New lane in the information highway: alternative reading frame peptides elicit T cells with potent antiretrovirus activity

CD8+ T cells rapidly recognize virus-infected cells due to the generation of antigenic peptides from defective ribosomal products (DRiPs) that are encoded by standard open reading frames (ORFs). New data now show that alternative reading frame (ARF) DRiPs can also induce robust CD8+ T cell responses. ARF-specific T cells control retroviral replication and select for viral escape in monkeys, providing the most compelling evidence to date for the biological relevance of ARF immunosurveillance

Administrators' perspectives on ethical issues in long-term care research

ETHICAL ISSUES ARE A SIGNIFICANT potential barrier to much-needed research in long-term care settings. LTC stakeholder perspectives are largely absent from the development of regulation and guidelines. Fifteen long-term care administrators were interviewed as part of a study of ethical issues in community-based, long-term care research. Established qualitative procedures for conducting content analysis were used to organize the data. Findings suggest that existing mechanisms to protect human subjects do not take into account important differences between academic and long-term care settings. The full potential of LTC research will not be realized until supportive processes to enhance human subjects protections are developed in a way that is reflective of the LTC environment

Does Liver Transplantation in the Rat Cause a Regenerative Response

This study was conducted to determine the pattern of early regenerative response to orthotopic intact liver transplantation in the rat and to investigate whether the response differed in grafts with or without revascularisation of the arterial bed

Socioeconomic Deprivation and Cardiometabolic Risk Factors in Individuals with Type 1 Diabetes: T1D Exchange Clinic Registry

Aims: Social determinants of health (SDOH) influence cardiovascular health in the general population; however, the degree to which this occurs in individuals with type 1 diabetes (T1D) is not well understood. We evaluated associations among socioeconomic deprivation and cardiometabolic risk factors (hemoglobin A1c, low-density lipoprotein, blood pressure, body mass index, physical activity) in individuals with T1D from the T1D Clinic Exchange Registry. Methods: We evaluated the association between the social deprivation index (SDI) and cardiometabolic risk factors using multivariable and logistic regression among 18,754 participants ages 13 – 90 years (mean 29.2 ± 17) in the T1D Exchange clinic registry from 6,320 zip code tabulation areas (2007–2017). Results: SDI was associated with multiple cardiometabolic risk factors even after adjusting for covariates (age, biological sex, T1D duration, and race/ethnicity) in the multivariable linear regression models. Those in the highest socially deprived areas had 1.69 (unadjusted) and 1.78 (adjusted) times odds of a triple concomitant risk burden of poor glycemia, dyslipidemia, and hypertension. Conclusions: Persistent SDOH differences could account for a substantial degree of poor achievement of cardiometabolic targets in individuals with T1D. Our results suggest the need for a broader framework to understand the association between T1D and adverse cardiometabolic outcomes

Exploratory trial of a school-based alcohol prevention intervention with a family component: Implications for implementation

Purpose – Involvement of parents/carers may increase effectiveness of primary school-based alcohol-misuse prevention projects through strengthening family-based protective factors, but rates of parental engagement are typically low. This paper reports findings from an exploratory trial of a school-based prevention intervention – Kids, Adults Together (KAT), based on the Social Development Model, which aimed to promote pro-social family communication in order to prevent alcohol misuse, and incorporated strategies to engage parents/carers. The purpose of this paper is to assess the feasibility and value of conducting an effectiveness trial of KAT. Design/methodology/approach – The study was a parallel-group cluster randomised exploratory trial with an embedded process evaluation. The study took place in south Wales, UK, and involved nine primary schools, 367 pupils in Years 5/6 (aged 9-11 years) and their parents/carers and teachers. Questionnaires were completed by pupils at baseline and four month follow-up, and by parents at six month follow-up. Findings – Overall KAT was delivered with good fidelity, but two of five intervention schools withdrew from the study without completing implementation. In total, 50 per cent of eligible parents participated in the intervention, and KAT had good acceptability among pupils, parents and teachers. However, a number of “progression to effectiveness trial” criteria were not met. Intermediate outcomes on family communication (hypothesised to prevent alcohol misuse) showed insufficient evidence of an intervention effect. Difficulties were encountered in identifying age appropriate outcome measures for primary school-age children, particularly in relation to family communication processes. The study was unable to find comprehensive methodological guidance on exploratory trials. Research limitations/implications – It would not be appropriate to conduct an effectiveness trial as key progression criteria relating to intervention and trial feasibility were not met. There is a need for new measures of family communication which are suitable for primary school-age children, and more guidance on the design and conduct of exploratory/feasibility trials. Originality/value – KAT achieved high rates of parental involvement, and its theoretical framework and processes could be adapted by other interventions which experience difficulties with recruitment of parents/carers

Poxviruses and paramyxoviruses use a conserved mechanism of STAT1 antagonism to inhibit interferon signaling.

The induction of interferon (IFN)-stimulated genes by STATs is a critical host defense mechanism against virus infection. Here, we report that a highly expressed poxvirus protein, 018, inhibits IFN-induced signaling by binding to the SH2 domain of STAT1, thereby preventing the association of STAT1 with an activated IFN receptor. Despite encoding other inhibitors of IFN-induced signaling, a poxvirus mutant lacking 018 was attenuated in mice. The 2.0 Å crystal structure of the 018:STAT1 complex reveals a phosphotyrosine-independent mode of 018 binding to the SH2 domain of STAT1. Moreover, the STAT1-binding motif of 018 shows similarity to the STAT1-binding proteins from Nipah virus, which, similar to 018, block the association of STAT1 with an IFN receptor. Overall, these results uncover a conserved mechanism of STAT1 antagonism that is employed independently by distinct virus families

The impact of opiate substitution treatment on mortality risk in drug addicts: a natural experiment study

Background Opiate substitution treatment (OST) is the main treatment for people addicted to heroin and other opioid drugs. However, there is limited information on how the delivery of this treatment affects mortality risk.Objectives To investigate the associations of mortality risk with periods during treatment and following cessation of treatment, medication type, co-prescription of other medication and dosing regimens during titration and detoxification. The trends with time of prescribed medication, dose and treatment duration were also explored.Design Prospective longitudinal observational study.Setting UK primary care between 1998 and 2014.Participants A total of 12,780 patients receiving methadone, buprenorphine or dihydrocodeine.Main outcome measures All-cause mortality relating to 657 deaths and drug-related poisoning relating to 113 deaths.Data sources Clinical Practice Research Datalink with linked information on cause of death from the Office for National Statistics.Results For both outcomes, the lowest mortality risk was observed after 4 weeks of treatment and the highest risk was observed in the first 4 weeks following cessation of treatment [e.g. for drug-related poisoning, incidence rate ratio (IRR) 8.15, 95% confidence interval (CI) 5.45 to 12.19]. There was evidence that the treatment period risks varied with OST medication. The largest difference in risk was for the first 4 weeks of treatment for both outcomes, with patients on buprenorphine being at lower risk than those on methadone (e.g. for drug-related poisoning, IRR 0.08, 95% CI 0.01 to 0.48). The co-prescription of benzodiazepines was associated with linearly increasing the risk of drug-related deaths by dose (IRR 2.02, 95% CI 1.66 to 2.47), whereas z-drugs (zolpidem, zopiclone and zaleplon) were associated with increased risk of both all-cause (IRR 1.83, 95% CI 1.59 to 2.12) and drug-related (IRR 3.31, 95% CI 2.45 to 4.47) mortality. There was weak evidence that higher initial and final doses were associated with increased all-cause mortality risk. In the first 4 weeks of treatment, the risk increased by 4% for each 5-mg increment in methadone dose (1-mg increase in buprenorphine) (hazard ratio 1.04, 95% CI 1.00 to 1.09). In the first 4 weeks after treatment ceased, a similar increment in final dose increased the risk by 3% (hazard ratio 1.03, 95% CI 0.99 to 1.07). There were too few deaths to evaluate the effects on drug-related poisoning. The proportion of OST patients receiving buprenorphine increased between 1998 and 2006. Median treatment duration was consistently shorter for buprenorphine than for methadone for each year studied (overall median duration of 48 and 106 days, respectively).Limitations As this was an observational study, the possibility remains of bias from unmeasured factors, which covariate adjustment and inverse probability weighting can eliminate only partially.Conclusions Using buprenorphine as an alternative to methadone may not reduce mortality overall despite resulting in lower IRRs from shorter treatment duration. Clinical guidance needs to consider strengthening warnings about the co-prescription of a range of drugs for OST patients.Future work Our analyses need to be replicated using other clinical data sets in the UK and in other countries. New interventions and trials are required to investigate improving the retention of OST patients in primary care.Funding The National Institute for Health Research Health Services and Delivery Research programme

Evolution of MPCV Service Module Propulsion and GNC Interface Requirements

The Orion Multi-Purpose Crew Vehicle Service Module Propulsion Subsystem provides propulsion for the integrated Crew and Service Module. Updates in the exploration architecture between Constellation and MPCV as well as NASA's partnership with the European Space Agency have resulted in design changes to the SM Propulsion Subsystem and updates to the Propulsion interface requirements with Guidance Navigation and Control. This paper focuses on the Propulsion and GNC interface requirement updates between the Constellation Service Module and the European Service Module and how the requirement updates were driven or supported by architecture updates and the desired use of hardware with heritage to United States and European spacecraft for the Exploration Missions, EM-1 and EM-2

Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift

Refer to Web version on PubMed Central for supplementary material.Rapid antigenic evolution in the influenza A virus hemagglutinin precludes effective vaccination with existing vaccines. To understand this phenomenon, we passaged virus in mice immunized with influenza vaccine. Neutralizing antibodies selected mutants with single–amino acid hemagglutinin substitutions that increased virus binding to cell surface glycan receptors. Passaging these high-avidity binding mutants in naïve mice, but not immune mice, selected for additional hemagglutinin substitutions that decreased cellular receptor binding avidity. Analyzing a panel of monoclonal antibody hemagglutinin escape mutants revealed a positive correlation between receptor binding avidity and escape from polyclonal antibodies. We propose that in response to variation in neutralizing antibody pressure between individuals, influenza A virus evolves by adjusting receptor binding avidity via amino acid substitutions throughout the hemagglutinin globular domain, many of which simultaneously alter antigenicity.National Institute of Mental Health (U.S.). Division of Intramural ResearchNational Institute of Allergy and Infectious Diseases (U.S.)Singapore-MIT Alliance for Research and TechnologyNational Institute of General Medical Sciences (U.S.) (GM 57073)National Institute of General Medical Sciences (U.S.) (U54GM62116