Animal models for SARS-CoV-2 and SARS-CoV-1 pathogenesis,transmission and therapeutic evaluation

There is a critical need to develop animal models to alleviate vaccine and drug development difficulties against zoonotic viral infections. The coronavirus family, which includes severe acute respiratory syndrome coronavirus 1 and severe acute respiratory syndrome coronavirus 2, crossed the species barrier and infected humans, causing a global outbreak in the 21^st century. Because humans do not have pre-existing immunity against these viral infections and with ethics governing clinical trials, animal models are therefore being used in clinical studies to facilitate drug discovery and testing efficacy of vaccines. The ideal animal models should reflect the viral replication, clinical signs, and pathological responses observed in humans. Different animal species should be tested to establish an appropriate animal model to study the disease pathology, transmission and evaluation of novel vaccine and drug candidates to treat coronavirus disease 2019. In this context, the present review summarizes the recent progress in developing animal models for these two pathogenic viruses and highlights the utility of these models in studying SARS-associated coronavirus diseases.     

Malignant mediastinal chemodectoma.

A 20-year-old man with a posterior mediastinal mass and erosion of the rib proved to have a malignant chemodectoma. The case is of interest because of the rare location and malignant fatal course.     

Assessing the impact of attrition in randomized controlled trials

ObjectivesA survey of randomized controlled trials found that almost a quarter of trials had more than 10% of responses missing for the primary outcome. There are a number of ways in which data could be missing: the subject is unable to provide it, or they withdraw, or become lost to follow-up. Such attrition means that balance in baseline characteristics for those randomized may not be maintained in the subsample who has outcome data. For individual trials, if the attrition is systematic and linked to outcome, then this will result in biased estimates of the overall effect. It then follows that if such trials are combined in a meta-analysis, it will result in a biased estimate of the overall effect and be misleading. The aim of this study was to investigate the impact of attrition on baseline imbalance within individual trials and across multiple trials.Study Design and SettingIn this article, we used individual patient data from a convenience sample of 10 trials evaluating interventions for the treatment of musculoskeletal disorders. Meta-analyses using the mean difference at baseline between the trial arms were carried out using individual patient data from these trials. The analyses were first carried out using all randomized participants and secondly only including participants with outcome data on the quality-of-life score. Meta-regression was carried out to evaluate whether the level of baseline imbalance was associated with the level of attrition.ResultsThe overall attrition rates for the quality-of-life score ranged between 4% and 28% of the total randomized patients. All trials showed some level of differential attrition between the treatment arms, ranging from 1% to 14%. Attrition within the control group ranged from 3% to 25% and within the intervention group, it ranged from 0% to 31%. For individual trials, there was no indication that attrition altered the results in favor of either the treatment or the control. Forest plots highlighted that the attrition had some impact on the baseline imbalance for the primary outcome score as more heterogeneity was introduced (I-squared value of 0.4% for the initial data set vs. I-squared value of 16.9% for the analyzed data set). However, the standardized mean difference increased only slightly (from 0.01 to 0.03 with 95% confidence interval [CI]: ?0.05, 0.10). Meta-regression showed little or no evidence of a significant dose–response relationship between the level of attrition and the baseline imbalance (coefficient 0.73, 95% CI: ?0.81, 2.28).ConclusionAlthough, in theory, attrition can introduce selection bias in randomized trials, we did not find sufficient evidence to support this claim in our convenience sample of trials. However, the number of trials included was relatively small, which may have led to small but important differences in outcomes being missed. In addition, only 2 of 10 trials included had attrition levels greater than 15% suggesting a low level of potential bias. Meta-analyses and systematic reviews should always consider the impact of attrition on baseline imbalances and where possible any baseline imbalances in the analyzed data set and their impact on the outcomes reported.     

Deceased donor liver transplant: Experience from a public sector hospital in India

Background

Deceased donor liver transplant (DDLT) is an uncommon procedure in India. We present our experience of DDLT from a public sector teaching hospital.

Methods

A retrospective analysis of all DDLT was performed from April 2012 till September 2016. Demographics, intraoperative, donor factors, morbidity, and outcome were analyzed.

Results

During the study period, 305 liver transplants were performed, of which 36 were DDLT (adult 32, pediatric 4; 35 grafts; 1 split). The median age was 42.5 (1–62) years; 78% were men. The median donor age was 28 (1–77) years; 72.2% were men. About 45% of organs were procured from outside of Delhi and 67% of all grafts used were marginal. Three of 38 liver grafts (7.8%) were rejected due to gross steatosis. Commonest indication was cryptogenic cirrhosis (19.4%). The median model for end-stage liver disease sodium and pediatric end-stage liver disease scores were 23.5 (9–40) and 14.5 (9–22), respectively. Median warm and cold ischemia times were 40 (23–56) and 396 (111–750) min, respectively. Major morbidity of grade III and above occurred in 63.8%. In hospital (90 days), mortality was 16.7% and there were two late deaths because of chronic rejection and biliary sepsis. The overall survival was 77.8% at median follow up of 8.6 (1–54) months.

Conclusions

DDLT can be performed with increasing frequency and safety in a public sector hospital. The perioperative and long-term outcomes are acceptable despite the fact that most organs were extended criteria grafts.

     

Major Liver Resection for Large and Locally Advanced Hepatocellular Carcinoma

Optimal management of large and locally advanced hepatocellular carcinoma (HCC) remains a clinical challenge especially in patients with chronic liver disease (CLD). We present our experience of major liver resection for large and locally advanced HCC. Prospectively collected data of patients with large and locally advanced HCC who underwent major liver resection between March 2011 and May 2015. The outcome measures of interest were the characteristics of tumor, surgical outcome, and overall as well as disease-free survival. Eighteen patients (14 male) with median age of 59 years (20 to 73 years) with good performance status underwent resection. Fifteen patients were in Child Pugh class A and three in class B. On contrast-enhanced computed tomography (CECT) scan, four patients had lobar/segmental portal vein involvement, two patients had bilobar disease, and one had biliary obstruction. Seven patients underwent extended resection (>5 segments), five right hepatectomy, two modified right hepatectomy, one modified right hepatectomy with wedge resection of segment six, two left hepatectomy, and one left lateral sectionectomy. On histopathology, 12 were solitary and six were multiple, the median tumor diameter was 9 cm (5–18 cm). All 18 patients had R0 resection. Eight patients had cirrhosis, six had fibrosis, and four had chronic hepatitis. Vascular invasion was noticed in 12 and out of these, six had large-vessel embolization. Morbidity according to Clavien-Dindo class was grades 1–11, grades 2–5, grade 3B-1, and grades 5–1. After a median follow-up of 32 months (6–54 months), the overall survival at 1 and 3 years was 83 and 54 %, respectively. The disease-free survival at 1 and 3 years was 75 and 54 % respectively. In carefully selected patients with large and locally advanced HCC, acceptable perioperative and medium term outcomes can be achieved with major liver resection.