Prophylactic anticoagulants for non-hospitalised people with COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare systems worldwide. Multiple reports on thromboembolic complications related to COVID-19 have been published, and researchers have described that people with COVID-19 are at high risk for developing venous thromboembolism (VTE). Anticoagulants have been used as pharmacological interventions to prevent arterial and venous thrombosis, and their use in the outpatient setting could potentially reduce the prevalence of vascular thrombosis and associated mortality in people with COVID-19. However, even lower doses used for a prophylactic purpose may result in adverse events such as bleeding. It is important to consider the evidence for anticoagulant use in non-hospitalised people with COVID-19. OBJECTIVES: To evaluate the benefits and harms of prophylactic anticoagulants versus active comparators, placebo or no intervention, or non-pharmacological interventions in non-hospitalised people with COVID-19. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 18 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing prophylactic anticoagulants with placebo or no treatment, another active comparator, or non-pharmacological interventions in non-hospitalised people with COVID-19. We included studies that compared anticoagulants with a different dose of the same anticoagulant. We excluded studies with a duration of under two weeks. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were all-cause mortality, VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE)), and major bleeding. Our secondary outcomes were DVT, PE, need for hospitalisation, minor bleeding, adverse events, and quality of life. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included five RCTs with up to 90 days of follow-up (short term). Data were available for meta-analysis from 1777 participants. Anticoagulant compared to placebo or no treatment Five studies compared anticoagulants with placebo or no treatment and provided data for three of our outcomes of interest (all-cause mortality, major bleeding, and adverse events). The evidence suggests that prophylactic anticoagulants may lead to little or no difference in all-cause mortality (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.04 to 3.61; 5 studies; 1777 participants; low-certainty evidence) and probably reduce VTE from 3% in the placebo group to 1% in the anticoagulant group (RR 0.36, 95% CI 0.16 to 0.85; 4 studies; 1259 participants; number needed to treat for an additional beneficial outcome (NNTB) = 50; moderate-certainty evidence). There may be little to no difference in major bleeding (RR 0.36, 95% CI 0.01 to 8.78; 5 studies; 1777 participants; low-certainty evidence). Anticoagulants probably result in little or no difference in DVT (RR 1.02, 95% CI 0.30 to 3.46; 3 studies; 1009 participants; moderate-certainty evidence), but probably reduce the risk of PE from 2.7% in the placebo group to 0.7% in the anticoagulant group (RR 0.25, 95% CI 0.08 to 0.79; 3 studies; 1009 participants; NNTB 50; moderate-certainty evidence). Anticoagulants probably lead to little or no difference in reducing hospitalisation (RR 1.01, 95% CI 0.59 to 1.75; 4 studies; 1459 participants; moderate-certainty evidence) and may lead to little or no difference in adverse events (minor bleeding, RR 2.46, 95% CI 0.90 to 6.72; 5 studies, 1777 participants; low-certainty evidence). Anticoagulant compared to a different dose of the same anticoagulant One study compared anticoagulant (higher-dose apixaban) with a different (standard) dose of the same anticoagulant and reported five relevant outcomes. No cases of all-cause mortality, VTE, or major bleeding occurred in either group during the 45-day follow-up (moderate-certainty evidence). Higher-dose apixaban compared to standard-dose apixaban may lead to little or no difference in reducing the need for hospitalisation (RR 1.89, 95% CI 0.17 to 20.58; 1 study; 278 participants; low-certainty evidence) or in the number of adverse events (minor bleeding, RR 0.47, 95% CI 0.09 to 2.54; 1 study; 278 participants; low-certainty evidence). Anticoagulant compared to antiplatelet agent One study compared anticoagulant (apixaban) with antiplatelet agent (aspirin) and reported five relevant outcomes. No cases of all-cause mortality or major bleeding occurred during the 45-day follow-up (moderate-certainty evidence). Apixaban may lead to little or no difference in VTE (RR 0.36, 95% CI 0.01 to 8.65; 1 study; 279 participants; low-certainty evidence), need for hospitalisation (RR 3.20, 95% CI 0.13 to 77.85; 1 study; 279 participants; low-certainty evidence), or adverse events (minor bleeding, RR 2.13, 95% CI 0.40 to 11.46; 1 study; 279 participants; low-certainty evidence). No included studies reported on quality of life or investigated anticoagulants compared to a different anticoagulant, or anticoagulants compared to non-pharmacological interventions. AUTHORS' CONCLUSIONS: We found low- to moderate-certainty evidence from five RCTs that prophylactic anticoagulants result in little or no difference in major bleeding, DVT, need for hospitalisation, or adverse events when compared with placebo or no treatment in non-hospitalised people with COVID-19. Low-certainty evidence indicates that prophylactic anticoagulants may result in little or no difference in all-cause mortality when compared with placebo or no treatment, but moderate-certainty evidence indicates that prophylactic anticoagulants probably reduce the incidence of VTE and PE. Low-certainty evidence suggests that comparing different doses of the same prophylactic anticoagulant may result in little or no difference in need for hospitalisation or adverse events. Prophylactic anticoagulants may result in little or no difference in risk of VTE, hospitalisation, or adverse events when compared with antiplatelet agents (low-certainty evidence). Given that there were only short-term data from one study, these results should be interpreted with caution. Additional trials of sufficient duration are needed to clearly determine any effect on clinical outcomes.

The limited use of instructional design guidelines in healthcare simulation scenarios: an expert appraisal.

BACKGROUND: Systematic reviews on simulation training effectiveness have pointed to the need to adhere to evidence-based instructional design (ID) guidelines. ID guidelines derive from sound cognitive theories and aim to optimize complex learning (integration of knowledge, skills, and attitudes) and learning transfer (application of acquired knowledge and skills in the workplace). The purpose of this study was to explore adherence to ID guidelines in simulation training programs for dealing with postpartum hemorrhage (PPH), a high-risk situation and the leading cause of maternal mortality worldwide. METHODS: A total of 40 raters analyzed simulation training programs as described in 32 articles. The articles were divided into four subsets of seven articles and one subset of four articles. Each subset was judged by seven to ten raters on adherence to ID guidelines. The 5-point Likert score rating scale was based on Merrill's First Principles of Instruction and included items relating to key ID features categorized into five subscales: authenticity, activation of prior knowledge, demonstration, application, and integration/transfer. The authors searched for articles published in English between January 2007 and March 2017 in PubMed, Eric, and Google Scholar and calculated the mean Likert-scale score, per subscale, and interrater reliability (IRR). RESULTS: The mean Likert-scale scores calculated for all subscales were < 3.00. For the number of raters used to judge the papers in this study (varying between 7 and 10), the IRR was found to be excellent for the authenticity and integration/transfer subscales, good-to-excellent for the activation of prior knowledge and application subscales, and fair-to-good for the demonstration subscale. CONCLUSION: The results demonstrate a paucity of the description of adherence to evidence-based ID guidelines in current simulation trainings for a high-risk situation such as PPH.

First Case of Idiopathic Eosinophilic Meningoencephalitis in a Sheep.

A 1.5-year-old ewe was presented with neurological signs that had been observed from about 2 days prior to death. There had been no clinical response to anti-inflammatory and antibiotic treatment. Histopathological examination of the brain revealed a severe and widespread eosinophilic meningoencephalomyelitis of unknown aetiology. Defining histological features included diffuse angiocentric eosinophilic infiltrates in the neuroparenchyma and meninges, neuronal necrosis, astrocytosis, neuropil vacuolation and occasional glial scars. Differential diagnostics for eosinophilic meningoencephalitis were taken into account and investigated by means of special stains, immunohistochemistry, bacteriology and polymerase chain reaction. No pathological changes or ancillary tests were supportive or revealed a specific aetiology for the condition and therefore it was considered idiopathic. Idiopathic meningoencephalitis is a rare disease, mainly described in man and rarely in dogs, with no apparent aetiological cause or potential breed predisposition. To our knowledge this is the first case of idiopathic eosinophilic meningoencephalitis in a sheep and provides a histopathological guideline for prospective comparative pathology studies.

Longitudinal study on the occurrence in pigs of colistin-resistant Escherichia coli carrying mcr-1 following the cessation of use of colistin.

AIMS: In 2015, colistin-resistant Escherichia coli and Salmonella with the mcr-1 gene were isolated from a pig farm in Great Britain. Pigs were subsequently monitored over a ~20-month period for the occurrence of mcr-1-mediated colistin resistance and the risk of mcr-1 E. coli entering the food chain was assessed. METHODS AND RESULTS: Pig faeces and slurry were cultured for colistin-resistant E. coli and Salmonella, tested for the mcr-1 gene by PCR and selected isolates were further analysed. Seventy-eight per cent of faecal samples (n = 275) from pigs yielded mcr-1 E. coli after selective culture, but in positive samples only 0·2-1·3% of the total E. coli carried mcr-1. Twenty months after the initial sampling, faecal samples (n = 59) were negative for E. coli carrying mcr-1. CONCLUSIONS: The risk to public health from porcine E. coli carrying mcr-1 was assessed as very low. Twenty months after cessation of colistin use, E. coli carrying mcr-1 was not detected in pig faeces on a farm where it was previously present. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggest that cessation of colistin use may help over time to reduce or possibly eliminate mcr-1 E. coli on pig farms where it occurs.

The use of instructional design guidelines to increase effectiveness of postpartum hemorrhage simulation training.

OBJECTIVE: To compare learning outcomes of postpartum hemorrhage simulation training based on either instructional design guidelines or best practice. METHODS: A pretest-post-test non-equivalent groups study was conducted among obstetrics and gynecology residents in Recife, Brazil, from June 8 to August 30, 2013. The instructional design group included 13 teams, whereas the best practice group included seven teams. A standardized task checklist was used for scenario analysis and the proportion of correctly executed tasks compared (post-test minus pretest). RESULTS: The instructional design group scored higher than the best practice group for total number of tasks completed (median difference 0.46 vs 0.17; P<0.001; effect size [r]=0.72). Similar results were observed for communication (median difference 0.56 vs 0.22; P=0.004; r=0.58), laboratory evaluation (median difference 0.83 vs 0.00; P<0.001; r=0.76), and mechanical management (median difference 0.25 vs -0.15; P=0.048; r=0.39). Speed of learning was also increased. The median differences were 0.20 for the instructional design group compared with 0.05 for the best practice group at 60 seconds (P=0.015; r=0.49), and 0.49 versus 0.26 (P=0.001; r=0.65) at 360 seconds. CONCLUSION: The use of simulation training for postpartum hemorrhage that was based on instructional design guidelines yielded better learning outcomes than did training based on best practice.

Abd-B expression in Porcellio scaber Latreille, 1804 (Isopoda: Crustacea): conserved pattern versus novel roles in development and evolution.

The Hox genes are intimately involved in patterning the animal body during development and are considered to have had a pivotal role in the evolution of different body plans among the metazoans. From this perspective, crustaceans, a group that has evolved an extreme diversity of body structures, represent a choice group in which to study the evolution of these genes and their expression. The expression of one of these genes, Abdominal-B (Abd-B), has only been studied in two distantly related crustaceans, Artemia and Sacculina, where it shows dissimilar patterns, highly differentiated from the one described in other arthropods. Moreover, we have no information for the Malacostraca. Thus, we cloned the gene Abd-B and followed its expression through development by in situ hybridization in the isopod Porcellio scaber. We found a highly dynamic expression pattern of PsAbd-B during embryonic development. In early stages, it is expressed in the posterior-most part of the germ band, in a domain common to several arthropods studied to date, and later it is expressed in the developing limb buds of the pleon and still later in the endopodites of the third to fifth pleopodites. This raises the interesting possibility of the involvement of this gene in the later respiratory specialization of these appendages. In association with the above expression domain, Abd-B appears to be expressed in later stages also in the ventral ectoderm, raising the further suggestion of its possible involvement in patterning the developing nervous system. Moreover, we show that the first pleopod and the endopodite of the second pleopod, whereas present as limb buds in early embryonic stages, are later reduced and actually absent in the first postembryonic stage, although they reappear again in adults. These appendages thus represent an example of Lazarus appendages. Our data show strong plasticity in the use of a key developmental gene and point out the necessity of further research that may end with a revision of the current understanding of its role in animal evolution.

The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration.

This study examined the association between the sequence variation/expression of CX3CR1, a chemokine receptor, and age-related macular degeneration (AMD). Peripheral blood from 85 AMD patients and 105 subjects without AMD (controls), as well as ocular tissue from 40 pathological sections with AMD and two normal eye sections, were screened for V249I and T280M, two single nucleotide polymorphisms (SNPs) in CX3CR1. An increased prevalence, with the highest odds ratio of 3.57, of the I249 and M280 carriers was found among the AMD cases as compared with the controls. When comparing CX3CR1 expression in the archived eye sections, CX3CR1 transcripts were not detectable in the maculae of AMD eyes bearing T/M280; however, transcripts were detected in the maculae of normal eyes bearing T/T280 or T/M280 as well as in the AMD maculae bearing T/T280. Furthermore, lower CX3CR1 protein expression was observed in the maculae of AMD eyes bearing T/M280 compared with the controls bearing T/T280. The I249 and M280 alleles result in a lowered number of receptor binding sites and a decreased ligand affinity. Our data suggest that a decrease, caused by sequence variation and/or lower CX3CR1 expression, in CX3CR1-induced cellular activities could contribute to AMD development.

Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes.

Chronic nephropathies are associated with enhanced renal synthesis of endothelin (ET)-1. A recent study demonstrated that an ET(A) receptor antagonist given to diabetic rats at the moment of disease induction prevented the development of renal injury. Here we investigated whether an unselective ET(A)/ET(B) receptor antagonist, PD 142,893, was renoprotective when given to streptozotocin diabetic rats when animals were already proteinuric. The effect of PD 142,893 was compared with that of an ACE inhibitor, lisinopril, known to retard progressive renal disease in experimental and human diabetes. PD 142,893 normalized systemic blood pressure, reduced urinary protein and albumin excretion, and ameliorated renal blood flow in diabetic rats, but it did not affect such parameters in control rats. Lisinopril had a renoprotective effect comparable to PD 142,893, although lisinopril controlled systemic blood pressure better. Northern blot analysis of ET-1 mRNA revealed upregulation of ET-1 gene in the diabetic kidney. Similar results were obtained by in situ hybridization in glomeruli and tubuli of diabetic rats. Both treatments remarkably attenuated exaggerated renal ET-1 gene expression. These data suggest that ET-1 is a contributory mediator of kidney damage in diabetes and indicate that ET receptor antagonists may represent a new therapeutic mean for treatment of progressive diabetic nephropathy.