Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system (CNS). Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 10⁵ plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed on day 3 and declined on days 5 and 6 after infection. By contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals on days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.     

An efficient and environmentally sustainable domino protocol for the synthesis of structurally diverse spiroannulated pyrimidophenazines using erbium doped TiO2 nanoparticles as a recyclable and reusable heterogeneous acid catalyst

An efficient and environmentally sustainable domino protocol has been presented for the synthesis of structurally diverse spiroannulated pyrimidophenazines involving a four component reaction of 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, cyclic ketones and amino derivatives in the presence of erbium doped TiO₂ nanoparticles as a recyclable and reusable heterogeneous acid catalyst. The present synthetic protocol features mild reaction conditions with operational simplicity, excellent yield with high purity, short reaction time and high atom economy with the use of a recoverable and reusable environmentally sustainable heterogeneous catalyst.

An efficient and environmentally sustainable domino protocol has been presented for the synthesis of structurally diverse spiroannulated pyrimidophenazines using erbium doped TiO₂ nanoparticles as a recyclable and reusable heterogeneous acid catalyst.     

Clinical safety profile of ticagrelor compared to clopidogrel in 1208 patients: Real world evidence

Introduction

Dual antiplatelet treatment is recommended by current clinical practice guidelines for patients undergoing PCI. The PLATO trial showed superiority of ticagrelor to clopidogrel in reducing the rate of death from vascular causes, myocardial infarction and stroke without increase in the rate of overall major bleeding in ACS patients. However, real world evidence in Indian patients is limited. The objective of this study is to compare safety profile of ticagrelor with clopidogrel in real world settings.

Improved Post-Transplant Survival in the United States for Patients with Cholangiocarcinoma After 2000

Background

The incidence of cholangiocarcinoma (CCA) continues to rise. Orthotopic liver transplantation (OLT) can be used for selected patients with localized but unresectable hilar CCA. Although initial post-OLT survival rates were poor, outcomes after introduction of the Mayo Clinic protocol have been more promising and there has been increased interest in OLT for CCA nationally.

Aims

The aim of this study is to determine post-transplant survival and prognostic factors for patients undergoing OLT for CCA.

Methods

A retrospective analysis of all patients with CCA listed nationwide for OLT between October 1987 and May 2008 was performed using the Scientific Registry of Transplant Recipients database. Survival curves were generated using the Kaplan–Meier method and compared using log-rank test.

Results

Of 595 patients with CCA listed for OLT, 359 (60.3 %) underwent OLT. Median age at OLT was 49 years, 66 % were male and 91 % were Caucasian. The median follow-up time was 2 years. There has been an increasing number of liver transplants performed for CCA since 2000. The 1- and 5-year probability of survival was 85.8 and 51.4 %, respectively. On multivariate analysis, significant prognostic factors for decreased post-OLT survival included transplant before 2000 (HR 11.25, 95 % CI 1.28–98.7) and acute cellular rejection (HR 5.64, 95 % CI 1.14–27.8).

Conclusions

Survival after transplant for CCA has improved over time, and OLT is being used more frequently in the treatment of CCA. Significant predictors of post-OLT survival include a history of acute rejection and date of transplant in relation to the publication of Mayo protocol results.     

Mandatory reporting of child physical abuse and dental neglect by Australian dentists

Child protection measures are organized into three major themes: laws; service programs; and status of outcomes of these interventions. Contextually, mandatory reporting of child abuse and neglect is governed by a complex system of State legislation across Australia. The purpose of this review was to investigate the evidence base for the legislative obligations of Australian dentists as mandatory reporters; the functionality of dental practice in the determination of orofacial signs of abuse and neglect; and, relevant knowledge and practice demonstrated by the Australian dental work force. Our research question explores the role of Australian dentists in intervention of child physical abuse and dental neglect. Information was sourced from literature and web-based reviews. Peer reviewed articles included reviews and empirical studies. Official websites/databases were accessed for relevant legislation. The study found that child protection laws lack an evidence base for including/excluding dentists as reporters. Child abuse and neglect is associated with strong orofacial signs, thus imparting a key advantage to utilizing dentists as potential notifiers. An action response to child abuse is not seen in the Australian dental service. This review identifies gaps in the dental literature concerning mandatory reporting, calls for optimization of the related evidence base, and uniform Australian child abuse reporting requirements.

     

A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease

Background

Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).

Methods and results

We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.

Conclusions

In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.     

Instituting a Sugar-Sweetened Beverage Ban: Experience From a Children’s Hospital

Sugar-sweetened beverage (SSB) consumption is linked to increased weight and obesity in children and remains the major source of added sugar in the typical US diet across all age groups. In an effort to improve the nutritional offerings for patients and employees within our institution, Nationwide Children’s Hospital in Columbus, Ohio, implemented an SSB ban in 2011 in all food establishments within the hospital. In this report, we describe how the ban was implemented. We found that an institutional SSB ban altered beverage sales without revenue loss at nonvending food locations. From a process perspective, we found that successful implementation requires excellent communication and bold leadership at several levels throughout the hospital environment.Sugar-sweetened beverage (SSB) consumption is linked to increased weight and obesity in children and remains the major source of added sugar in the typical US diet across all age groups.1 For the purposes of this report, we define SSBs as soft drinks (soda or pop), fruit drinks, sports drinks, energy drinks, and any other beverages to which sugar, typically high fructose corn syrup or sucrose (table sugar), has been added.2 Although recent studies indicate an overall trending down of SSB intake, higher rates of consumption occur among low-income and minority children.1In 2010 the Ohio legislature passed the Healthy Choices for Healthy Children Act to help schools play an active role in decreasing the high childhood obesity rates.3 A component of this law includes an SSB ban in schools. In an effort to recognize the importance of and support this statewide initiative, Nationwide Children’s Hospital (NCH) partnered with leaders in the business community to gain bipartisan support for this legislation. To further emphasize support, NCH decided to lead by example and expand the hospital’s already existing Wellness Initiative to improve the nutritional offerings for patients and employees through implementation of an SSB ban in all food establishments within the hospital and approved catering companies. Such a ban would not only impact the food environment for children but also their families as well as hospital staff. In this report, we describe our implementation of an organizational SSB ban and report the beverage consumption and sales revenue for the years preceding and following the ban, as well as key steps to implementation.     

Development and preclinical testing of HNVAC,a cell culture-based H1N1 pandemic influenza vaccine from India

Several limitations of the use of embryonated eggs and the threat of pandemics have highlighted the need for other platforms for the production of influenza vaccines. We report the indigenous development and pre-clinical testing of an MDCK-based H1N1 pandemic influenza vaccine HNVAC from India. The cell bank and virus seed were characterized extensively. The cells were characterized by PCR, electron microscopy, and karyotyping, and found to be of female canine epithelial origin. The virus was confirmed by neutralization, haemagglutination inhibition, neuraminidase inhibition, and PCR and nucleotide sequencing. Adventitious agent testing was performed by both in vitro and in vivo studies. The in vitro studies included culturing, haemadsorption, haemagglutination, PCR and RT-PCR, whereas in vivo studies included passage in embryonated eggs and in laboratory animals. Both cell bank and virus seed were free of adventitious agents. MDCK cell lysates as well as cellular DNA did not produce tumours in newborn or adult laboratory animals. The bioprocess parameters were standardized to recover antigen with minimal levels of process-related impurities. The vaccine bulk was tested for the presence of specific antigen, and quantified by single radial immunodiffusion. Finally, non-adjuvanted and aluminium hydroxide adjuvanted vaccine formulations were found to be safe in preclinical toxicity studies in mice, rats, guinea pigs and rabbits, and immunogenic in mice and rabbits. This is the first and only cell culture-based influenza vaccine platform developed in any developing country.