The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC ...inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency.
In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals.
Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells.
These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed.
Clinicaltrials.gov NCT01319383.
NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109.
Desirability of outcome ranking (DOOR) is an emerging approach to clinical trial outcome measurement using an ordinal scale to incorporate efficacy and safety endpoints.
We applied a previously ...validated DOOR endpoint to a cohort of CAMERA2 trial participants with methicillin-resistant
bacteremia (MRSAB). Participants were randomly assigned to standard therapy, or to standard therapy plus an antistaphylococcal β-lactam (combination therapy). Each participant was assigned a DOOR category, within which they were further ranked according to their hospital length of stay (LOS) and duration of intravenous antibiotic treatment. We calculated the probability and the generalized odds ratio of participants receiving combination therapy having worse outcomes than those receiving standard therapy.
Participants assigned combination therapy had a 54.5% (95% confidence interval CI, 48.9%-60.1%;
= .11) probability and a 1.2-fold odds (95% CI, .95-1.50;
= .12) of having a worse outcome than participants on standard therapy. When further ranked according to LOS and duration of antibiotic treatment, participants in the combination group had a 55.6% (95% CI, 49.5%-61.7%) and 55.3% (95% CI, 49.2%-61.4%) probability of having a worse outcome than participants in the standard treatment group, respectively.
When considering both efficacy and safety, treatment of MRSAB with a combination of standard therapy and a β-lactam likely results in a worse clinical outcome than standard therapy. However, a small benefit of combination therapy cannot be excluded. Most likely the toxicity of combination therapy outweighed any benefit from faster clearance of bacteremia.
Recent evidence links sedentary behaviour (or too much sitting) with poorer health outcomes; many adults accumulate the majority of their daily sitting time through occupational sitting and TV ...viewing. To further the development and targeting of evidence-based strategies there is a need for identification of the factors associated with higher levels of these behaviours. This study examined socio-demographic and health-related correlates of occupational sitting and of combined high levels of occupational sitting/TV viewing time amongst working adults.
Participants were attendees of the third wave (2011/12) of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study who worked full-time (≥35 h/week; n = 1,235; 38 % women; mean ± SD age 53 ± 7 years). Logistic and multinomial logistic regression analyses were conducted (separately for women and men) to assess cross-sectional associations of self-reported occupational sitting time (categorised as high/low based on the median) and also the combination of occupational sitting time/TV viewing time (high/low for each outcome), with a number of potential socio-demographic and health-related correlates.
Higher levels of occupational sitting (>6 h/day) were associated with higher household income for both genders. Lower levels of occupational sitting were associated with being older (women only); and, for men only, having a blue collar occupation, having a technical/vocational educational attainment, and undertaking more leisure-time physical activity (LTPA). Attributes associated with high levels of both occupational sitting and TV viewing time included white collar occupation (men only), lower levels of LTPA (both genders), higher BMI (men), and higher energy consumption (women).
Higher household income (both genders) and professional/managerial occupations (men only) were correlates of high occupational sitting time, relative to low occupational sitting time, while health-related factors (lower LTPA, higher BMI - men, and higher energy consumption - women) were associated with high levels of both occupational sitting and TV viewing time, relative to low occupational sitting and low TV viewing time. These findings suggest possible high-risk groups that may benefit from targeted interventions. Further research is needed on potentially modifiable environmental and social correlates of occupational sitting time, in order to inform workplace initiatives.
Activating mutations of the serine threonine kinase v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) are frequent in benign and malignant human tumors and are emerging as an important biomarker. ...Over 95% of BRAF mutations are of the V600E type and specific small molecular inhibitors are currently under pre-clinical or clinical investigation.
BRAF
mutation status is determined by DNA-based methods, most commonly by sequencing. Here we describe the development of a monoclonal BRAF V600E mutation-specific antibody that can differentiate BRAF V600E and wild type protein in routinely processed formalin-fixed and paraffin-embedded tissue. A total of 47 intracerebral melanoma metastases and 21 primary papillary thyroid carcinomas were evaluated by direct sequencing of
BRAF
and by immunohistochemistry using the BRAF V600E mutation-specific antibody clone VE1. Correlation of VE1 immunohistochemistry and BRAF sequencing revealed a perfect match for both papillary thyroid carcinomas and melanoma metastases. The staining intensity in
BRAF
V600E mutated tumor samples ranged from weak to strong. The generally homogenous VE1 staining patterns argue against a clonal heterogeneity of the tumors investigated. Caution is essential when only poorly preserved tissue is available for VE1 immunohistochemical analysis or when tissues with only little total BRAF protein are analyzed. Immunohistochemistry using antibody VE1 may substantially facilitate molecular analysis of BRAF V600E status for diagnostic, prognostic, and predictive purposes.
NMDA receptors (NMDA-R) typically contribute to excitatory synaptic transmission in the central nervous system. While calcium influx through NMDA-R plays a critical role in synaptic plasticity, ...experimental evidence indicates that NMDAR-mediated calcium influx also modifies neuronal excitability through the activation of calcium-activated potassium channels. This mechanism has not yet been studied theoretically. Our theoretical model provides a simple description of neuronal electrical activity that takes into account the tonic activity of extrasynaptic NMDA receptors and a cytosolic calcium compartment. We show that calcium influx mediated by the tonic activity of NMDA-R can be coupled directly to the activation of calcium-activated potassium channels, resulting in an overall inhibitory effect on neuronal excitability. Furthermore, the presence of tonic NMDA-R activity promotes bistability in electrical activity by dramatically increasing the stimulus interval where both a stable steady state and repetitive firing can coexist. These results could provide an intrinsic mechanism for the constitution of memory traces in neuronal circuits. They also shed light on the way by which β -amyloids can alter neuronal activity when interfering with NMDA-R in Alzheimer's disease and cerebral ischemia.
Prolonged sedentary time is now recognised as an emergent ergonomics issue. We aimed to review current occupational safety and health policies relevant to occupational sedentary behaviour.
An ...electronic search for documents was conducted on websites of ergonomics and occupational safety and health organisations from 10 countries and six international/pan-European agencies. Additionally, 43 informants (nine countries) were contacted and an international conference workshop held. 119 documents (e.g. legislation, guidelines, codes of practice) were identified. Using a qualitative synthesis, it was observed that many jurisdictions had legal frameworks establishing a duty of care for employers, designers/manufacturers/suppliers and employees. While no occupational authority policies focusing specifically on sedentary behaviour were found, relevant aspects of existing policies were identified.
We highlight implications for ergonomics research and practice and recommend the development of policy to specifically address occupational sedentary behaviour and support workplace initiatives to assess and control the risks of this emergent hazard.
•Prolonged sedentary time is an emergent occupational safety and health issue.•Policies on occupational sedentary behaviour were reviewed.•No occupational authority policies focusing on sedentary behaviour were found.•Relevant aspects of existing policies (119 documents identified) were synthesized.•We recommend developing policies specifically addressing occupational sedentary behaviour.
Carbapenem-resistant Enterobacteriaceae (CRE) are a pressing public health issue due to limited therapeutic options to treat such infections. CREs have been predominantly isolated from humans and ...environmental samples and they are rarely reported among companion animals. In this study we report on the isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from a companion animal. Carbapenemase-producing S. enterica Typhimurium carrying bla
was identified from a systemically unwell (index) cat and three additional cats at an animal shelter. All isolates were identical and belonged to ST19. Genome sequencing revealed the acquisition of a multidrug-resistant IncHI2 plasmid (pIMP4-SEM1) that encoded resistance to nine antimicrobial classes including carbapenems and carried the bla
-qacG-aacA4-catB3 cassette array. The plasmid also encoded resistance to arsenic (MIC-150 mM). Comparative analysis revealed that the plasmid pIMP4-SEM1 showed greatest similarity to two bla
carrying IncHI2 plasmids from Enterobacter spp. isolated from humans in China. This is the first report of CRE carrying a bla
gene causing a clinical infection in a companion animal, with presumed nosocomial spread. This study illustrates the broader community risk entailed in escalating CRE transmission within a zoonotic species such as Salmonella, and in a cycle that encompasses humans, animals and the environment.
Research activities undertaken during University studies contribute to preparation of medical students for practice of evidence-based medicine. This study aimed to understand medical students' ...experiences, perceived research skills development and satisfaction associated with completion of mandatory research projects.
An online survey was sent to five cohorts of students (n = 1375) from years 2017-2021 at the completion of their research projects. Univariate analysis was conducted to understand students' perception of research skills development, followed by linear regression modeling to explore factors influencing satisfaction with their research project. Manifest content analysis employing a framework approach was used to analyse qualitative data from responses to open ended questions.
Response rate was 42%, with 513 (89%) returned surveys being complete and included in analysis. Whilst 37% of students felt they had requisite research skills before undertaking the research project, 84% reported they had these skills after completing the project (χ
= 8.99, P = 0.02). Mean satisfaction score of the students was 5.0/10 (+/- 2.5, median = 6 (IQR = 3.0-7.0) with 59% of students reporting satisfaction scores higher than the average. Higher satisfaction scores were reported by those who perceived that: research methods and teaching was useful in preparing them for conducting research; the research project helped them acquire new skills; the project resulted in peer-reviewed publication; and, who felt supported by their supervisors. Responses to open ended questions offered important insights into student experience and emphasised the importance of supportive supervisors and the need for a dedicated research block in the busy medical program.
The majority of students reported positive outcomes from the mandatory research project. Student satisfaction can be improved by ensuring supportive research environments and high-quality supervision, and inclusion of dedicated research time in the medical curriculum.
Flame retardants (FRs) are common bodily and environmental pollutants, creating concern about their potential toxicity. We and others have found that the commercial mixture FireMaster® 550 (FM 550) ...or its individual brominated (BFR) and organophosphate ester (OPFR) components are potential developmental neurotoxicants. Using Wistar rats, we previously reported that developmental exposure to FM 550 or its component classes produced sex- and compound-specific effects on adult socioemotional behaviors. The underlying mechanisms driving the behavioral phenotypes are unknown.
To further mechanistic understanding, here we conducted transcriptomics in parallel with a novel lipidomics approach using cortical tissues from newborn siblings of the rats in the published behavioral study. Inclusion of lipid composition is significant because it is rarely examined in developmental neurotoxicity studies. Pups were gestationally exposed via oral dosing to the dam to FM 550 or the BFR or OPFR components at environmentally relevant doses.
The neonatal cortex was highly sexually dimorphic in lipid and transcriptome composition, and males were more significantly impacted by FR exposure. Multiple adverse modes of action for the BFRs and OPFRs on neurodevelopment were identified, with the OPFRs being more disruptive than the BFRs via multiple mechanisms including dysregulation of mitochondrial function and disruption of cholinergic and glutamatergic systems. Disrupted mitochondrial function by environmental factors has been linked to a higher risk of autism spectrum disorders and neurodegenerative disorders. Impacted lipid classes included ceramides, sphingomyelins, and triacylglycerides. Robust ceramide upregulation in the OPFR females could suggest a heightened risk of brain metabolic disease.
This study reveals multiple mechanisms by which the components of a common FR mixture are developmentally neurotoxic and that the OPFRs may be the compounds of greatest concern.
Background: Hospitals that provide early postdischarge follow-up after heart failure (HF) hospitalization tend to have lower rates of readmission. However, HF postdischarge (bridge) clinics have not ...been extensively evaluated. Objective: To assess the impact of a pharmacist-managed HF bridge clinic in a veteran population. Methods: HF patients hospitalized from November 2010 to August 2013 were identified. Retrospective chart review was conducted of 122 HF patients seen at bridge clinic compared with 122 randomly selected HF patients not seen at this clinic (usual care). Primary end point was 90-day all-cause readmission and death. Secondary outcomes were 30-day all-cause readmission and death, time to first postdischarge follow-up, first all-cause readmission. Results: Bridge clinic patients were at higher baseline risk of readmission and death; other characteristics were similar. 90-day death and all-cause readmission trended lower in bridge clinic patients (adjusted hazard ratio HR = 0.64; 95% CI = 0.40-1.02; P = 0.06). Time to first follow-up was shorter in bridge clinic patients (11 ± 6 vs 20 ± 23 days; P < 0.001); time to first all-cause readmission trended longer (40 ± 20 vs 33 ± 25days; P = 0.11). 30-day death and all-cause readmission was significantly lower in bridge clinic patients (adjusted HR = 0.44; 95% CI = 0.22-0.88; P = 0.02). Conclusions: In veteran patients hospitalized for HF, pharmacist-managed HF bridge clinic significantly reduced the time to initial follow-up compared with usual care. Improved short-term outcomes and trend toward improvement of longer-term outcomes in bridge clinic patients was shown.
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