Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity.

Introduction: The success of the human body in fighting SARS-CoV2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance. Methods: We report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV2 compared with uninfected controls. Results: In contrast to previous studies, our approach successfully stratifies non-infected from infected individuals, as well as disease level of severity. The features that drive this classification are based on somatic hypermutation patterns, and point to alterations in the somatic hypermutation process in COVID-19 patients. Discussion: These features may be used to build and adapt therapeutic strategies to COVID-19, in particular to quantitatively assess potential diagnostic and therapeutic antibodies. These results constitute a proof of concept for future epidemiological challenges.

Outcomes of Extracorporeal Membrane Oxygenation (ECMO) for COVID-19 Patients: A Multi-Institutional Analysis.

BACKGROUND: In March 2020, COVID-19 was announced as a global pandemic. The first COVID-19 patient was connected to an ECMO device in Israel during that time. Since then, over 200 patients have required ECMO support due to COVID-19 infection. The present study is a multi-institutional analysis of all COVID-19 patients requiring veno-venous (VV) ECMO in Israel. The aim was to characterize and compare the survivors and deceased patients as well as establish risk factors for mortality. METHODS: This retrospective multi-institutional study was conducted from March 2020 to March 2021 in eleven of twelve ECMO centers operating in Israel. All COVID-19 patients on VV ECMO support were included in the cohort. The patients were analyzed based on their comorbidities, procedural data, adverse event on ECMO, and outcomes. Univariate and multivariate analyses were used to compare the deceased and the surviving patients. RESULTS: The study included 197 patients, of which 150 (76%) were males, and the mean age was 50.7 ± 12 years. Overall mortality was 106 (54%). Compared with the deceased subjects, survivors were significantly younger (48 ± 11 vs. 53 ± 12 years), suffered less from ischemic heart disease (IHD) (3% vs. 12%), and were ventilated for a significantly shorter period (≤4 days) prior to cannulation (77% vs. 63%). Patients in the deceased group experienced more kidney failure and sepsis. Rates of other complications were comparable between groups. CONCLUSIONS: Based on this study, we conclude that early cannulation (≤4 days) of younger patients (≤55 years) may improve overall survival and that a history of IHD might indicate a reduced prognosis.

In vivo and in vitro protein mediated synthesis of palladium nanoparticles for hydrogenation reactions.

We report the biosynthesis of size confined palladium nanoparticles (Pd-NPs). The 2-3 nm size Pd-NPs were grown in 12-mer protein stable protein 1 (SP1), which serves as a template for the NP formation. We further show that by controlling the protein expression levels in the cells we can alter the cells' catalytic activity. The in vivo grown Pd-NPs were utilized in a hydrogenation reaction, converting acetylene feedstock into ethylene and ethane. The presented concept can be further used for a wide range of applications by exploiting the synergetic effect of the biotic elements with the abiotic ones.

Clinical Course and Outcomes of Severe Covid-19: A National Scale Study.

Knowledge of the outcomes of critically ill patients is crucial for health and government officials who are planning how to address local outbreaks. The factors associated with outcomes of critically ill patients with coronavirus disease 2019 (Covid-19) who required treatment in an intensive care unit (ICU) are yet to be determined. METHODS: This was a retrospective registry-based case series of patients with laboratory-confirmed SARS-CoV-2 who were referred for ICU admission and treated in the ICUs of the 13 participating centers in Israel between 5 March and 27 April 2020. Demographic and clinical data including clinical management were collected and subjected to a multivariable analysis; primary outcome was mortality. RESULTS: This study included 156 patients (median age = 72 years (range = 22-97 years)); 69% (108 of 156) were male. Eighty-nine percent (139 of 156) of patients had at least one comorbidity. One hundred three patients (66%) required invasive mechanical ventilation. As of 8 May 2020, the median length of stay in the ICU was 10 days (range = 0-37 days). The overall mortality rate was 56%; a multivariable regression model revealed that increasing age (OR = 1.08 for each year of age, 95%CI = 1.03-1.13), the presence of sepsis (OR = 1.08 for each year of age, 95%CI = 1.03-1.13), and a shorter ICU stay(OR = 0.90 for each day, 95% CI = 0.84-0.96) were independent prognostic factors. CONCLUSIONS: In our case series, we found lower mortality rates than those in exhausted health systems. The results of our multivariable model suggest that further evaluation is needed of antiviral and antibacterial agents in the treatment of sepsis and secondary infection.

Anxiety and Suicidality in a Hospitalized Patient with COVID-19 Infection.

We describe the case of a young man admitted due to mild COVID-19 infection. During his hospitalization in an isolation ward, he had no respiratory distress or fever but developed symptoms consistent with anxiety and insomnia. Despite the appropriate supportive intervention, on hospital day 7, he attempted suicide by jumping from the third-floor ward. The patient underwent urgent surgery and was transferred to a level I trauma center under strict isolation. Our findings emphasize the importance of the mental health aspects of patients treated during the COVID-19 pandemic. LEARNING POINTS: The COVID-19 pandemic requires social distancing, quarantine and isolation, which may precipitate new psychiatric symptoms in people without mental illness or aggravate existing conditions.Mental health service providers, including psychiatrists, clinical psychologists and social workers, should be available in every facility taking care of COVID-19 patients.Health workers treating patients during the COVID-19 pandemic should be aware of symptoms of depression, anxiety, insomnia and/or distress developing in their patients and colleagues.

Heparanase level and procoagulant activity are reduced in severe sepsis.

BACKGROUND: During severe sepsis, levels and activity of all coagulation proteins are reduced. Heparanase is implicated in angiogenesis and tumor progression. We previously demonstrated that heparanase also affected the hemostatic system. It forms a complex and increases the activity of the blood coagulation initiator tissue factor. AIM: To evaluate heparanase levels and procoagulant activity as predictors of sepsis severity. MATERIALS AND METHODS: Twenty-one patients with non-trauma, non-surgical sepsis admitted to the intensive care unit and 35 controls were recruited. Plasma samples were drawn from the study participants on days 1 and 7 following admission. RESULTS: Heparanase levels and procoagulant activity on day 1 were significantly reduced in patients compared to controls (P < .0001, P < .0001, respectively). Day 1 heparanase procoagulant activity ≥350 ng/mL yielded a negative predictive value for severe sepsis of 89%. Additionally, heparanase procoagulant activity on day 7 correlated with the change in the APACHE score between days 1 and 7 (r = .66, P = .007). CONCLUSIONS: Heparanase procoagulant activity decreases during sepsis and returns to normal levels as soon as the patient recovers. Hence, it can be potentially used to predict the risk of severe sepsis. These findings need to be further explored in large-scale studies.

Heparanase procoagulant activity is elevated in women using oral contraceptives.

STUDY QUESTION: What is the effect of estrogen on heparanase procogulant activity? SUMMARY ANSWER: Estrogen increases heparanase procoagulant activity. WHAT IS KNOWN ALREADY: Estrogen therapy increases the risk of thrombosis and was previously found to up-regulate heparanase expression. Heparanase is involved in angiogenesis and metastasis, and has been shown to form a complex with tissue factor (TF) and also shown to enhance the generation of factor Xa. STUDY DESIGN, SIZE, DURATION: A case-control study. Thirty-four healthy women using oral contraceptives (OC) and 41 women not using hormonal therapy and not pregnant per history were enrolled, over a 5-month period, at the Rambam Medical Center, Haifa, Israel. In vitro, estrogen receptor-positive (MCF-7) and -negative (MDA-231) cell lines were incubated with estrogen, tamoxifen and ICI-182.780 a pure estrogen receptor antagonist. The cell medium was evaluated for TF/heparanase complex activity, TF activity and heparanase procoagulant activity by chromogenic substrate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exclusion criteria included age <18 years, post-menopausal women, concomitant medications other than supplement minerals and vitamins, acute or chronic illness. MAIN RESULTS AND THE ROLE OF CHANCE: The study demonstrates increased risk of high heparanase procoagulant activity in OC users. When a cutoff level of 0.25 (absorbance 405-490 nm) was set, the odds ratio was 131 (P < 0.0001). When all results were studied by quartiles, in quartiles 3 and 4 the results were almost exclusively of the OC users (P < 0.0001). In cell cultures, estrogen and tamoxifen increased heparanase procoagulant activity in the medium of estrogen receptor-positive (MCF-7) cells. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the current study is that the two estrogens given to the women and cell cultures, ethinyl estradiol (EE) and 17-ß-estradiol (E2), respectively, may have different effects on the coagulation system, although an increase in heparanase procoagulant activity was demonstrated in both of them. Although the sample size of the study group was limited, significant differences in the activation of the extrinsic coagulation pathway were demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: The clinical relevance of the heparanase procoagulant activity assay as a screening tool in thrombophilia work-up should further be elucidated.