały wypłycenie jeziora, z okresowym odsłanianiem osadów dennych w jego strefie przybrzeżnej. Skutkiem okresowego odsłaniania i zatapiania części dna zbiornika jest intensywna mineralizacja osadów dennych. Powoduje to wtórne zanieczyszczenie wód powierzchniowych składnikami mineralnymi, głównie związkami azotu i fosforu. W zbiorniku zlokalizowanym w strefie wododziałowej wykazano niskie i stabilne wartości przewodnictwa elektrolitycznego (średnio 113 µS·cm-1), niski odczyn wody (średnio pH 6,72), osiągający okresowo pH 4,70 oraz sezonową cykliczność stężeń biogenów (związków azotu i fosforu). Stosunkowo wysokie stężenia N-NO3 (średnio 1,25 mg dm-3) występowały w okresie zimowo-wiosennym, a niskie (średnio 0,18 mg·dm-3) w okresie letnio-jesiennym. Stężenia P-PO4 wykazywały tendencję wzrastającą od średnio 0,26 mg·dm-3 wiosną do średnio 0,70 mg·dm-3 latem. Duże obciążenie wody substancjami biogennymi, przekraczające wielokrotnie dopuszczalne i niebezpieczne poziomy N i P, przyśpieszyło eutrofizację wody i spowodowało ewoluowanie całego ekosystemu w kierunku stopniowej samolikwidacji zbiornika. Odtworzenie równowagi ekologicznej w badanym ekosystemie, powinno opierać się na sezonowości zjawisk klimatycznych i hydrologicznych występujących w regionie przy ponownym włączeniu zbiornika w poziomy obieg wody

Fuzzy Cognitive Model of Flows of Receipt of Funds from Investment Projects Нечеткая когнитивная модель потоков поступления средств инвестиционных проектов

The goal of the article is development of methods of building up a fuzzy cognitive model of flows of receipt of funds from realisation of investment projects. In the result of analysis of existing methods and models of assessment of investment projects the article finds out that one of the problems is forecasting benefits expected from them (profit, saving). The article shows that forecasting of outgoing flows of investment projects is characterised with uncertainty and subjectivity of original data, which results in the necessity to use models and methods that use fuzzy logic. The article offers methods of building up a fuzzy cognitive model, the essence of which lie in a transition from linguistic description of the data domain to the cognitive model with further allocation of fuzzy dependencies between the data domain objects (model concepts and which ends with mathematical description of these dependencies. Such an approach allows reduction of the subjective component in assessment of investment projects and making the process of their assessment more transparent. The article also gives an example of realisation of a fuzzy cognitive model for assessment of an investment project of development of the coal mining enterprise, which illustrates a practical application of the methods.Целью статьи является разработка методики построения нечеткой когнитивной модели потоков поступления средств от реализации инвестиционных проектов. В результате анализа существующих методов и моделей оценки инвестиционных проектов выявлено, что одной из проблем является предсказание ожидаемых от них выгод (прибыли, экономии). Показано, что прогнозирование исходящих потоков инвестиционных проектов характеризуется неопределенностью и субъективностью исходных данных, что приводит к необходимости использования моделей и методов, использующих нечеткую логику. В статье предложена методика построения нечеткой когнитивной модели, суть которой состоит в переходе от лингвистического описания предметной области к когнитивной модели с последующим выделением нечетких зависимостей между объектами предметной области (концептами модели), и завершающаяся математическим описанием этих зависимостей. Такой подход позволяет уменьшить субъективную составляющую в оценке инвестиционных проектов, сделать процесс их оценки более прозрачным. В статье также представлен пример реализации нечеткой когнитивной модели для оценки инвестиционного проекта развития угледобывающего предприятия, иллюстрирующий практическое применение методики

Proba oceny wplywu jakosci wod na strukture jakosciowo-ilosciowa epifauny zasiedlajacej Stratiotes aloides L. na przykladzie starorzecza Lyny

The paper contains the results of a study on the dependence of the qualitative and quantitative structure of the phytophilous macrofauna dwelling on Stratiotes aloides L. (water soldier) on the quality of waters in a lentic oxbow lake of the £yna River. The observations were carried out during the vegetative season (April – June) 2006 at high and moderate water levels. During the study, a total of 18 taxa of invertebrates dwelling on the above plant species were identified, with the exact number of taxa varying in time: 11 taxa were noticed in April and May, and in June their number went up to 13. The examination of hydrochemical parameters of the oxbow lake waters revealed that the density of macrofauna was lower at higher values of proper conductivity and macronutrients, ammonia nitrogen and COD, increasing at high levels of sulphates. High concentrations of ammonia nitrogen and non-organic components coincided with decreased biomass of epiphytic animals on water soldier. Additionally, it has been observed that elevated concentrations of potassium ions have a negative influence on the biomass of most epiphytic animals (except Erpobdella sp.).W pracy przedstawiono wyniki badań nad próbę określenia zależności struktury jakościowo- ilościowej makrofauny fitofilnej zasiedlającej Stratiotes aloides L. od jakości wód w lentycznym starorzeczu rzeki Łyny. Badania prowadzono w okresie wegetacyjnym (IV- -VI) 2006 r. przy wysokich i średnich stanach wód. W czasie badań zidentyfikowano łącznie 18 taksonów bezkręgowców zasiedlających ten gatunek roślinny, przy czym ilości te podlegały zmienności czasowej: w kwietniu i maju zanotowano 11 taksonów, a w czerwcu 13. Spośród badanych parametrów hydrochemicznych wód starorzecza zagęszczenie makrofauny epifitycznej było niższe w przypadku wysokich wartości przewodnictwa właściwego i makroskładników, azotu amonowego i ChZT, natomiast wzrastało w przypadku wysokich stężeń siarczanów. Wysokie stężenia azotu amonowego i składników nieorganicznych towarzyszyły spadkowi biomasy zwierząt epifitycznych zamieszkujących osokę. Ponadto stwierdzono negatywny wpływ podwyższonych stężeń jonów potasu na biomasę zwierząt naroślinnych (z wyjątkiem Erpobdella sp.)