<AbstractText>Since December, <em>2</em>019, Wuhan, China, has experience<em>d</em> an outbreak of coronavirus <em>d</em>isease <em>2</em>019 (COVID-19), cause<em>d</em> by the severe acute respiratory syn<em>d</em>rome coronavirus <em>2</em> (SARS-CoV-<em>2</em>). Epi<em>d</em>emiological an<em>d</em> clinical characteristics of patients with COVID-19 have been reporte<em>d</em> but risk factors for mortality an<em>d</em> a <em>d</em>etaile<em>d</em> clinical course of illness, inclu<em>d</em>ing viral she<em>d</em><em>d</em>ing, have not been well <em>d</em>escribe<em>d</em>.</AbstractText><AbstractText>In this retrospective, multicentre cohort stu<em>d</em>y, we inclu<em>d</em>e<em>d</em> all a<em>d</em>ult inpatients (≥18 years ol<em>d</em>) with laboratory-confirme<em>d</em> COVID-19 from Jinyintan Hospital an<em>d</em> Wuhan Pulmonary Hospital (Wuhan, China) who ha<em>d</em> been <em>d</em>ischarge<em>d</em> or ha<em>d</em> <em>d</em>ie<em>d</em> by Jan 31, <em>2</em>0<em>2</em>0. Demographic, clinical, treatment, an<em>d</em> laboratory <em>d</em>ata, inclu<em>d</em>ing serial samples for viral RNA <em>d</em>etection, were extracte<em>d</em> from electronic me<em>d</em>ical recor<em>d</em>s an<em>d</em> compare<em>d</em> between survivors an<em>d</em> non-survivors. We use<em>d</em> univariable an<em>d</em> multivariable logistic regression metho<em>d</em>s to explore the risk factors associate<em>d</em> with in-hospital <em>d</em>eath.</AbstractText><AbstractText>191 patients (135 from Jinyintan Hospital an<em>d</em> 56 from Wuhan Pulmonary Hospital) were inclu<em>d</em>e<em>d</em> in this stu<em>d</em>y, of whom 137 were <em>d</em>ischarge<em>d</em> an<em>d</em> 54 <em>d</em>ie<em>d</em> in hospital. 91 (48%) patients ha<em>d</em> a comorbi<em>d</em>ity, with hypertension being the most common (58 [30%] patients), followe<em>d</em> by <em>d</em>iabetes (36 [19%] patients) an<em>d</em> coronary heart <em>d</em>isease (15 [8%] patients). Multivariable regression showe<em>d</em> increasing o<em>d</em><em>d</em>s of in-hospital <em>d</em>eath associate<em>d</em> with ol<em>d</em>er age (o<em>d</em><em>d</em>s ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, <em>2</em>·61-1<em>2</em>·<em>2</em>3; p<0·0001), an<em>d</em> <em>d</em>-<em>dimer</em> greater than 1 μg/L (18·4<em>2</em>, <em>2</em>·64-1<em>2</em>8·55; p=0·0033) on a<em>d</em>mission. Me<em>d</em>ian <em>d</em>uration of viral she<em>d</em><em>d</em>ing was <em>2</em>0·0 <em>d</em>ays (IQR 17·0-<em>2</em>4·0) in survivors, but SARS-CoV-<em>2</em> was <em>d</em>etectable until <em>d</em>eath in non-survivors. The longest observe<em>d</em> <em>d</em>uration of viral she<em>d</em><em>d</em>ing in survivors was 37 <em>d</em>ays.</AbstractText><AbstractText>The potential risk factors of ol<em>d</em>er age, high SOFA score, an<em>d</em> <em>d</em>-<em>dimer</em> greater than 1 μg/L coul<em>d</em> help clinicians to i<em>d</em>entify patients with poor prognosis at an early stage. Prolonge<em>d</em> viral she<em>d</em><em>d</em>ing provi<em>d</em>es the rationale for a strategy of isolation of infecte<em>d</em> patients an<em>d</em> optimal antiviral interventions in the future.</AbstractText><AbstractText>Chinese Aca<em>d</em>emy of Me<em>d</em>ical Sciences Innovation Fun<em>d</em> for Me<em>d</em>ical Sciences; National Science Grant for Distinguishe<em>d</em> Young Scholars; National Key Research an<em>d</em> Development Program of China; The Beijing Science an<em>d</em> Technology Project; an<em>d</em> Major Projects of National Science an<em>d</em> Technology on New Drug Creation an<em>d</em> Development.</AbstractText>

<AbstractText>Since <em>D</em>ecember <em>2</em>019, an outbreak of Coronavirus <em>D</em>isease <em>2</em>019 (COVI<em>D</em>-19) caused by severe acute respiratory syndrome coronavirus <em>2</em> (SARS-CoV-<em>2</em>) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunologic features of severe and moderate COVI<em>D</em>-19.</AbstractText><AbstractText>In this retrospective study, the clinical and immunologic characteristics of <em>2</em>1 patients (17 male and 4 female) with COVI<em>D</em>-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the Guidelines released by the National Health Commission of China.</AbstractText><AbstractText>The median age of severe and moderate cases was 61.0 and 5<em>2</em>.0 years, respectively. Common clinical manifestations included fever, cough and fatigue. Compared to moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin and <em>D</em>-<em>dimer</em> as well as markedly higher levels of IL-<em>2</em>R, IL-6, IL-10, and TNF-α. Absolute number of T lymphocytes, C<em>D</em>4+T and C<em>D</em>8+T cells decreased in nearly all the patients, and were markedly lower in severe cases (<em>2</em>94.0, 177.5 and 89.0 × 106/L) than moderate cases (640.5, 381.5 and <em>2</em>54.0 × 106/L). The expressions of IFN-γ by C<em>D</em>4+T cells tended to be lower in severe cases (14.1%) than moderate cases (<em>2</em><em>2</em>.8%).</AbstractText><AbstractText>The SARS-CoV-<em>2</em> infection may affect primarily T lymphocytes particularly C<em>D</em>4+T and C<em>D</em>8+ T cells, resulting in decrease in numbers as well as IFN-γ production. These potential immunological markers may be of importance due to their correlation with disease severity in COVI<em>D</em>-19.</AbstractText>

The backbone dynamics of the C-terminal SH<em>2</em> domain of phospholipase C gamma 1 have been investigated. Two forms of the domain were studied, one in complex with a high-affinity binding peptide derived from the platelet-derived growth factor receptor and the other in the absence of this peptide. <em>2</em>-<em>D</em> 1H-15N NMR methods, employing pulsed field gradients, were used to determine steady-state 1H-15N NOE values and T1 and T<em>2</em> 15N relaxation times. Backbone dynamics were characterized by the overall correlation time (tau m), order parameters (S<em>2</em>), effective correlation times for internal motions (tau e), and, if required, terms to account for motions on a microsecond-to-millisecond-time scale. An extended two-time-scale formalism was used for residues having relaxation data and that could not be fit adequately using a single-time-scale formalism. The overall correlation times of the uncomplexed and complexed forms of SH<em>2</em> were found to be 9.<em>2</em> and 6.5 ns, respectively, suggesting that the uncomplexed form is in a monomer-<em>dimer</em> equilibrium. This was subsequently confirmed by hydrodynamic measurements. Analysis of order parameters reveals that residues in the so-called phosphotyrosine-binding loop exhibited higher than average disorder in both forms of SH<em>2</em>. Although localized differences in order parameters were observed between the uncomplexed and complexed forms of SH<em>2</em>, overall, higher order parameters were not found in the peptide-bound form, indicating that on average, picosecond-time-scale disorder is not reduced upon binding peptide. The relaxation data of the SH<em>2</em>-phosphopeptide complex were fit with fewer exchange terms than the uncomplexed form. This may reflect the monomer-<em>dimer</em> equilibrium that exists in the uncomplexed form or may indicate that the complexed form has lower conformational flexibility on a microsecond-to-millisecond-time scale.

BACKGROUND

In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CDDC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.

RESULTS

Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, <em>D</em>-<em>dimer</em>, and prothrombin fragment 1+<em>2</em>. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (<em>2</em>) a study to compare <em>D</em>C and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (<em>2</em>), the biomarkers were assessed for <em>2</em>49 <em>D</em>C and <em>2</em>50 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and <em>D</em>-<em>dimer</em> at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were <em>2</em>.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-<em>2</em>0.8; p < 0.0001), and 1<em>2</em>.4 (95% CI, 4.<em>2</em>-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the <em>D</em>C and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and <em>D</em>-<em>dimer</em> increased at 1 mo by 30% and 16% in the <em>D</em>C group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the <em>D</em>C group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (<em>D</em>C/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.0<em>2</em>) to 1.5 (95% CI, 0.8-<em>2</em>.8) and 1.4 (95% CI, 0.8-<em>2</em>.5) after adjustment for latest levels of IL-6 and <em>D</em>-<em>dimer</em>, respectively.

CONCLUSIONS

IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.

<AbstractText>To delineate the clinical characteristics of patients with coronavirus disease <em>2</em>019 (covid-19) who died.</AbstractText><AbstractText>Retrospective case series.</AbstractText><AbstractText>Tongji Hospital in Wuhan, China.</AbstractText><AbstractText>Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed. <em>D</em>ata were collected until <em>2</em>8 February <em>2</em>0<em>2</em>0.</AbstractText><AbstractText>Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms.</AbstractText><AbstractText>The median age of deceased patients (68 years) was significantly older than recovered patients (51 years). Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%). Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (<em>2</em>4%) and 7 (4%)). <em>D</em>yspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (6<em>2</em>%), 55 (49%), and <em>2</em>5 (<em>2</em><em>2</em>%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)). The median time from disease onset to death in deceased patients was 16 (interquartile range 1<em>2</em>.0-<em>2</em>0.0) days. Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively. Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and <em>D</em>-<em>dimer</em> were markedly higher in deceased patients than in recovered patients. Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (7<em>2</em>/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (4<em>2</em>; 37%), acute kidney injury (<em>2</em>8; <em>2</em>5%), and hypoxic encephalopathy (<em>2</em>3; <em>2</em>0%). Patients with cardiovascular comorbidity were more likely to develop cardiac complications. Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients.</AbstractText><AbstractText>Severe acute respiratory syndrome coronavirus <em>2</em> infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk. Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19.</AbstractText>

<AbstractText>Coronavirus <em>D</em>isease <em>2</em>019 (COVI<em>D</em>-19) caused by Severe Acute Respiratory Syndrome Coronavirus -<em>2</em> (SARS-CoV-<em>2</em>) infection has been widely spread. We aim to investigate the clinical characteristic and allergy status of patients infected by SARS-CoV-<em>2</em>.</AbstractText><AbstractText>Electronical medical records including demographics, clinical manifestation, comorbidities, laboratory data and radiological materials of 140 hospitalized COVI<em>D</em>-19 patients, with confirmed result of SARS-CoV-<em>2</em> viral infection were extracted and analysed.</AbstractText><AbstractText>An approximately 1:1 ratio of male (50.7%) and female COVI<em>D</em>-19 patients was found, with an overall median age of 57.0 years. All patients were community acquired cases. Fever (91.7%), cough (75.0%), fatigue (75.0%) and gastrointestinal symptoms (39.6%) were the most common clinical manifestations, whereas hypertension (30.0%) and diabetes mellitus (1<em>2</em>.1%) were the most common comorbidities. <em>D</em>rug hypersensitivity (11.4%) and urticaria (1.4%) were self-reported by several patients. Asthma or other allergic diseases was not reported by any of the patients. Chronic obstructive pulmonary disease (COP<em>D</em>, 1.4%) and current smokers (1.4%) were rare. Bilateral ground glass or patchy opacity (89.6%) were the most common signs of radiological finding. Lymphopenia (75.4%) and eosinopenia (5<em>2</em>.9%) were observed in most patients. Blood eosinophil counts correlate positively with lymphocyte counts in severe (r=0.486, p<0.001) and non-severe (r=0.469, p<0.001) patients after hospital admission. Significantly higher levels of <em>D</em>-<em>dimer</em>, C-reactive protein and procalcitonin were associated with severe patients compared to non-severe patients (all p<0.001).</AbstractText><AbstractText><em>D</em>etailed clinical investigation of 140 hospitalized COVI<em>D</em>-19 cases suggest eosinopenia together with lymphopenia may be a potential indicator for diagnosis. Allergic diseases, asthma and COP<em>D</em> are not risk factors for SARS-CoV-<em>2</em> infection. Elder age, high number of comorbidities and more prominent laboratory abnormalities were associated with severe patients.</AbstractText>

<AbstractText>Little evidence of increased thrombotic risk is available in COVI<em>D</em>-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-<em>2</em> infection.</AbstractText><AbstractText>All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (AR<em>D</em>S) due to COVI<em>D</em>-19 between March 3rd and 31st <em>2</em>0<em>2</em>0 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVI<em>D</em>-19 AR<em>D</em>S and COVI<em>D</em>-19 AR<em>D</em>S patients.</AbstractText><AbstractText>150 COVI<em>D</em>-19 patients were included (1<em>2</em><em>2</em> men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). <em>2</em>8/<em>2</em>9 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in <em>2</em> patients) of centrifugal pump occurred in 1<em>2</em> patients (8%) supported by ECMO. Most patients (> 95%) had elevated <em>D</em>-<em>dimer</em> and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVI<em>D</em>-19 AR<em>D</em>S patients (n = 145) confirmed that COVI<em>D</em>-19 AR<em>D</em>S patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. <em>2</em>.1%, p < 0.008). Coagulation parameters significantly differed between the two groups.</AbstractText><AbstractText><em>D</em>espite anticoagulation, a high number of patients with AR<em>D</em>S secondary to COVI<em>D</em>-19 developed life-threatening thrombotic complications. Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.</AbstractText>

Ionotropic glutamate receptors me<em>d</em>iate most excitatory neurotransmission in the central nervous system an<em>d</em> function by opening a transmembrane ion channel upon bin<em>d</em>ing of glutamate. <em>D</em>espite their crucial role in neurobiology, the architecture an<em>d</em> atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hy<em>d</em>roxy-5-methyl-4-isoxazole propionic aci<em>d</em> (AMPA)-sensitive, homotetrameric, rat GluA<em>2</em> receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fol<em>d</em> symmetry with the extracellular <em>d</em>omains organize<em>d</em> as pairs of local <em>dimers</em> an<em>d</em> with the ion channel <em>d</em>omain exhibiting four-fol<em>d</em> symmetry. A symmetry mismatch between the extracellular an<em>d</em> ion channel <em>d</em>omains is me<em>d</em>iate<em>d</em> by two pairs of conformationally <em>d</em>istinct subunits, A/C an<em>d</em> B/<em>D</em>. Therefore, the stereochemical manner in which the A/C subunits are couple<em>d</em> to the ion channel gate is <em>d</em>ifferent from the B/<em>D</em> subunits. Gui<em>d</em>e<em>d</em> by the GluA<em>2</em> structure an<em>d</em> site-<em>d</em>irecte<em>d</em> cysteine mutagenesis, we suggest that GluN1 an<em>d</em> GluN<em>2</em>A NM<em>D</em>A (N-methyl-<em>d</em>-aspartate) receptors have a similar architecture, with subunits arrange<em>d</em> in a 1-<em>2</em>-1-<em>2</em> pattern. We exploit the GluA<em>2</em> structure to <em>d</em>evelop mechanisms of ion channel activation, <em>d</em>esensitization an<em>d</em> inhibition by non-competitive antagonists an<em>d</em> pore blockers.

The SARS-CoV-<em>2</em> coronavirus (COVI<em>D</em>-19) induced infection can be associated with a coagulopathy, findings consistent with infection induced inflammatory changes as observed in patients with disseminated intravascular coagulopathy (<em>D</em>IC). The lack of prior immunity to COVI<em>D</em>-19 has resulted in large numbers of infected patients across the globe and uncertainty regarding management of the complications that arise in the course of this viral illness. The lungs are the target organ for COVI<em>D</em>-19; patients develop acute lung injury which can progress to respiratory failure, although multiorgan failure can also occur. The initial coagulopathy of COVI<em>D</em>-19 presents with prominent elevation of <em>D</em>-<em>dimer</em> and fibrin/fibrinogen degradation products, while abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations. Coagulation test screening, including the measurement of <em>D</em>-<em>dimer</em> and fibrinogen levels, is suggested. COVI<em>D</em>-19 associated coagulopathy should be managed as it would be for any critically ill patient, following the established practice of using thromboembolic prophylaxis for critically ill hospitalized patients, and standard supportive care measures for those with sepsis-induced coagulopathy or <em>D</em>IC. Although <em>D</em>-<em>dimer</em>, sepsis physiology, and consumptive coagulopathy are indicators of mortality, current data do not suggest the use of full intensity anticoagulation doses unless otherwise clinically indicated. Even though there is an associated coagulopathy with COVI<em>D</em>-19, bleeding manifestations, even in those with <em>D</em>IC, have not been reported. If bleeding does occur, standard guidelines for the management of <em>D</em>IC and bleeding should be followed.

<strong class="sub-title"> Objective: </strong> To describe outcomes of people admitted to hospital with coronavirus disease <em>2</em>019 (covid-19) in the United States, and the clinical and laboratory characteristics associated with severity of illness.

Design: Prospective cohort study.

Setting: Single academic medical center in New York City and Long Island.

<strong class="sub-title"> Participants: </strong> 5<em>2</em>79 patients with laboratory confirmed severe acute respiratory syndrome coronavirus <em>2</em> (SARS-Cov-<em>2</em>) infection between 1 March <em>2</em>0<em>2</em>0 and 8 April <em>2</em>0<em>2</em>0. The final date of follow up was 5 May <em>2</em>0<em>2</em>0.

Main outcome measures: Outcomes were admission to hospital, critical illness (intensive care, mechanical ventilation, discharge to hospice care, or death), and discharge to hospice care or death. Predictors included patient characteristics, medical history, vital signs, and laboratory results. Multivariable logistic regression was conducted to identify risk factors for adverse outcomes, and competing risk survival analysis for mortality.

<strong class="sub-title"> Results: </strong> Of 11 544 people tested for SARS-Cov-<em>2</em>, 5566 (48.<em>2</em>%) were positive. After exclusions, 5<em>2</em>79 were included. <em>2</em>741 of these 5<em>2</em>79 (51.9%) were admitted to hospital, of whom 1904 (69.5%) were discharged alive without hospice care and 665 (<em>2</em>4.3%) were discharged to hospice care or died. Of 647 (<em>2</em>3.6%) patients requiring mechanical ventilation, 391 (60.4%) died and 170 (<em>2</em>6.<em>2</em>%) were extubated or discharged. The strongest risk for hospital admission was associated with age, with an odds ratio of ><em>2</em> for all age groups older than 44 years and 37.9 (95% confidence interval <em>2</em>6.1 to 56.0) for ages 75 years and older. Other risks were heart failure (4.4, <em>2</em>.6 to 8.0), male sex (<em>2</em>.8, <em>2</em>.4 to 3.<em>2</em>), chronic kidney disease (<em>2</em>.6, 1.9 to 3.6), and any increase in body mass index (BMI) (eg, for BMI >40: <em>2</em>.5, 1.8 to 3.4). The strongest risks for critical illness besides age were associated with heart failure (1.9, 1.4 to <em>2</em>.5), BMI >40 (1.5, 1.0 to <em>2</em>.<em>2</em>), and male sex (1.5, 1.3 to 1.8). Admission oxygen saturation of <88% (3.7, <em>2</em>.8 to 4.8), troponin level >1 (4.8, <em>2</em>.1 to 10.9), C reactive protein level ><em>2</em>00 (5.1, <em>2</em>.8 to 9.<em>2</em>), and D-dimer level ><em>2</em>500 (3.9, <em>2</em>.6 to 6.0) were, however, more strongly associated with critical illness than age or comorbidities. Risk of critical illness decreased significantly over the study period. Similar associations were found for mortality alone.

Conclusions: Age and comorbidities were found to be strong predictors of hospital admission and to a lesser extent of critical illness and mortality in people with covid-19; however, impairment of oxygen on admission and markers of inflammation were most strongly associated with critical illness and mortality. Outcomes seem to be improving over time, potentially suggesting improvements in care.

<strong class="sub-title">Background:</strong> Over 40 000 patients with COVID-19 have been hospitalised in New York City (NY, USA) as of April <em>2</em>8, <em>2</em>0<em>2</em>0. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed.

<strong class="sub-title">Methods:</strong> This prospective observational cohort study took place at two NewYork-Presbyterian hospitals affiliated with Columbia University Irving Medical Center in northern Manhattan. We prospectively identified adult patients (aged ≥18 years) admitted to both hospitals from March <em>2</em> to April 1, <em>2</em>0<em>2</em>0, who were diagnosed with laboratory-confirmed COVID-19 and were critically ill with acute hypoxaemic respiratory failure, and collected clinical, biomarker, and treatment data. The primary outcome was the rate of in-hospital death. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal replacement therapy, and time to in-hospital clinical deterioration following admission. The relation between clinical risk factors, biomarkers, and in-hospital mortality was modelled using Cox proportional hazards regression. Follow-up time was right-censored on April <em>2</em>8, <em>2</em>0<em>2</em>0 so that each patient had at least <em>2</em>8 days of observation.

<strong class="sub-title">Findings:</strong> Between March <em>2</em> and April 1, <em>2</em>0<em>2</em>0, 1150 adults were admitted to both hospitals with laboratory-confirmed COVID-19, of which <em>2</em>57 (<em>2</em><em>2</em>%) were critically ill. The median age of patients was 6<em>2</em> years (IQR 51-7<em>2</em>), 171 (67%) were men. <em>2</em>1<em>2</em> (8<em>2</em>%) patients had at least one chronic illness, the most common of which were hypertension (16<em>2</em> [63%]) and diabetes (9<em>2</em> [36%]). 119 (46%) patients had obesity. As of April <em>2</em>8, <em>2</em>0<em>2</em>0, 101 (39%) patients had died and 94 (37%) remained hospitalised. <em>2</em>03 (79%) patients received invasive mechanical ventilation for a median of 18 days (IQR 9-<em>2</em>8), 170 (66%) of <em>2</em>57 patients received vasopressors and 79 (31%) received renal replacement therapy. The median time to in-hospital deterioration was 3 days (IQR 1-6). In the multivariable Cox model, older age (adjusted hazard ratio [aHR] 1·31 [1·09-1·57] per 10-year increase), chronic cardiac disease (aHR 1·76 [1·08-<em>2</em>·86]), chronic pulmonary disease (aHR <em>2</em>·94 [1·48-5·84]), higher concentrations of interleukin-6 (aHR 1·11 [95%CI 1·0<em>2</em>-1·<em>2</em>0] per decile increase), and higher concentrations of D-dimer (aHR 1·10 [1·01-1·19] per decile increase) were independently associated with in-hospital mortality.

Interpretation: Critical illness among patients hospitalised with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality.

Funding: National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health, and the Columbia University Irving Institute for Clinical and Translational Research.

<AbstractText>Since 3 months ago, severe acute respiratory syndrome coronavirus <em>2</em> (SARS-CoV-<em>2</em>) broke out in Wuhan, China, and spread rapidly around the world. Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism(VTE) prevalence is still rarely mentioned.</AbstractText><AbstractText>To determine the incidence of VTE in patients with severe NCP.</AbstractText><AbstractText>In this study, 81 severe NCP patients in the Intensive Care Unit (ICU) of Union Hospital (Wuhan, China) were enrolled. The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed.</AbstractText><AbstractText>The incidence of VTE in these patients was <em>2</em>5%(<em>2</em>0/81), of which 8 patients with VTE events died. VTE group was different from non-VTE group in age, lymphocytes counts, activated partial thromboplastin time (APTT), <em>D</em>-<em>dimer</em>, etc. If 1.5 µg/mL was used as the <em>D</em>-<em>dimer</em> cut-off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5% and the negative predictive value (NPV) was 94.7%.</AbstractText><AbstractText>The incidence of VTE in patients with severe NCP is <em>2</em>5% (<em>2</em>0/81), which may be related to poor prognosis. The significant increase of <em>D</em>-<em>dimer</em> in severe NCP patients is a good index for identifying high-risk groups of VTE.</AbstractText>

<AbstractText>An epidemic of Coronavirus <em>D</em>isease <em>2</em>019 (COVI<em>D</em>-19) began in <em>D</em>ecember <em>2</em>019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVI<em>D</em>-19 to help reducing the risk of critical illness and death for clinical help.</AbstractText><AbstractText>The data of COVI<em>D</em>-19 patients until March <em>2</em>0, <em>2</em>0<em>2</em>0 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVI<em>D</em>-19 patients with meta-analysis.</AbstractText><p><div><b>RESULTS</b></div>Thirteen studies were included in Meta-analysis, including a total number of 30<em>2</em>7 patients with SARS-CoV-<em>2</em> infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVI<em>D</em>-19 (male: OR = 1.76, 95% CI (1.41, <em>2</em>.18), P < 0.00001; age over 65 years old: OR =6.06, 95% CI(3.98, 9.<em>2</em><em>2</em>), P < 0.00001; current smoking: OR =<em>2</em>.51, 95% CI(1.39, 3.3<em>2</em>), P = 0.0006). The proportion of underlying diseases such as hypertension, diabetes, cardiovascular disease, and respiratory disease were statistically significant higher in critical/mortal patients compared to the non-critical patients (diabetes: OR=3.68, 95% CI (<em>2</em>.68, 5.03), P < 0.00001; hypertension: OR = <em>2</em>.7<em>2</em>, 95% CI (1.60,4.64), P = 0.000<em>2</em>; cardiovascular disease: OR = 5.19, 95% CI(3.<em>2</em>5, 8.<em>2</em>9), P < 0.00001; respiratory disease: OR = 5.15, 95% CI(<em>2</em>.51, 10.57), P < 0.00001). Clinical manifestations such as fever, shortness of breath or dyspnea were associated with the progression of disease [fever: 0R = 0.56, 95% CI (0.38, 0.8<em>2</em>), P = 0.003;shortness of breath or dyspnea: 0R=4.16, 95% CI (3.13, 5.53), P < 0.00001]. Laboratory examination such as aspartate amino transferase(AST) > 40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI) > <em>2</em>8pg/mL, procalcitonin(PCT) > 0.5ng/mL, lactatede hydrogenase(L<em>D</em>H) > <em>2</em>45U/L, and <em>D</em>-<em>dimer</em> > 0.5mg/L predicted the deterioration of disease while white blood cells(WBC)<4 × 10⁹/L meant a better clinical status[AST > 40U/L:OR=4.00, 95% CI (<em>2</em>.46, 6.5<em>2</em>), P < 0.00001; Cr ≥ 133μmol/L: OR = 5.30, 95% CI (<em>2</em>.19, 1<em>2</em>.83), P = 0.000<em>2</em>; hs-cTnI > <em>2</em>8 pg/mL: OR = 43.<em>2</em>4, 95% CI (9.9<em>2</em>, 188.49), P < 0.00001; PCT > 0.5 ng/mL: OR = 43.<em>2</em>4, 95% CI (9.9<em>2</em>, 188.49), P < 0.00001;L<em>D</em>H > <em>2</em>45U/L: OR = 43.<em>2</em>4, 95% CI (9.9<em>2</em>, 188.49), P < 0.00001; <em>D</em>-<em>dimer</em> > 0.5mg/L: OR = 43.<em>2</em>4, 95% CI (9.9<em>2</em>, 188.49), P < 0.00001; WBC < 4 × 10⁹/L: OR = 0.30, 95% CI (0.17, 0.51), P < 0.00001].</p><AbstractText>Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVI<em>D</em>-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, L<em>D</em>H, hs-cTnI and <em>D</em>-<em>dimer</em> could imply the progression of COVI<em>D</em>-19.</AbstractText>

<strong class="sub-title"> Background: </strong> The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus <em>2</em> (SARS-CoV-<em>2</em>), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-<em>2</em> might be expected to be rare.

<strong class="sub-title"> Recent developments: </strong> A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of <em>2</em>14 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-<em>2</em> has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in <em>2</em>-6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. WHERE NEXT?: Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-<em>2</em>. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-<em>2</em> in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.

Fibrinogen molecules are comprised of two sets of disulfide-bridged Aalpha-, Bbeta-, and gamma-chains. Each molecule contains two outer <em>D</em> domains connected to a central E domain by a coiled-coil segment. Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. <em>D</em>ouble-stranded fibrils form through end-to-middle domain (<em>D</em>:E) associations, and concomitant lateral fibril associations and branching create a clot network. Fibrin assembly facilitates intermolecular antiparallel C-terminal alignment of gamma-chain pairs, which are then covalently 'cross-linked' by factor XIII ('plasma protransglutaminase') or XIIIa to form 'gamma-<em>dimers</em>'. In addition to its primary role of providing scaffolding for the intravascular thrombus and also accounting for important clot viscoelastic properties, fibrin(ogen) participates in other biologic functions involving unique binding sites, some of which become exposed as a consequence of fibrin formation. This review provides details about fibrinogen and fibrin structure, and correlates this information with biological functions that include: (i) suppression of plasma factor XIII-mediated cross-linking activity in blood by binding the factor XIII A<em>2</em>B<em>2</em> complex. (ii) Non-substrate thrombin binding to fibrin, termed antithrombin I (AT-I), which down-regulates thrombin generation in clotting blood. (iii) Tissue-type plasminogen activator (tPA)-stimulated plasminogen activation by fibrin that results from formation of a ternary tPA-plasminogen-fibrin complex. Binding of inhibitors such as alpha<em>2</em>-antiplasmin, plasminogen activator inhibitor-<em>2</em>, lipoprotein(a), or histidine-rich glycoprotein, impairs plasminogen activation. (iv) Enhanced interactions with the extracellular matrix by binding of fibronectin to fibrin(ogen). (v) Molecular and cellular interactions of fibrin beta15-4<em>2</em>. This sequence binds to heparin and mediates platelet and endothelial cell spreading, fibroblast proliferation, and capillary tube formation. Interactions between beta15-4<em>2</em> and vascular endothelial (VE)-cadherin, an endothelial cell receptor, also promote capillary tube formation and angiogenesis. These activities are enhanced by binding of growth factors like fibroblast growth factor-<em>2</em> (FGF-<em>2</em>) and vascular endothelial growth factor (VEGF), and cytokines like interleukin (IL)-1. (vi) Fibrinogen binding to the platelet alpha(IIb)beta3 receptor, which is important for incorporating platelets into a developing thrombus. (vii) Leukocyte binding to fibrin(ogen) via integrin alpha(M)beta<em>2</em> (Mac-1), which is a high affinity receptor on stimulated monocytes and neutrophils.

Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin <em>D</em> (CyP<em>D</em>), which also binds the lateral stalk of the FOF1 ATP synthase. We show that CyP<em>D</em> binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 4<em>2</em>3 (Bz-4<em>2</em>3), that Bz-4<em>2</em>3 sensitizes the PTP to Ca(<em>2</em>+) like CyP<em>D</em> itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca(<em>2</em>+). Purified <em>dimers</em> of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca(<em>2</em>+), addition of Bz-4<em>2</em>3 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP, a nonhydrolyzable ATP analog) and Mg(<em>2</em>+)/A<em>D</em>P. These results indicate that the PTP forms from <em>dimers</em> of the ATP synthase.

The crystal structure of the beta subunit (processivity factor) of DNA polymerase III holoenzyme has been determined at <em>2</em>.5 A resolution. A <em>dimer</em> of the beta subunit (M(r) = <em>2</em> x 40.6 kd, <em>2</em> x 366 amino acid residues) forms a ring-shaped structure lined by 1<em>2</em> alpha helices that can encircle duplex DNA. The structure is highly symmetrical, with each monomer containing three domains of identical topology. The charge distribution and orientation of the helices indicate that the molecule functions by forming a tight clamp that can slide on DNA, as shown biochemically. A potential structural relationship is suggested between the beta subunit and proliferating cell nuclear antigen (PCNA, the eukaryotic polymerase <em>delta</em> [and epsilon] processivity factor), and the gene 45 protein of the bacteriophage T4 DNA polymerase.

The structure of the octameric histone core of the nucleosome has been determined by x-ray crystallography to a resolution of 3.1 A. The histone octamer is a tripartite assembly in which a centrally located (H3-H4)<em>2</em> tetramer is flanked by two H<em>2</em>A-H<em>2</em>B <em>dimers</em>. It has a complex outer surface; depending on the perspective, the structure appears as a wedge or as a flat disk. The disk represents the planar projection of a left-handed proteinaceous superhelix with approximately <em>2</em>8 A pitch. The diameter of the particle is 65 A and the length is 60 A at its maximum and approximately 10 A at its minimum extension; these dimensions are in agreement with those reported earlier by Klug et al. [Klug, A., Rhodes, <em>D</em>., Smith, J., Finch, J. T. & Thomas, J. O. (1980) Nature (London) <em>2</em>87, 509-516]. The folded histone chains are elongated rather than globular and are assembled in a characteristic "handshake" motif. The individual polypeptides share a common central structural element of the helix-loop-helix type, which we name the histone fold.

The novel coronavirus disease (COVI<em>D</em>-19) outbreak, caused by SARS-CoV-<em>2</em>, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVI<em>D</em>-19, its comorbidities, and mechanistic considerations for future therapies. While COVI<em>D</em>-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (AR<em>D</em>S), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (<em>D</em>IC). Mechanistically, SARS-CoV-<em>2</em>, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme <em>2</em> (ACE<em>2</em>) -a homologue of ACE-to enter type <em>2</em> pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE<em>2</em> is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVI<em>D</em>-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-<em>2</em><em>2</em>, IL-17, etc.] during the rapid progression phase of COVI<em>D</em>-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (<em>D</em>-<em>dimer</em>) after hospitalization may identify patients with cardiac injury and predict COVI<em>D</em>-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE<em>2</em> (rhACE<em>2</em>), are discussed.

We have previously demonstrated that a clinical model can be safely used in a management strategy in patients with suspected pulmonary embolism (PE). We sought to simplify the clinical model and determine a scoring system, that when combined with <em>D</em>-<em>dimer</em> results, would safely exclude PE without the need for other tests, in a large proportion of patients. We used a randomly selected sample of 80% of the patients that participated in a prospective cohort study of patients with suspected PE to perform a logistic regression analysis on 40 clinical variables to create a simple clinical prediction rule. Cut points on the new rule were determined to create two scoring systems. In the first scoring system patients were classified as having low, moderate and high probability of PE with the proportions being similar to those determined in our original study. The second system was designed to create two categories, PE likely and unlikely. The goal in the latter was that PE unlikely patients with a negative <em>D</em>-<em>dimer</em> result would have PE in less than <em>2</em>% of cases. The proportion of patients with PE in each category was determined overall and according to a positive or negative SimpliRE<em>D</em> <em>D</em>-<em>dimer</em> result. After these determinations we applied the models to the remaining <em>2</em>0% of patients as a validation of the results. The following seven variables and assigned scores (in brackets) were included in the clinical prediction rule: Clinical symptoms of <em>D</em>VT (3.0), no alternative diagnosis (3.0), heart rate >100 (1.5), immobilization or surgery in the previous four weeks (1.5), previous <em>D</em>VT/PE (1.5), hemoptysis (1.0) and malignancy (1.0). Patients were considered low probability if the score was (<em>2</em>.0, moderate of the score was <em>2</em>.0 to 6.0 and high if the score was over 6.0. Pulmonary embolism unlikely was assigned to patients with scores < or =4.0 and PE likely if the score was >4.0. 7.8% of patients with scores of less than or equal to 4 had PE but if the <em>D</em>-<em>dimer</em> was negative in these patients the rate of PE was only <em>2</em>.<em>2</em>% (95% CI = 1.0% to 4.0%) in the derivation set and 1.7% in the validation set. Importantly this combination occurred in 46% of our study patients. A score of (<em>2</em>.0 and a negative <em>D</em>-<em>dimer</em> results in a PE rate of 1.5% (95% CI = 0.4% to 3.7%) in the derivation set and <em>2</em>.7% (95% CI = 0.3% to 9.0%) in the validation set and only occurred in <em>2</em>9% of patients. The combination of a score < or =4.0 by our simple clinical prediction rule and a negative SimpliRE<em>D</em> <em>D</em>-<em>Dimer</em> result may safely exclude PE in a large proportion of patients with suspected PE.

Beginning with three partial cDNA clones of the RNA genome of human hepatitis <em>delta</em> virus (HDV), we assembled the complete 1,679-base sequence on a single molecule and then inserted a trimer of this into plasmid pSLV, a simian virus 40-based eucaryotic expression vector. This construct was used to transfect both monkey kidney (COS7) and human hepatocellular carcinoma (HuH7) cell lines. In this way we obtained replication of the HDV RNA genome and the appearance, in the nucleoli, of the <em>delta</em> antigen, the only known virus-coded protein. This proved both that the HDV genome could replicate in nonliver as well as liver cells and that there was no requirement for the presence of hepatitis B virus sequences or proteins. When the pSVL construct was made with a <em>dimer</em> of an HDV sequence with a <em>2</em>-base-pair deletion in the open reading frame, genome replication was reduced at least 40-fold. However, when we cotransfected with a plasmid that expressed the correct <em>delta</em> antigen, the mutated <em>dimer</em> achieved a level of genome replication comparable to that of the nonmutated sequence. We thus conclude that the <em>delta</em> antigen can act in trans and is essential for replication of the HDV genome.

Background As the number of patients increases, there is a growing understanding of the form of pneumonia sustained by the <em>2</em>019 novel coronavirus (SARS-CoV-<em>2</em>), which has caused an outbreak in China. Up to now, clinical features and treatment of patients infected with SARS-CoV-<em>2</em> have been reported in detail. However, the relationship between SARS-CoV-<em>2</em> and coagulation has been scarcely addressed. Our aim is to investigate the blood coagulation function of patients with SARS-CoV-<em>2</em> infection. Methods In our study, 94 patients with confirmed SARS-CoV-<em>2</em> infection were admitted in Renmin Hospital of Wuhan University. We prospectively collect blood coagulation data in these patients and in 40 healthy controls during the same period. Results Antithrombin values in patients were lower than that in the control group (p < 0.001). The values of <em>D</em>-<em>dimer</em>, fibrin/fibrinogen degradation products (F<em>D</em>P), and fibrinogen (FIB) in all SARS-CoV-<em>2</em> cases were substantially higher than those in healthy controls. Moreover, <em>D</em>-<em>dimer</em> and F<em>D</em>P values in patients with severe SARS-CoV-<em>2</em> infection were higher than those in patients with milder forms. Compared with healthy controls, prothrombin time activity (PT-act) was lower in SARS-CoV-<em>2</em> patients. Thrombin time in critical SARS-CoV-<em>2</em> patients was also shorter than that in controls. Conclusions The coagulation function in patients with SARS-CoV-<em>2</em> is significantly deranged compared with healthy people, but monitoring <em>D</em>-<em>dimer</em> and F<em>D</em>P values may be helpful for the early identification of severe cases.

The subunit structure of islet-activating protein (IAP), pertussis toxin, has been analyzed to study a possibility that this protein is one of the A-B toxins [Gill, <em>D</em>. M. (1978) in Bacterial Toxins and Cell Membranes (Jeljaszewicz, J., & Wadstrom, T., Eds.) pp <em>2</em>91-33<em>2</em>, Academic Press, New York]. Heating IAP with 1% sodium dodecyl sulfate caused its dissociation into five dissimilar subunits named S-1 (with a molecular weight of <em>2</em>8 000), S-<em>2</em> (<em>2</em>3 000), S-3 (<em>2</em><em>2</em> 000), S-4 (11 700), and S-5 (9300), as revealed by polyacrylamide gel electrophoresis; their molar ratio in the native IAP was 1:1:1:<em>2</em>:1. The molecular weight of IAP estimated by equilibrium ultracentrifugation was 117 000 which was not at variance with the value obtained by summing up molecular weights of the constituent subunits. The preparative separation of these IAP subunits was next undertaken; exposure of IAP to 5 M ice-cold urea for 4 days followed by column chromatography with carboxymethyl-Sepharose caused sharp separation of S-1 and S-5, leaving the other subunits as two <em>dimers</em>. These <em>dimers</em> were then dissociated into their constituent subunits, i.e., S-<em>2</em> and S-4 for one <em>dimer</em> and S-3 and S-4 for the other, after 16-h exposure to 8 M urea; these subunits were obtained individually upon further chromatography on a diethylaminoethyl-Sepharose column. Subunits other than S-1 were adsorbed as a pentamer by a column using haptoglobin as an affinity adsorbent. The same pentamer was obtained by adding S-5 to the mixture of two <em>dimers</em>. Neither this pentamer nor other oligomers (or protomers) exhibited biological activity in vivo. Recombination of S-1 with the pentamer at the 1:1 molar ratio yielded a hexamer which was identical with the native IAP in electrophoretic mobility and biological activity to enhance glucose-induced insulin secretion when injected into rats. In the broken-cell preparation, S-1 was biologically as effective as the native IAP; both catalyzed A<em>D</em>P-ribosylation of a protein in membrane preparations from rat C6 glioma cells. In conclusion, IAP is an oligomeric protein consisting of an A (active) protomer (the biggest subunit) and a B (binding) oligomer which is produced by connecting two <em>dimers</em> by the smallest subunit in a noncovalent manner. Rationale for this terminology is discussed based on the A-B model.

OBJECTIVE

Coagulopathy following major trauma is conventionally attributed to activation and consumption of coagulation factors. Recent studies have identified an acute coagulopathy present on admission that is independent of injury severity. We hypothesized that early coagulopathy is due to tissue hypoperfusion, and investigated derangements in coagulation associated with this.

METHODS

This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1+<em>2</em>, fibrinogen, thrombomodulin, protein C, plasminogen activator inhibitor-1, and <em>D</em>-<em>dimers</em>. Base deficit (B<em>D</em>) was used as a measure of tissue hypoperfusion.

RESULTS

A total of <em>2</em>08 patients were enrolled. Patients without tissue hypoperfusion were not coagulopathic, irrespective of the amount of thrombin generated. Prolongation of the partial thromboplastin and prothrombin times was only observed with an increased B<em>D</em>. An increasing B<em>D</em> was associated with high soluble thrombomodulin and low protein C levels. Low protein C levels were associated with prolongation of the partial thromboplastin and prothrombin times and hyperfibrinolysis with low levels of plasminogen activator inhibitor-1 and high <em>D</em>-dimer levels. High thrombomodulin and low protein C levels were significantly associated with increased mortality, blood transfusion requirements, acute renal injury, and reduced ventilator-free days.

CONCLUSIONS

Early traumatic coagulopathy occurs only in the presence of tissue hypoperfusion and appears to occur without significant consumption of coagulation factors. Alterations in the thrombomodulin-protein C pathway are consistent with activated protein C activation and systemic anticoagulation. Admission plasma thrombomodulin and protein C levels are predictive of clinical outcomes following major trauma.