Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial.

The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. The OVID study is conducted as a multicentre open-label superiority randomised controlled trial. Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study's background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous VTE, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin <8 g/dL and platelet count <50 x 10 <sup>9</sup> cells/L confirmed by recent laboratory test (<90 days). 6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. 7. Severe renal insufficiency (baseline creatinine clearance <30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (<90 days). 8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. 9. Current use of dual antiplatelet therapy. 10. Participation in other interventional studies over the past 30 days. 11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. 12. Cognitive impairment and/or inability to understand information provided in the study information. Patient enrolment will take place at seven Swiss centres, including five university hospitals and two large cantonal hospitals. Patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of 4,000 IU anti-Xa activity (40 mg/0.4 ml) once daily for 14 days. Patients randomized to the comparator group will receive no anticoagulation. Primary outcome: a composite of any hospitalization or all-cause death occurring within 30 days of randomization. (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within 14 days, 30 days, and 90 days of randomization; (ii) each component of the primary efficacy outcome, within 14 days, 30 days, and 90 days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within 14 days, 30 days, and 90 days of enrolment; (iv) primary efficacy outcome, within 14 days, and 90 days of enrolment; (v) disseminated intravascular coagulation (ISTH criteria, in-hospital diagnosis) within 14 days, 30 days, and 90 days of enrolment. Patients will undergo block stratified randomization (by age: 50-70 vs. >70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24). In this open-label study, no blinding procedures will be used. The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1-β = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group. Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021. ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Impacto del ENOS sobre los rendimientos de maíz en la región pampeana argentina

El fenómeno de “El Niño - Oscilación del Sur” (ENOS) es uno de los principales responsables de la variabilidad climática inter-anual, con influencia sobrela región pampeana argentina. El objetivo de este trabajo fue analizar el impacto del ENOS sobre las variaciones anuales de la producción de maíz. La región fue dividida en 10 zonas en las cuales los rendimientos tienen una variabilidad inter anual homogénea. Se utilizaron diferentes índices del ENOS. Los resultados indicaron que, en la mayor parte de la región, los desvíos de los rendimientos son, en general, positivos durante eventos “El Niño” y negativos durante “La Niña”. Sin embargo, el impacto es muy fuerte al norte y centro de la región analizada, y se debilita hacia el sur. En el sudeste de la provincia de Buenos Aires el comportamiento es diferente que en el resto. Los índices promediados de mayo a julio son, en general, un buen indicador de la influencia del ENOS sobre la productividad de los cultivos, y brindan una adecuada información para la toma de decisiones de la empresa agropecuaria, con suficiente anticipación respecto del comienzo de la campaña

Microbiological contamination of pig and cattle carcasses in different small-scale Swiss abattoirs.

A total of 750 pig carcasses and 535 cattle carcasses from 17 small-scale abattoirs were sampled by excision at four sites (pig: neck, belly, back, ham; cattle: neck, brisket, flank, rump). Samples were examined for total viable counts (TVC) and Enterobacteriaceae. Mean TVCs ranged from 2.4 to 4.2 log10 CFU cm-2 on pig carcasses and from 2.7 to 3.8 log10 CFU cm-2 on cattle carcasses. With regard to EU Regulation (EC) No 2073/2005, TVCs were mainly considered satisfactory (pig: 81.3%; cattle: 71.4%). Amongst sites, the back (pigs) and neck (cattle) tended to yield higher TVCs. Enterobacteriaceae were detected in low counts and on 23.9% of pig carcasses and 21.7% of cattle carcasses. Amongst abattoirs, Enterobacteriaceae prevalence on pig and cattle carcasses ranged from 2.0% to 56.0% and from 0.0% to 55.0%, respectively. Consequently, criteria of the EU Regulation proved to be a suitable tool for the appraisal of microbiological results (TVCs) from pig and cattle carcasses also from small-scale abattoirs. Because the occurrence of Enterobacteriaceae on carcasses was too infrequent to ensure log normality, frequencies should be compared for these organisms

The Probable Impact of Global Change on the Water Resources of Patagonia, Argentina

Very little work has been undertaken on the hydrological impact of global warming in South America. In this study, some initial estimates are made using IPCC and Hadley Centre scenarios, supported by an analysis of long-term trends in rainfall patterns. Under the global warming scenarios, we expect a drying trend in the north of Argentina and a wetter climate in the south, accompanied by a reduced meridional temperature gradient. Snowlines are likely to rise, although the overall response of glaciers needs detailed investigation. However, analyses of rainfall records suggest that rainfall has been increasing in the north, contrary to the expected global warming pattern.Facultad de Humanidades y Ciencias de la Educació

Aging induces endothelial dysfunction while sparing arterial thrombosis

OBJECTIVE: To assess the effects of aging on arterial thrombus formation by comparing 2-year-old with 11-week-old C57Bl6 mice. METHODS AND RESULTS: Aging is a major risk factor for cardiovascular disease. In humans, assessing the direct effects of aging on vascular homeostasis is difficult because it occurs in the presence of other risk factors. Arterial thrombosis is the critical event in cardiovascular diseases; however, it is not known whether aging per se promotes its occurrence. Mice represent an interesting system to address this issue because they age without spontaneously developing other risk factors. Organ chamber experiments confirmed the advanced level of aging of old mice. As previously shown, old mice exhibited endothelial dysfunction; however, arterial thrombosis induced by photochemical injury was unchanged. Arterial tissue factor expression and activity; expressions of tissue factor pathway inhibitor, thrombomodulin, and plasminogen activator inhibitor 1; prothrombin time; partial thromboplastin time; thrombin-antithrombin complex; and platelet activation were comparable in both groups. CONCLUSIONS: Although these results cannot be directly extrapolated to humans, this study contributes novel important information on the direct effect of aging on arterial thrombosis and underscores the importance of controlling modifiable risk factors in aged individuals

Genetic ablation of the p66(Shc) adaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer's disease

The mammalian ShcA adaptor protein p66(Shc) is a key regulator of mitochondrial reactive oxygen species (ROS) production and has previously been shown to mediate amyloid β (Aβ)-peptide-induced cytotoxicity in vitro. Moreover, p66(Shc) is involved in mammalian longevity and lifespan determination as revealed in the p66(Shc) knockout mice, which are characterized by a 30% prolonged lifespan, lower ROS levels and protection from age-related impairment of physical and cognitive performance. In this study, we hypothesized a role for p66(Shc) in Aβ-induced toxicity in vivo and investigated the effects of genetic p66(Shc) deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of β-amyloidosis. p66(Shc)-ablated PSAPP mice were characterized by an improved survival and a complete rescue of Aβ-induced cognitive deficits at the age of 15 months. Importantly, these beneficial effects on survival and cognitive performance were independent of Aβ levels and amyloid plaque deposition, but were associated with improved brain mitochondrial respiration, a reversal of mitochondrial complex I dysfunction, restored adenosine triphosphate production and reduced ROS levels. The results of this study support a role for p66(Shc) in Aβ-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66(Shc) ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment.Molecular Psychiatry advance online publication, 19 July 2016; doi:10.1038/mp.2016.112

Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in cardiovascular disease by modulating apoptosis and oxidative stress. We hypothesized that LOX-1 may be involved in pathophysiology of stroke by mediating ischaemia/reperfusion (I/R)-dependent cell death. Transient middle cerebral artery occlusion (tMCAO) was performed in wild-type (WT) mice, endothelial-specific LOX-1 transgenic mice (eLOX-1TG) and WT animals treated with LOX-1 silencing RNA (siRNA). In WT mice exposed to tMCAO, LOX-1 expression and function were increased in the MCA. Compared to WT animals, eLOX-1TG mice displayed increased stroke volumes and worsened outcome after I/R. Conversely, LOX-1-silencing decreased both stroke volume and neurological impairment. Similarly, in HBMVECs, hypoxia/reoxygenation increased LOX-1 expression, while LOX-1 overexpressing cells showed increased death following hypoxia reoxygenation. Increased caspase-3 activation was observed following LOX-1 overexpression both in vivo and in vitro, thus representing a likely mediator. Finally, monocytes from ischaemic stroke patients exhibited increased LOX-1 expression which also correlated with disease severity. Our data unequivocally demonstrate a key role for LOX-1 in determining outcome following I/R brain damage. Our findings could be corroborated in human brain endothelial cells and monocytes from patients, underscoring their translational relevance and suggesting siRNA-mediated LOX-1 knockdown as a novel therapeutic strategy for stroke patients

Characteristics of Staphylococcus Hyicus strains isolated from pig carcasses in two different slaughterhouses

In a previous study, we showed that coagulase positive staphylococci (CPS), which are often used as indicators for S. aureus, are frequently found on pig carcasses at slaughter. Further characterization of the CPS identified only a minor part as S. aureus. Selected non-S. aureus strains were all identified as S. hyicus, However, two studies have described also in this species strains that produce staphylococcal enterotoxins. The aim of the present study was therefore to further characterize such coagulase positive S. hyicus strains isolated from pig carcasses and to assess the results also in view of their food safety relevance. A total of 189 S. hyicus strains from abattoirs A (n=36) and B (n=153) were characterized. Phenotypically, 98.9% showed non-pigmented colonies, 99.5% no haemolysis and 67.7% were egg yolk-positive. DNase activity was found in all but one isolate. Only five of the 189 strains were resistant to the antimicrobials tested. One strain harboured the mecA gene. Exfoliative toxin genes were detected in 31 (16.4%) strains. Six strains harboured the exhA and 25 strains the exhD gene. S. aureus Enterotoxin (SE) genes were detected in none of the strains. The PFGE genotyping results show only a limited number of clusters. Cluster I included more than 50% of the strains. The fact that similar or closely related PFGE patterns of S. hyicus can be found on carcasses after bleeding in both abattoirs indicates the occurrence of widespread strains in the Swiss pig population. Moreover, the genotyping results revealed a remarkable homogeneity in S. hyicus strains isolated from different slaughter process stages in abattoir B, which could indicate a recontamination problem with persisting strains