BACKGROUND

Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown.

OBJECTIVE

To assess arterial wall inflammation in HIV, using 18fluorine-<em>2</em>-deoxy-<em>D</em>-glucose positron emission tomography (18F-F<em>D</em>G-PET), in relationship to traditional and nontraditional risk markers, including soluble C<em>D</em>163 (sC<em>D</em>163), a marker of monocyte and macrophage activation.

METHODS

A cross-sectional study of 81 participants investigated between November <em>2</em>009 and July <em>2</em>011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-F<em>D</em>G-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with <em>2</em> separate non-HIV control groups. One control group (n = <em>2</em>7) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = <em>2</em>7) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls).

METHODS

Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR).

RESULTS

Participants with HIV demonstrated well-controlled HIV disease (mean [S<em>D</em>] C<em>D</em>4 cell count, 641 [<em>2</em>88] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [S<em>D</em>] duration, 1<em>2</em>.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.<em>2</em>; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (<em>2</em>.<em>2</em>3; 95% CI, <em>2</em>.07-<em>2</em>.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (<em>2</em>.<em>2</em>3; 95% CI, <em>2</em>.07-<em>2</em>.40 vs <em>2</em>.13; 95% CI, <em>2</em>.03-<em>2</em>.<em>2</em>3; P = .<em>2</em>9). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .00<em>2</em>) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL ((<em>2</em>.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sC<em>D</em>163 level (P = .04) but not with C-reactive protein (P = .65) or <em>D</em>-dimer (P = .08) among patients with HIV.

CONCLUSIONS

Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

OBJECTIVE

The cell-surface molecule C<em>D</em>40 activates antigen-presenting cells and enhances immune responses. C<em>D</em>40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective C<em>D</em>40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.

METHODS

Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response.

RESULTS

Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. <em>D</em>ose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MT<em>D</em> was estimated as 0.<em>2</em> mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to <em>2</em>) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, <em>D</em>-<em>dimer</em> and liver function tests were observed <em>2</em>4 to 48 hours after infusion. Four patients with melanoma (14% of all patients and <em>2</em>7% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of C<em>D</em>19+ B cells in blood (93% depletion at the MT<em>D</em> for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment.

CONCLUSIONS

The C<em>D</em>40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.

<AbstractText>Since <em>D</em>ecember, <em>2</em>019, an outbreak of coronavirus disease <em>2</em>019 (COVI<em>D</em>-19) has spread globally. Little is known about the epidemiological and clinical features of paediatric patients with COVI<em>D</em>-19.</AbstractText><AbstractText>We retrospectively retrieved data for paediatric patients (aged 0-16 years) with confirmed COVI<em>D</em>-19 from electronic medical records in three hospitals in Zhejiang, China. We recorded patients' epidemiological and clinical features.</AbstractText><AbstractText>From Jan 17 to March 1, <em>2</em>0<em>2</em>0, 36 children (mean age 8·3 [S<em>D</em> 3·5] years) were identified to be infected with severe acute respiratory syndrome coronavirus <em>2</em>. The route of transmission was by close contact with family members (3<em>2</em> [89%]) or a history of exposure to the epidemic area (1<em>2</em> [33%]); eight (<em>2</em><em>2</em>%) patients had both exposures. 19 (53%) patients had moderate clinical type with pneumonia; 17 (47%) had mild clinical type and either were asymptomatic (ten [<em>2</em>8%]) or had acute upper respiratory symptoms (seven [19%]). Common symptoms on admission were fever (13 [36%]) and dry cough (seven [19%]). Of those with fever, four (11%) had a body temperature of 38·5°C or higher, and nine (<em>2</em>5%) had a body temperature of 37·5-38·5°C. Typical abnormal laboratory findings were elevated creatine kinase MB (11 [31%]), decreased lymphocytes (11 [31%]), leucopenia (seven [19%]), and elevated procalcitonin (six [17%]). Besides radiographic presentations, variables that were associated significantly with severity of COVI<em>D</em>-19 were decreased lymphocytes, elevated body temperature, and high levels of procalcitonin, <em>D</em>-<em>dimer</em>, and creatine kinase MB. All children received interferon alfa by aerosolisation twice a day, 14 (39%) received lopinavir-ritonavir syrup twice a day, and six (17%) needed oxygen inhalation. Mean time in hospital was 14 (S<em>D</em> 3) days. By Feb <em>2</em>8, <em>2</em>0<em>2</em>0, all patients were cured.</AbstractText><AbstractText>Although all paediatric patients in our cohort had mild or moderate type of COVI<em>D</em>-19, the large proportion of asymptomatic children indicates the difficulty in identifying paediatric patients who do not have clear epidemiological information, leading to a dangerous situation in community-acquired infections.</AbstractText><AbstractText>Ningbo Clinical Research Center for Children's Health and <em>D</em>iseases, Ningbo Reproductive Medicine Centre, and Key Scientific and Technological Innovation Projects of Wenzhou.</AbstractText>

Coronavirus disease <em>2</em>019 (COVI<em>D</em>-19) or severe acute respiratory syndrome coronavirus <em>2</em> (SARS-CoV-<em>2</em>), a novel coronavirus strain disease, has recently emerged in China and rapidly spread worldwide. This novel strain is highly transmittable and severe disease has been reported in up to 16% of hospitalized cases. More than 600,000 cases have been confirmed and the number of deaths is constantly increasing. COVI<em>D</em>-19 hospitalized patients, especially those suffering from severe respiratory or systemic manifestations, fall under the spectrum of the acutely ill medical population, which is at increased venous thromboembolism risk. Thrombotic complications seem to emerge as an important issue in patients infected with COVI<em>D</em>-19. Preliminary reports on COVI<em>D</em>-19 patients' clinical and laboratory findings include thrombocytopenia, elevated <em>D</em>-<em>dimer</em>, prolonged prothrombin time, and disseminated intravascular coagulation. As the pandemic is spreading and the whole picture is yet unknown, we highlight the importance of coagulation disorders in COVI<em>D</em>-19 infected patients and review relevant data of previous coronavirus epidemics caused by the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV).

<b>Background:</b> Cardiac injury and myocarditis have been described in adults with COVI<em>D</em>-19. SARS-CoV-<em>2</em> infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-<em>2</em> infection and the multisystem inflammatory syndrome in children (MIS-C) as defined by the US Centers for <em>D</em>isease Control. <b>Methods:</b> Over a two-month period contemporary with the SARS-CoV-<em>2</em> pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction and severe inflammatory state. <b>Results:</b> Thirty-five children were identified and included in the study. Median age at admission was 10 years (range <em>2</em>-16 years). Co-morbidities were present in <em>2</em>8% including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one third; 80% required inotropic support with <em>2</em>8% treated with ECMO. Inflammation markers were suggestive of cytokine storm (interleukin 6 median 135 pg/mL) and macrophage activation (<em>D</em>-<em>dimer</em> median 5<em>2</em>84 ng/mL). Mean brain natriuretic peptide was elevated (5743 pg/mL). Thirty-one/35 (88%) patients tested positive for SARS-CoV-<em>2</em> infection by PCR of nasopharyngeal swab or serology. All patients received intravenous immune globulin, with adjunctive steroid therapy used in one third. Left ventricular function was restored in the <em>2</em>5/35 of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned. <b>Conclusion:</b> Children may experience an acute cardiac decompensation due to severe inflammatory state following SARS-CoV-<em>2</em> infection (multisystem inflammatory syndrome in children - MIS-C). Treatment with immune globulin appears to be associated with recovery of left ventricular systolic function.

<strong class="sub-title">Keywords:</strong> COVI<em>D</em>-19; SARS-CoV-<em>2</em>; myocardial stunning.

<AbstractText>The outbreak of the novel coronavirus in China (SARS CoV-<em>2</em>) that began in <em>D</em>ecember <em>2</em>019 presents a significant and urgent threat to global health. This study was conducted to provide the international community with a deeper understanding of this new infectious disease.</AbstractText><AbstractText>Epidemiological, clinical features, laboratory findings, radiological characteristics, treatment, and clinical outcomes of 135 patients in northeast Chongqing were collected and analyzed in this study.</AbstractText><AbstractText>A total of 135 hospitalized patients with COVI<em>D</em>-19 were enrolled. The median age was 47 years (IQR 36-55), and there was no significant gender difference (53.3% men). The majority of patients had contact with people from the Wuhan area. Forty-three (31.9%) patients had underlying disease, primarily hypertension (13 [9.6%]), diabetes (1<em>2</em> [8.9%]), cardiovascular disease (7 [5.<em>2</em>%]), and malignancy (4 [3.0%]). Common symptoms included fever (1<em>2</em>0 [88.9%]), cough (10<em>2</em> [76.5%]), and fatigue (44 [3<em>2</em>.5%]). Chest CT scans showed bilateral patchy shadows or ground glass opacity in the lungs of all of the patients. All of the patients received antiviral therapy (135 [100%] (Kaletra and interferon were both used), antibacterial therapy (59 [43.7%]), and corticosteroids (36 [<em>2</em>6.7%]). In addition, many patients received traditional Chinese medicine (1<em>2</em>4 [91.8%]). It is suggested that patients should receive Kaletra early and should be treated by a combination of western and Chinese medicine. Compared with the mild cases, the severe cases had lower lymphocyte counts and higher plasma levels of Pt, APTT, <em>D</em>-<em>dimer</em>, L<em>D</em>H, PCT, ALB, CRP, and AST.</AbstractText><AbstractText>In this study, the clinic features and therapies of 135 COVI<em>D</em>-19 patients were demonstrated. Kaletra and traditional Chinese medicine played an important role in the treatment of the viral pneumonia. Further studies are required to explore the role of Kaletra and traditional Chinese medicine in the treatment of COVI<em>D</em>-19. This article is protected by copyright. All rights reserved.</AbstractText>

<AbstractText>Few observations exist with respect to the pro-coagulant profile of patients with COVI<em>D</em>-19 acute respiratory distress syndrome (AR<em>D</em>S). Reports of thromboembolic complications are scarce but suggestive for a clinical relevance of the problem.</AbstractText><AbstractText>Prospective observational study aimed to characterize the coagulation profile of COVI<em>D</em>-19 AR<em>D</em>S patients with standard and viscoelastic coagulation tests, and to evaluate their changes after establishment of an aggressive thromboprophylaxis.</AbstractText><AbstractText>Sixteen patients with COVI<em>D</em>-19 AR<em>D</em>S received a complete coagulation profile at the admission in the intensive care unit. Ten patients were followed in the subsequent 7 days, after increasing the dose of low molecular weight heparin, antithrombin levels correction, and clopidogrel in selected cases.</AbstractText><p><div><b>RESULTS</b></div>At baseline, the patients showed a pro-coagulant profile characterized by an increased clot strength (CS, median 55 hPa, 95% interquartile range 35-63), platelet contribution to CS (PCS, 43 hPa, interquartile range <em>2</em>4-45), fibrinogen contribution to CS (FCS, 1<em>2</em> hPa, interquartile range 6-13.5 elevated <em>D</em>-<em>dimer</em> levels (5.5 μg/mL, interquartile range <em>2</em>.5-6.5), hyperfibrinogenemia (794 mg/dL, interquartile range 583-933). Fibrinogen levels were associated (R^<em>2</em> =0.506, P=0.003) with interleukin-6 values. After increasing the thromboprophylaxis, there was a significant (P=0.001) time-related decrease of fibrinogen levels, <em>D</em>-<em>dimers</em> (P=0.017), CS (P=0.013), PCS (P=0.035) and FCS (P=0.038).</p><AbstractText>The pro-coagulant pattern of these patients may justify the clinical reports of thromboembolic complications (pulmonary embolism) during the course of the disease. Further studies are needed to assess the best prophylaxis and treatment of this condition.</AbstractText>

<strong class="sub-title"> Backgroun<em>d</em>: </strong> A multisystem inflammatory syn<em>d</em>rome in chil<em>d</em>ren (MIS-C) is associate<em>d</em> with coronavirus <em>d</em>isease <em>2</em>019. The New York State Department of Health (NYSDOH) establishe<em>d</em> active, statewi<em>d</em>e surveillance to <em>d</em>escribe hospitalize<em>d</em> patients with the syn<em>d</em>rome.

<strong class="sub-title"> Metho<em>d</em>s: </strong> Hospitals in New York State reporte<em>d</em> cases of Kawasaki's <em>d</em>isease, toxic shock syn<em>d</em>rome, myocar<em>d</em>itis, an<em>d</em> potential MIS-C in hospitalize<em>d</em> patients younger than <em>2</em>1 years of age an<em>d</em> sent me<em>d</em>ical recor<em>d</em>s to the NYSDOH. We carrie<em>d</em> out <em>d</em>escriptive analyses that summarize<em>d</em> the clinical presentation, complications, an<em>d</em> outcomes of patients who met the NYSDOH case <em>d</em>efinition for MIS-C between March 1 an<em>d</em> May 10, <em>2</em>0<em>2</em>0.

<strong class="sub-title"> Results: </strong> As of May 10, <em>2</em>0<em>2</em>0, a total of 191 potential cases were reporte<em>d</em> to the NYSDOH. Of 95 patients with confirme<em>d</em> MIS-C (laboratory-confirme<em>d</em> acute or recent severe acute respiratory syn<em>d</em>rome coronavirus <em>2</em> [SARS-CoV-<em>2</em>] infection) an<em>d</em> 4 with suspecte<em>d</em> MIS-C (met clinical an<em>d</em> epi<em>d</em>emiologic criteria), 53 (54%) were male; 31 of 78 (40%) were black, an<em>d</em> 31 of 85 (36%) were Hispanic. A total of 31 patients (31%) were 0 to 5 years of age, 4<em>2</em> (4<em>2</em>%) were 6 to 1<em>2</em> years of age, an<em>d</em> <em>2</em>6 (<em>2</em>6%) were 13 to <em>2</em>0 years of age. All presente<em>d</em> with subjective fever or chills; 97% ha<em>d</em> tachycar<em>d</em>ia, 80% ha<em>d</em> gastrointestinal symptoms, 60% ha<em>d</em> rash, 56% ha<em>d</em> conjunctival injection, an<em>d</em> <em>2</em>7% ha<em>d</em> mucosal changes. Elevate<em>d</em> levels of C-reactive protein, <em>d</em>-<em>dimer</em>, an<em>d</em> troponin were foun<em>d</em> in 100%, 91%, an<em>d</em> 71% of the patients, respectively; 6<em>2</em>% receive<em>d</em> vasopressor support, 53% ha<em>d</em> evi<em>d</em>ence of myocar<em>d</em>itis, 80% were a<em>d</em>mitte<em>d</em> to an intensive care unit, an<em>d</em> <em>2</em> <em>d</em>ie<em>d</em>. The me<em>d</em>ian length of hospital stay was 6 <em>d</em>ays.

<strong class="sub-title"> Conclusions: </strong> The emergence of multisystem inflammatory syn<em>d</em>rome in chil<em>d</em>ren in New York State coinci<em>d</em>e<em>d</em> with wi<em>d</em>esprea<em>d</em> SARS-CoV-<em>2</em> transmission; this hyperinflammatory syn<em>d</em>rome with <em>d</em>ermatologic, mucocutaneous, an<em>d</em> gastrointestinal manifestations was associate<em>d</em> with car<em>d</em>iac <em>d</em>ysfunction.

The transthyretin amyloi<em>d</em>oses (ATTR) are invariably fatal <em>d</em>iseases characterize<em>d</em> by progressive neuropathy an<em>d</em>/or car<em>d</em>iomyopathy. ATTR are cause<em>d</em> by aggregation of transthyretin (TTR), a natively tetrameric protein involve<em>d</em> in the transport of thyroxine an<em>d</em> the vitamin A-retinol-bin<em>d</em>ing protein complex. Mutations within TTR that cause autosomal <em>d</em>ominant forms of <em>d</em>isease facilitate tetramer <em>d</em>issociation, monomer misfol<em>d</em>ing, an<em>d</em> aggregation, although wil<em>d</em>-type TTR can also form amyloi<em>d</em> fibrils in el<em>d</em>erly patients. Because tetramer <em>d</em>issociation is the rate-limiting step in TTR amyloi<em>d</em>ogenesis, targete<em>d</em> therapies have focuse<em>d</em> on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloi<em>d</em> fibril formation. One such compoun<em>d</em>, tafami<em>d</em>is meglumine (Fx-1006A), has recently complete<em>d</em> Phase II/III trials for the treatment of Transthyretin Type Familial Amyloi<em>d</em> Polyneuropathy (TTR-FAP) an<em>d</em> <em>d</em>emonstrate<em>d</em> a slowing of <em>d</em>isease progression in patients heterozygous for the V30M TTR mutation. Herein we <em>d</em>escribe the molecular an<em>d</em> structural basis of TTR tetramer stabilization by tafami<em>d</em>is. Tafami<em>d</em>is bin<em>d</em>s selectively an<em>d</em> with negative cooperativity (K(<em>d</em>)s ~<em>2</em> nM an<em>d</em> ~<em>2</em>00 nM) to the two normally unoccupie<em>d</em> thyroxine-bin<em>d</em>ing sites of the tetramer, an<em>d</em> kinetically stabilizes TTR. Patient-<em>d</em>erive<em>d</em> amyloi<em>d</em>ogenic variants of TTR, inclu<em>d</em>ing kinetically an<em>d</em> thermo<em>d</em>ynamically less stable mutants, are also stabilize<em>d</em> by tafami<em>d</em>is bin<em>d</em>ing. The crystal structure of tafami<em>d</em>is-boun<em>d</em> TTR suggests that bin<em>d</em>ing stabilizes the weaker <em>dimer</em>-<em>dimer</em> interface against <em>d</em>issociation, the rate-limiting step of amyloi<em>d</em>ogenesis.

The progressive aggregation and deposition of amyloid beta-protein (Abeta) in brain regions subserving memory and cognition is an early and invariant feature of Alzheimer's disease, the most common cause of cognitive failure in aged humans. Inhibiting Abeta aggregation is therapeutically attractive because this process is believed to be an exclusively pathological event. Whereas many studies have examined the aggregation of synthetic Abeta peptides under nonphysiological conditions and concentrations, we have detected and characterized the oligomerization of naturally secreted Abeta at nanomolar levels in cultures of APP-expressing CHO cells [Podlisny, M. B., Ostaszewski, B. L., Squazzo, S. L., Koo, E. H., Rydell, R. E., Teplow, <em>D</em>. B., and Selkoe, <em>D</em>. J. (1995) J. Biol. Chem. <em>2</em>70, 9564-9570 (1); Podlisny, M. B., Walsh, <em>D</em>. M., Amarante, P., Ostaszewski, B. L., Stimson, E. R., Maggio, J. E., Teplow, <em>D</em>. B., and Selkoe, <em>D</em>. J. (1998) Biochemistry 37, 360<em>2</em>-3611 (<em>2</em>)]. To determine whether similar species occur in vivo, we probed samples of human cerebrospinal fluid (CSF) and detected S<em>D</em>S-stable <em>dimers</em> of Abeta in some subjects. Incubation of CSF or of CHO conditioned medium at 37 degrees C did not lead to new oligomer formation. This inability to induce oligomers extracellularly as well as the detection of oligomers in cell medium very early during the course of pulse-chase experiments suggested that natural Abeta oligomers might first form intracellularly. We therefore searched for and detected intracellular Abeta oligomers, principally <em>dimers</em>, in primary human neurons and in neuronal and nonneural cell lines. These <em>dimers</em> arose intracellularly rather than being derived from the medium by reuptake. The <em>dimers</em> were particularly detectable in neural cells: the ratio of intracellular to extracellular oligomers was much higher in brain-derived than nonbrain cells. We conclude that the pathogenically critical process of Abeta oligomerization begins intraneuronally.

BACKGROUND

While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.

METHODS

We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 1<em>2</em> months of treatment-mediated viral suppression were each matched to <em>2</em> control individuals (total number of controls, 1<em>2</em>8) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.

RESULTS

Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P ≤ .001). A higher percentage of CD38(+)HLA-DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD<em>2</em>8(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality.

CONCLUSIONS

Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

BACKGROUND

Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.

METHODS

Healthy older volunteers were given 5 mg of apixaban twice daily or <em>2</em>0 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a <em>2</em>-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.

RESULTS

Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (<em>2</em>4 participants), as compared with <em>2</em>1% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within <em>2</em> to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 9<em>2</em>% among those who received an andexanet bolus (<em>2</em>7 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by <em>2</em>3.4 ng per milliliter versus 4.<em>2</em> ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and <em>2</em> were observed, which resolved within <em>2</em>4 to 7<em>2</em> hours. No serious adverse or thrombotic events were reported.

CONCLUSIONS

Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT0<em>2</em><em>2</em>077<em>2</em>5 and NCT0<em>2</em><em>2</em><em>2</em>07<em>2</em>5.).

Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the coagulation proteases until it binds to the heparan side chains that line the microvasculature. The binding specifically occurs to a core pentasaccharide present both in the heparans and in their therapeutic derivative heparin. The accompanying conformational change of antithrombin is revealed in a <em>2</em>.9-A structure of a <em>dimer</em> of latent and active antithrombins, each in complex with the high-affinity pentasaccharide. Inhibitory activation results from a shift in the main sheet of the molecule from a partially six-stranded to a five-stranded form, with extrusion of the reactive center loop to give a more exposed orientation. There is a tilting and elongation of helix <em>D</em> with the formation of a <em>2</em>-turn helix P between the C and <em>D</em> helices. Concomitant conformational changes at the heparin binding site explain both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin-protease complex into the circulation. The pentasaccharide binds by hydrogen bonding of its sulfates and carboxylates to Arg-1<em>2</em>9 and Lys-1<em>2</em>5 in the <em>D</em>-helix, to Arg-46 and Arg-47 in the A-helix, to Lys-114 and Glu-113 in the P-helix, and to Lys-11 and Arg-13 in a cleft formed by the amino terminus. This clear definition of the binding site will provide a structural basis for developing heparin analogues that are more specific toward their intended target antithrombin and therefore less likely to exhibit side effects.

BACKGROUND

Coagulopathy is present at admission in <em>2</em>5% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock.

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> (PF1 + <em>2</em>), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and <em>D</em>-<em>dimers</em>. Base deficit was used as a measure of tissue hypoperfusion.

RESULTS

Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + <em>2</em> levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and <em>D</em>-<em>D</em>imers, associated with the observed reduction in PAI-1 and not alterations in TAFI.

CONCLUSIONS

Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.

<strong class="sub-title"> Background and purpose: </strong> COVID-19 is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus <em>2</em> (SARS-CoV-<em>2</em>). Apart from respiratory complications, acute cerebrovascular disease (CVD) has been observed in some patients with COVID-19. Therefore, we described the clinical characteristics, laboratory features, treatment and outcomes of CVD complicating SARS-CoV-<em>2</em> infection.

Materials and methods: Demographic and clinical characteristics, laboratory findings, treatments and clinical outcomes were collected and analysed. Clinical characteristics and laboratory findings of patients with COVID-19 with or without new-onset CVD were compared.

<strong class="sub-title"> Results: </strong> Of <em>2</em>19 patients with COVID-19, 10 (4.6%) developed acute ischaemic stroke and 1 (0.5%) had intracerebral haemorrhage. COVID-19 with new onset of CVD were significantly older (75.7±10.8 years vs 5<em>2</em>.1±15.3 years, p<0.001), more likely to present with severe COVID-19 (81.8% vs 39.9%, p<0.01) and were more likely to have cardiovascular risk factors, including hypertension, diabetes and medical history of CVD (all p<0.05). In addition, they were more likely to have increased inflammatory response and hypercoagulable state as reflected in C reactive protein (51.1 (1.3-1<em>2</em>7.9) vs 1<em>2</em>.1 (0.1-<em>2</em>1<em>2</em>.0) mg/L, p<0.05) and D-dimer (6.9 (0.3-<em>2</em>0.0) vs 0.5 (0.1-<em>2</em>0.0) mg/L, p<0.001). Of 10 patients with ischemic stroke; 6 received antiplatelet treatment with aspirin or clopidogrel; and 3 of them died. The other four patients received anticoagulant treatment with enoxaparin and <em>2</em> of them died. As of <em>2</em>4 March <em>2</em>0<em>2</em>0, six patients with CVD died (54.5%).

Conclusion: Acute CVD is not uncommon in COVID-19. Our findings suggest that older patients with risk factors are more likely to develop CVD. The development of CVD is an important negative prognostic factor which requires further study to identify optimal management strategy to combat the COVID-19 outbreak.

Keywords: Anticoagulation therapy; COVID-19; Cerebrovascular disease; Thromboembolic events; stroke.

BACKGROUND

Substantial morbidity occurs during the first year of antiretroviral therapy (ART) in persons with advanced human immunodeficiency virus (HIV) disease despite HIV suppression. Biomarkers may identify high-risk groups.

METHODS

Pre-ART and 1-month samples from an initial ART trial were evaluated for biomarkers associated with AIDS events or death within 1-1<em>2</em> months. Case patients (n = 63) and control patients (n = 1<em>2</em>6) were 1:<em>2</em> matched on baseline CD4 cell count, hepatitis status, and randomization date. All had ≥ 1 log(10) HIV RNA level decrease at 1 month.

RESULTS

Case patients had more frequent prior AIDS events, compared with control patients (P = .004), but similar HIV RNA levels at baseline. Pre-ART and 1-month C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) levels and pre-ART hyaluronic acid (HA) levels were associated with new AIDS events or death (P ≤ .01). Patients who experienced immune reconstitution inflammatory syndrome (IRIS) events had higher pre-ART tumor necrosis factor α (TNF-α) and HIV RNA levels and significant 1-month increases in CRP, D-dimer, IL-6, interleukin 8, CXCL10, TNF-α, and interferon-γ levels, compared with patients who experienced non-IRIS events (P ≤ .03). Individuals with baseline CRP and HA levels above the cohort median >><em>2</em>.1 mg/L and >50.0 ng/mL, respectively) had increased risk of AIDS or death (OR, 4.6 [95% CI, <em>2</em>.0-10.3]; P < .001) and IRIS (OR, 8.7 [95% CI, <em>2</em>.<em>2</em>-34.8] P = .00<em>2</em>).

CONCLUSIONS

Biomarkers of Inflammation (CRP, IL-6), coagulation (D-dimer), and tissue fibrosis (HA) measured pre-ART and at 1 month are associated with higher risk of AIDS events, IRIS, or death, warranting additional study as risk stratification strategies.

We present an extension of the CHARMM hexopyranose monosacchari<em>d</em>e a<em>d</em><em>d</em>itive all-atom force fiel<em>d</em> to enable mo<em>d</em>eling of glycosi<em>d</em>ic-linke<em>d</em> hexopyranose polysacchari<em>d</em>es. The new force fiel<em>d</em> parameters encompass 1→1, 1→<em>2</em>, 1→3, 1→4, an<em>d</em> 1→6 hexopyranose glycosi<em>d</em>ic linkages, as well as O-methylation at the C(1) anomeric carbon, an<em>d</em> are <em>d</em>evelope<em>d</em> to be consistent with the CHARMM all-atom biomolecular force fiel<em>d</em>s for proteins, nucleic aci<em>d</em>s, an<em>d</em> lipi<em>d</em>s. The parameters are <em>d</em>evelope<em>d</em> in a hierarchical fashion using mo<em>d</em>el compoun<em>d</em>s containing the key atoms in the full carbohy<em>d</em>rates, in particular O-methyl-tetrahy<em>d</em>ropyran an<em>d</em> glycosi<em>d</em>ic-linke<em>d</em> <em>dimers</em> consisting of two molecules of tetrahyropyran or one of tetrahy<em>d</em>ropyran an<em>d</em> one of cyclohexane. Target <em>d</em>ata for parameter optimization inclu<em>d</em>e full two-<em>d</em>imensional energy surfaces <em>d</em>efine<em>d</em> by the Φ/Ψ glycosi<em>d</em>ic <em>d</em>ihe<em>d</em>ral angles in the <em>d</em>isacchari<em>d</em>e analogs as <em>d</em>etermine<em>d</em> by quantum mechanical MP<em>2</em>/cc-pVTZ single point energies on MP<em>2</em>/6-31G(<em>d</em>) optimize<em>d</em> structures (MP<em>2</em>/cc-pVTZ//MP<em>2</em>/6-31G(<em>d</em>)). In or<em>d</em>er to achieve balance<em>d</em>, transferable <em>d</em>ihe<em>d</em>ral parameters for the Φ/Ψ glycosi<em>d</em>ic <em>d</em>ihe<em>d</em>ral angles, surfaces for all possible chiralities at the ring carbon atoms involve<em>d</em> in the glycosi<em>d</em>ic linkages are consi<em>d</em>ere<em>d</em>, resulting in over 5000 MP<em>2</em>/cc-pVTZ//MP<em>2</em>/6-31G(<em>d</em>) conformational energies. Also inclu<em>d</em>e<em>d</em> as target <em>d</em>ata are vibrational frequencies, pair interaction energies an<em>d</em> <em>d</em>istances with water molecules, an<em>d</em> intramolecular geometries inclu<em>d</em>ing <em>d</em>istortion of the glycosi<em>d</em>ic valence angle as a function of the glycosi<em>d</em>ic <em>d</em>ihe<em>d</em>ral angles. The mo<em>d</em>el-compoun<em>d</em> optimize<em>d</em> force fiel<em>d</em> parameters are vali<em>d</em>ate<em>d</em> on full <em>d</em>isacchari<em>d</em>es through comparison of molecular <em>d</em>ynamics results to available experimental <em>d</em>ata. Goo<em>d</em> agreement is achieve<em>d</em> with experiment for a variety of properties inclu<em>d</em>ing crystal cell parameters an<em>d</em> intramolecular geometries, aqueous <em>d</em>ensities, an<em>d</em> aqueous NMR coupling constants associate<em>d</em> with the glycosi<em>d</em>ic linkage. The newly-<em>d</em>evelope<em>d</em> parameters allow for the mo<em>d</em>eling of linear, branche<em>d</em>, an<em>d</em> cyclic hexopyranose glycosi<em>d</em>es both alone an<em>d</em> in heterogenous systems inclu<em>d</em>ing proteins, nucleic aci<em>d</em>s an<em>d</em>/or lipi<em>d</em>s when combine<em>d</em> with existing CHARMM biomolecular force fiel<em>d</em>s.

Single molecule atomic force microscopy was used to characterize structure, binding strength (unbinding force), and binding kinetics of a classical cadherin, vascular endothelial (VE)-cadherin, secreted by transfected Chinese hamster ovary cells as cis-dimerized full-length external domain fused to Fc-portion of human IgG. In physiological buffer, the external domain of VE-cadherin <em>dimers</em> is a approximately <em>2</em>0-nm-long rod-shaped molecule that collapses and dissociates into monomers (V-shaped structures) in the absence of Ca(<em>2</em>+). Trans-interaction of <em>dimers</em> is a low-affinity reaction (K(<em>D</em>) = 10(-3)-10(-5) M, k(off) = 1.8 s(-1), k(on) = 10(3)-10(5) M(-1) x s(-1)) with relatively low unbinding force (35-55 pN at retrace velocities of <em>2</em>00-4,000 nm x s(-1)). Higher order unbinding forces, that increase with interaction time, indicate association of cadherins into complexes with cumulative binding strength. These observations favor a model by which the inherently weak unit binding strength and affinity of cadherin trans-interaction requires clustering and cytoskeletal immobilization for amplification. Binding is regulated by low-affinity Ca(<em>2</em>+) binding sites (K(<em>D</em>) = 1.15 mM) with high cooperativity (Hill coefficient of 5.04). Local changes of free extracellular Ca(<em>2</em>+) in the narrow intercellular space may be of physiological importance to facilitate rapid remodeling of intercellular adhesion and communication.

In late <em>D</em>ecember <em>2</em>019 an outbreak of a novel coronavirus (SARS-CoV-<em>2</em>) causing severe pneumonia (COVI<em>D</em>-19) was reported in Wuhan, Hubei Province, China. A common finding in most COVI<em>D</em>-19 patients is high <em>D</em>-<em>dimer</em> levels which are associated with a worse prognosis. We aimed to evaluate coagulation abnormalities via traditional tests and whole blood thromboelastometry profiles in a group of <em>2</em><em>2</em> (mean age 67 ± 8 years, M:F <em>2</em>0:<em>2</em>) consecutive patients admitted to the Intensive Care Unit of Padova University Hospital for acute respiratory failure due to COVI<em>D</em>-19. Cases showed significantly higher fibrinogen and <em>D</em>-<em>dimer</em> plasma levels versus healthy controls (<i>p</i> < 0.0001 in both comparisons). Interestingly enough, markedly hypercoagulable thromboelastometry profiles were observed in COVI<em>D</em>-19 patients, as reflected by shorter Clot Formation Time (CFT) in INTEM (<i>p</i> = 0.000<em>2</em>) and EXTEM (<i>p</i> = 0.01) and higher Maximum Clot Firmness (MCF) in INTEM, EXTEM and FIBTEM (<i>p</i> < 0.001 in all comparisons). In conclusion, COVI<em>D</em>-19 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome.

All 13 lipids, including two cardiolipins, one phosphatidylcholine, three phosphatidylethanolamines, four phosphatidylglycerols and three triglycerides, were identified in a crystalline bovine heart cytochrome c oxidase (CcO) preparation. The chain lengths and unsaturated bond positions of the fatty acid moieties determined by mass spectrometry suggest that each lipid head group identifies its specific binding site within CcOs. The X-ray structure demonstrates that the flexibility of the fatty acid tails facilitates their effective space-filling functions and that the four phospholipids stabilize the CcO <em>dimer</em>. Binding of dicyclohexylcarbodiimide to the O(<em>2</em>) transfer pathway of CcO causes two palmitate tails of phosphatidylglycerols to block the pathway, suggesting that the palmitates control the O(<em>2</em>) transfer process.The phosphatidylglycerol with vaccenate (cis-<em>Delta</em>(11)-octadecenoate) was found in CcOs of bovine and Paracoccus denitrificans, the ancestor of mitochondrion, indicating that the vaccenate is conserved in bovine CcO in spite of the abundance of oleate (cis-<em>Delta</em>(9)-octadecenoate). The X-ray structure indicates that the protein moiety selects cis-vaccenate near the O(<em>2</em>) transfer pathway against trans-vaccenate. These results suggest that vaccenate plays a critical role in the O(<em>2</em>) transfer mechanism.

Hyperglycemia is associate<em>d</em> with increase<em>d</em> susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the en<em>d</em>othelium, is involve<em>d</em> in the protective capacity of the vessel wall. We therefore evaluate<em>d</em> whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimate<em>d</em> by comparing the <em>d</em>istribution volume of a glycocalyx permeable tracer (<em>d</em>extran 40) with that of a glycocalyx impermeable tracer (labele<em>d</em> erythrocytes) in 10 healthy male subjects. Measurements were performe<em>d</em> in ran<em>d</em>om or<em>d</em>er on five occasions: two control measurements, two measurements <em>d</em>uring normoinsulinemic hyperglycemia with or without N-acetylcysteine (NAC) infusion, an<em>d</em> one <em>d</em>uring mannitol infusion. Glycocalyx measurements were repro<em>d</em>ucible (1.7 +/- 0.<em>2</em> vs. 1.7 +/- 0.3 l). Hyperglycemia re<em>d</em>uce<em>d</em> glycocalyx volume (to 0.8 +/- 0.<em>2</em> l; P < 0.05), an<em>d</em> NAC was able to prevent the re<em>d</em>uction (1.4 +/- 0.<em>2</em> l). Mannitol infusion ha<em>d</em> no effect on glycocalyx volume (1.6 +/- 0.1 l). Hyperglycemia resulte<em>d</em> in en<em>d</em>othelial <em>d</em>ysfunction, increase<em>d</em> plasma hyaluronan levels (from 70 +/- 6 to 11<em>2</em> +/- 16 ng/ml; P < 0.05) an<em>d</em> coagulation activation (prothrombin activation fragment 1 + <em>2</em>: from 0.4 +/- 0.1 to 1.1 +/- 0.<em>2</em> nmol/l; <em>d</em>-<em>dimer</em>: from 0.<em>2</em>7 +/- 0.1 to 0.55 +/- 0.<em>2</em> g/l; P < 0.05). Taken together, these <em>d</em>ata in<em>d</em>icate a potential role for glycocalyx perturbation in me<em>d</em>iating vascular <em>d</em>ysfunction <em>d</em>uring hyperglycemia.

Eleven patients with relapse<em>d</em> flu<em>d</em>arabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-gra<em>d</em>e B-cell non-Ho<em>d</em>gkin's lymphoma (NHL) were treate<em>d</em> with the chimeric monoclonal anti-CD<em>2</em>0 antibo<em>d</em>y rituximab (IDEC-C<em>2</em>B8). Peripheral lymphocyte counts at baseline varie<em>d</em> from 0.<em>2</em> to <em>2</em>94.3 x 10(9)/L. During the first rituximab infusion, patients with lymphocyte counts excee<em>d</em>ing 50.0 x 10(9)/L experience<em>d</em> a severe cytokine-release syn<em>d</em>rome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor-alpha (TNF-alpha) an<em>d</em> interleukin-6 (IL-6) peake<em>d</em> in all patients. Elevate<em>d</em> cytokine levels <em>d</em>uring treatment were associate<em>d</em> with clinical symptoms, inclu<em>d</em>ing fever, chills, nausea, vomiting, hypotension, an<em>d</em> <em>d</em>yspnea. Lymphocyte an<em>d</em> platelet counts <em>d</em>roppe<em>d</em> to 50% to 75% of baseline values within 1<em>2</em> hours after the onset of the infusion. Simultaneously, there was a 5-fol<em>d</em> to 10-fol<em>d</em> increase of liver enzymes, <em>d</em>-<em>dimers</em>, an<em>d</em> lactate <em>d</em>ehy<em>d</em>rogenase (LDH), as well as a prolongation of the prothrombin time. Frequency an<em>d</em> severity of first-<em>d</em>ose a<em>d</em>verse events were <em>d</em>epen<em>d</em>ent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 x 10(9)/L experience<em>d</em> significantly more a<em>d</em>verse events of National Cancer Institute (NCI) gra<em>d</em>e III/IV toxicity than patients with less than 50.0 x 10(9)/L peripheral tumor cells (P = .0017). Due to massive si<em>d</em>e effects in the first patient treate<em>d</em> with 375 mg/m(<em>2</em>) in 1 <em>d</em>ay, a fractionate<em>d</em> <em>d</em>osing sche<em>d</em>ule was use<em>d</em> in all subsequent patients with application of 50 mg rituximab on <em>d</em>ay 1, 150 mg on <em>d</em>ay <em>2</em>, an<em>d</em> the rest of the 375 mg/m(<em>2</em>) <em>d</em>ose on <em>d</em>ay 3. While the patient with the leukemic variant of the mantle-cell NHL achieve<em>d</em> a complete remission (9 months+) after treatment with 4 x 375 mg/m(<em>2</em>) rituximab, efficacy in patients with relapse<em>d</em> flu<em>d</em>arabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable <em>d</em>isease, an<em>d</em> 1 progressive <em>d</em>isease were observe<em>d</em> in 9 evaluable patients with CLL. On the basis of these <em>d</em>ata, <em>d</em>ifferent infusion sche<em>d</em>ules an<em>d</em>/or combination regimens with chemotherapeutic <em>d</em>rugs to re<em>d</em>uce tumor bur<em>d</em>en before treatment with rituximab will have to be evaluate<em>d</em>.

BACKGROUND

Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.

RESULTS

We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001).

CONCLUSIONS

Pre-ART increases in Th(17) and Th(2) responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.

<strong class="sub-title"> Background: </strong> The mainstay of control of the coronavirus disease <em>2</em>019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus <em>2</em> (SARS-CoV-<em>2</em>). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity.

<strong class="sub-title"> Methods: </strong> We report findings in <em>2</em>3 patients who presented with thrombosis and thrombocytopenia 6 to <em>2</em>4 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications.

<strong class="sub-title"> Results: </strong> In the absence of previous prothrombotic medical conditions, <em>2</em><em>2</em> patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d-dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in <em>2</em>1 patients, negative in 1 patient, and equivocal in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms.

<strong class="sub-title"> Conclusions: </strong> Vaccination against SARS-CoV-<em>2</em> remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.