Endogenous human cytomegalovirus gB is efficiently presented by MHC class II molecules to CD4+ CTL

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB--expressed by adenovirus vectors or after HCMV infection--and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells

Consenting to health record linkage: evidence from a multi-purpose longitudinal survey of a general population

Background: The British Household Panel Survey (BHPS) is the first long-running UK longitudinal survey with a non-medical focus and a sample covering the whole age range to have asked for permission to link to a range of administrative health records. This study determines whether informed consent led to selection bias and reflects on the value of the BHPS linked with health records for epidemiological research. Methods. Multivariate logistical regression is used, with whether the respondent gave consent to data linkage or not as the dependent variable. Independent variables were entered as four blocks; (i) a set of standard demographics likely to be found in most health registration data, (ii) a broader set of socio-economic characteristics, (iii) a set of indicators of health conditions and (iv) information about the use of health services. Results: Participants aged 16-24, males and those living in England were more likely to consent. Consent is not biased with respect to socio-economic characteristics or health. Recent users of GP services are underrepresented among consenters. Conclusions: Whilst data could only be linked for a minority of BHPS participants, the BHPS offers a great range of information on people's life histories, their attitudes and behaviours making it an invaluable source for epidemiological research. © 2012 Knies et al; licensee BioMed Central Ltd

The value of source data verification in a cancer clinical trial

Background Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial. Methods Data discrepancies and comparative treatment effects obtained following 100% SDV were compared to those based on data without SDV. Overall survival (OS) and Progression-free survival (PFS) were compared using Kaplan-Meier curves, log-rank tests and Cox models. Tumour response classifications and comparative treatment Odds Ratios (ORs) for the outcome objective response rate, and number of Serious Adverse Events (SAEs) were compared. OS estimates based on SDV data were compared against estimates obtained from centrally monitored data. Findings Data discrepancies were identified between different monitoring procedures for the majority of variables examined, with some variation in discrepancy rates. There were no systematic patterns to discrepancies and their impact was negligible on OS, the primary outcome of the trial (HR (95% CI): 1.18(0.99 to 1.41), p = 0.064 with 100% SDV; 1.18(0.99 to 1.42), p = 0.068 without SDV; 1.18(0.99 to 1.40), p = 0.073 with central monitoring). Results were similar for PFS. More extreme discrepancies were found for the subjective outcome overall objective response (OR (95% CI): 1.67(1.04 to 2.68), p = 0.03 with 100% SDV; 2.45(1.49 to 4.04), p = 0.0003 without any SDV) which was mostly due to differing CT scans. Interpretation Quality assurance methods used in clinical trials should be informed by empirical evidence. In this empirical comparison, SDV was expensive and identified random errors that made little impact on results and clinical conclusions of the trial. Central monitoring using an external data source was a more efficient approach for the primary outcome of OS. For the subjective outcome objective response, an independent blinded review committee and tracking system to monitor missing scan data could be more efficient than SDV

Can oral infection be a risk factor for Alzheimer’s disease?

Alzheimer’s disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (Herpes simplex type I) and yeasts (Candida species). A causal relationship between periodontal pathogens/non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteraemias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible aetiology of late onset AD (LOAD)

Project assessment: an international perspective

Project Assessment is an American Psychological Association (APA, 2018) initiative aimed at facilitating assessment of the five comprehensive learning goals of the APA guidelines for the undergraduate psychology major (2013). We believe that Project Assessment holds great promise for both U.S. and international use; moreover, we suggest that Project Assessment can benefit from consideration of international assessment initiatives, particularly those aimed at increasing mobility in our interconnected world. Internationally, particularly in Europe where all but one country adheres to the Bologna Process and many countries adhere to the related EuroPsy guidelines, assessment of psychology higher education is driven by a broader range of stakeholders than is typically considered in the United States. Indeed, Bologna countries explicitly consider input from external stakeholders such as employers when developing curricula and assessing outcomes, and they prioritize the assessment of skills at least as much as knowledge. In this paper, we outline the Bologna Process, EuroPsy, and similar collaborative agreements in other world regions. We highlight what the United States can learn from these projects, particularly the involvement of a broader range of stakeholders and an emphasis on mobility of degrees and graduates. While doing so, we explore evidence on internationally implemented assessment practices and on the extent to which harmonized curricula and assessment practices have increased mobility. As many world regions pursue Bologna-like structures, often with funding from the European Union, we believe that it is essential that those pursuing U.S. initiatives like Project Assessment actively join the global conversation about higher education in psychology. (PsycInfo Database Record (c) 2021 APA, all rights reserved

Evolution of protease inhibitor resistance in HIV-1-infected patients failing protease inhibitor monotherapy as second-line therapy in low-income countries: an observational analysis within the EARNEST randomised trial

BACKGROUND: Limited viral load (VL) testing in HIV-infected individuals on treatment in low-income countries often results in late detection of treatment failure. The impact of remaining on failing second-line, protease inhibitor (PI) containing regimens is unclear. METHODS: We retrospectively tested VL from 2,164 stored plasma samples from 386 patients randomised to receive PI-monotherapy (ritonavir-boosted lopinavir, after initial PI+raltegravir induction) in the EARNEST trial. Protease genotypic resistance testing was performed in samples with VL>1000 copies/ml. We assessed evolution of drug resistance mutations from virological failure (confirmed VL>1000 copies/ml) until discontinuation of PI-monotherapy and examined associations using Poisson and linear mixed-effects models. RESULTS: 118 patients had a median 68(IQR 48-88) weeks on PI-monotherapy post-failure. At failure, 21/107(20%) had intermediate/high resistance to lopinavir. 40-48 weeks post-failure, 49/72(68%) and 36/71(51%) had intermediate/high-level resistance to lopinavir and atazanavir. Most remained susceptible to darunavir (12/72[17%] intermediate, no high resistance). Common PI mutations were M46I, I54V, and V82A. On average, 1.7(95% CI 1.5,2.0) PI mutations developed per year; this increased after the first mutation developed, but decreased with subsequent mutations (p<0.0001). Modest VL changes were mainly driven by non-adherence (p=0.006) and PI mutation development. I47A was associated with a larger increase in log₁₀ VL(+0.53[+0.18,+0.87], p=0.003) than other PI mutations (+0.15[+0.07,+0.23] p<0.001; heterogeneity p=0.05). CONCLUSION: Most develop intermediate/high-level lopinavir resistance within one year when lopinavir/ritonavir is exposed to sustained VL replication without protection from other drugs. Even in this extreme situation, annual VL testing (current WHO recommendation) would identify failure when most would still benefit from switching to darunavir

Sibling interaction as a facilitator for talent development in sport

While current research has begun to address parental influences on talent development in sport, sibling interaction remains relatively under-examined. Therefore, this study aimed to explore the underpinning mechanisms through which sibling interaction impacts on talent development. Retrospective phenomenological interviews were conducted with four sets of siblings (N = 9), where at least one sibling had competed to an elite level. Findings revealed several higher-order themes that impacted positively on the talented athletes’ development: regularity of interaction in sport, emotional interpersonal skills, rivalry, resilience, co-operation and separation. Separation appeared as the athlete reached elite status, suggesting that these former mechanisms primarily impact during the development phase. Such findings support and extend the sibling, elite sport and talent development literature and provide valuable insight for both practitioners and academics. Importantly, coaches should consider a sibling’s role as an important mechanism outside of the formal coaching structure for talent development

A comparison of the development of audiovisual integration in children with autism spectrum disorders and typically developing children

This study aimed to investigate the development of audiovisual integration in children with Autism Spectrum Disorder (ASD). Audiovisual integration was measured using the McGurk effect in children with ASD aged 7–16 years and typically developing children (control group) matched approximately for age, sex, nonverbal ability and verbal ability. Results showed that the children with ASD were delayed in visual accuracy and audiovisual integration compared to the control group. However, in the audiovisual integration measure, children with ASD appeared to ‘catch-up’ with their typically developing peers at the older age ranges. The suggestion that children with ASD show a deficit in audiovisual integration which diminishes with age has clinical implications for those assessing and treating these children

Comparative run-time performance of evolutionary algorithms on multi-objective interpolated continuous optimisation problems.

We propose a new class of multi-objective benchmark problems on which we analyse the performance of four well established multi-objective evolutionary algorithms (MOEAs) – each implementing a different search paradigm – by comparing run-time convergence behaviour over a set of 1200 problem instances. The new benchmarks are created by fusing previously proposed single-objective interpolated continuous optimisation problems (ICOPs) via a common set of Pareto non-dominated seeds. They thus inherit the ICOP property of having tunable fitness landscape features. The benchmarks are of intrinsic interest as they derive from interpolation methods and so can approximate general problem instances. This property is revealed to be of particular importance as our extensive set of numerical experiments indicates that choices pertaining to (i) the weighting of the inverse distance interpolation function and (ii) the problem dimension can be used to construct problems that are challenging to all tested multi-objective search paradigms. This in turn means that the new multi-objective ICOPs problems (MO-ICOPs) can be used to construct well-balanced benchmark sets that discriminate well between the run-time convergence behaviour of different solvers