Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.     

Modulation of different human immunodeficiency virus type 1 Nef functions during progression to AIDS

The human immunodeficiency virus type 1 (HIV-1) Nef protein has several independent functions that might contribute to efficient viral replication in vivo. Since HIV-1 adapts rapidly to its host environment, we investigated if different Nef properties are associated with disease progression. Functional analysis revealed that nef alleles obtained during late stages of infection did not efficiently downmodulate class I major histocompatibility complex but were highly active in the stimulation of viral replication. In comparison, functional activity in downregulation of CD4 and enhancement of HIV-1 infectivity were maintained or enhanced after AIDS progression. Our results demonstrate that various Nef activities are modulated during the course of HIV-1 infection to maintain high viral loads at different stages of disease progression. These findings suggest that all in vitro Nef functions investigated contribute to AIDS pathogenesis and indicate that nef variants with increased pathogenicity emerge in a significant number of HIV-1-infected individuals.     

Inappropriate use of clinical practices in Canada: a systematic review

Background:Inappropriate health care leads to negative patient experiences, poor health outcomes and inefficient use of resources. We aimed to conduct a systematic review of inappropriately used clinical practices in Canada.Methods:We searched multiple bibliometric databases and grey literature to identify inappropriately used clinical practices in Canada between 2007 and 2021. Two team members independently screened citations, extracted data and assessed methodological quality. Findings were synthesized in 2 categories: diagnostics and therapeutics. We reported ranges of proportions of inappropriate use for all practices. Medians and interquartile ranges (IQRs), based on the percentage of patients not receiving recommended practices (underuse) or receiving practices not recommended (overuse), were calculated. All statistics are at the study summary level.Results:We included 174 studies, representing 228 clinical practices and 28 900 762 patients. The median proportion of inappropriate care, as assessed in the studies, was 30.0% (IQR 12.0%–56.6%). Underuse (median 43.9%, IQR 23.8%–66.3%) was more frequent than overuse (median 13.6%, IQR 3.2%–30.7%). The most frequently investigated diagnostics were glycated hemoglobin (underused, range 18.0%–85.7%, n = 9) and thyroid-stimulating hormone (overused, range 3.0%–35.1%, n = 5). The most frequently investigated therapeutics were statin medications (underused, range 18.5%–71.0%, n = 6) and potentially inappropriate medications (overused, range 13.5%–97.3%, n = 9).Interpretation:We have provided a summary of inappropriately used clinical practices in Canadian health care systems. Our findings can be used to support health care professionals and quality agencies to improve patient care and safety in Canada.

As health care systems struggle with sustainability, there is increased recognition that a substantial percentage of the health care received is inappropriate.¹ Inappropriate health care occurs when effective clinical practices are underused, ineffective clinical practices are overused or other practices are misused. It can lead to negative patient experiences,² poor health outcomes^3,4 and inefficient use of scarce health care resources.⁵ In response, there is widespread professional and policy interest in reducing inappropriate health care in Canada and abroad. For example, in 2014, Choosing Wisely Canada,⁶ a physician-led campaign in partnership with the Canadian Medical Association, was established. This initiative encourages conversations between clinicians and patients about low-value or overused care in efforts to reduce inappropriate care. Choosing Wisely Canada is endorsed across Canada by all provincial and territorial medical associations (https://choosingwiselycanada.org/about/).Although reducing inappropriate health care is a high priority for health care professionals, agencies and governments in Canada, designing effective initiatives for quality improvement has been a difficult goal to achieve without knowledge of which clinical practices are inappropriately used. This is further challenged because Canada does not have a mandatory and comprehensive national tracking system for quality. The Canadian Institute for Health Information (CIHI) houses multiple Canadian health databases, but it does not collect information on all clinical practices. Therefore, a systematic synthesis is necessary to provide an overview of inappropriate health care in Canada.⁷ Summaries of inappropriately used clinical practices exist for several countries: United States,^8,9 United Kingdom¹⁰ and Australia.¹¹ Each of these syntheses found high levels (50% on average) of inappropriately used practices and laid the foundation for several quality improvement initiatives in these countries. We aimed to conduct a systematic review to estimate the nature and amount of inappropriately used clinical practices in Canada.     

Calcium Ion Impedes Translation Initiation at the Synapse

Abstract: Stimulation of synaptoneurosome suspensions by the neurotransmitter glutamate gives rise to rapid loading of ribosomes onto mRNA and increased incorporation of amino acids into trichloroacetic acid-precipitable polypeptides. Metabotropic glutamate receptors (mGluRs) are responsible for this effect. Although simultaneous Ca²⁺ entry and mGluR stimulation do not change the response, entry of Ca²⁺ 30 s or 3 min before mGluR stimulation markedly depresses the polyribosomal loading. Either NMDA or ionophore (A23187) produces the depression. A calmodulin antagonist, W7, alleviates the effect, suggesting that inactivation of phospholipase A₂ by calcium-calmodulin-dependent kinase II is partially responsible for the phenomenon. Thus, interaction between different classes of glutamate receptors affects the control of protein translation at the synapse. This effect may partially explain recent observations of negative interactions between receptor classes in induction of long-term potentiation.     

Disposable syringes for insulin injection.

Results of a questionnaire on use of glass syringes among diabetic patients showed considerable variation in methods of keeping the syringes and in the duration of their useful life. Thirty patients took part in an investigation in which each patient used the same disposable syringe in place of the glass syringe for up to two months. No clinical or bacteriological evidence of infection was found. Used in this way, disposable syringes were less expensive than glass syringes. They are lighter than glass syringes, less susceptible to damage, and more easily carried on journeys.     

3D cell nuclei segmentation based on gradient flow tracking

Background  

Reliable segmentation of cell nuclei from three dimensional (3D) microscopic images is an important task in many biological studies. We present a novel, fully automated method for the segmentation of cell nuclei from 3D microscopic images. It was designed specifically to segment nuclei in images where the nuclei are closely juxtaposed or touching each other. The segmentation approach has three stages: 1) a gradient diffusion procedure, 2) gradient flow tracking and grouping, and 3) local adaptive thresholding.     

Context based mixture model for cell phase identification in automated fluorescence microscopy

Background  

Automated identification of cell cycle phases of individual live cells in a large population captured via automated fluorescence microscopy technique is important for cancer drug discovery and cell cycle studies. Time-lapse fluorescence microscopy images provide an important method to study the cell cycle process under different conditions of perturbation. Existing methods are limited in dealing with such time-lapse data sets while manual analysis is not feasible. This paper presents statistical data analysis and statistical pattern recognition to perform this task.     

Bioluminescence imaging reveals inhibition of tumor cell proliferation by Alzheimer's amyloid β protein

Background  

Cancer and Alzheimer's disease (AD) are two seemingly distinct diseases and rarely occur simultaneously in patients. To explore molecular determinants differentiating pathogenic routes towards AD or cancer, we investigate the role of amyloid β protein (Aβ) on multiple tumor cell lines that are stably expressing luciferase (human glioblastoma U87; human breast adenocarcinoma MDA-MB231; and mouse melanoma B16F).