Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation

HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation

Why older nurses leave the workforce and the implications of them staying

© 2014 John Wiley & Sons Ltd. Aims and objectives: To identify factors that motivate older nurses to leave the workforce. Background: As many older nurses are now reaching retirement age and will be eligible for government-funded pensions, governments are concerned about the impending financial burden. To prepare for this scenario, many are looking at increasing the age of retirement to 67 or 70 years. Little is known about how this will affect the continuing employment of older nurses and the consequences for employers and the nurses themselves if they remain longer in the workforce. Design: Prospective randomised quantitative survey study. Methods: The Mature Age Workers Questionnaire, Job Descriptive Index and Job in General Scale were used to measure job satisfaction, intention to retire and factors encouraging retirement in registered nurses aged 45 years and over (n = 352) in Australia (July-August 2007). Results: There were 319 respondents. The mean age proposed for leaving the workforce was 61·7 years. Key motivators were: financial considerations (40·1%), primarily financial security; nurse health (17·4%) and retirement age of partner (13·3%). Conclusions: Older nurses are leaving the workforce prior to retirement or pension age, primarily for financial, social and health reasons, taking with them significant experience and knowledge. As financial considerations are important in older nurses decisions to continue to work, increasing the age of retirement may retain them. However, consideration will need to be given to ensure that they continue to experience job satisfaction and are physically and mentally able to undertake demanding work. Relevance to clinical practice: Increasing retirement age may retain older nurses in the workforce, however, the impact on the health of older nurses is not known, nor is the impact for employers of older nurses continuing to work known. Employers must facilitate workplace changes to accommodate older nurses

Why do older RNs keep working?

Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. OBJECTIVE: To identify the reasons older RNs (≥45 years) remain in the healthcare workforce.BACKGROUND: Despite predictions of early retirements of older nurses, many continue to work past the age when they can gain access to their retirement funds.METHODS: The authors surveyed nurses older than 45 years in New South Wales, Australia.RESULTS: The need for income was the most common reason for staying in nursing (61.9%; n = 210), with nearly 43% (n = 130) identifying this as the main reason for staying.CONCLUSIONS: Retaining older nurses in the workforce is an important strategy for managing workforce shortages. Nurse executives will need to consider strategies that will enhance retention of older nurses and focus on the reasons older nurses want to keep working

Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients.

OBJECTIVE: In this study the safety and efficacy of imiquimod 5% cream for the treatments of actinic keratoses in kidney, heart and liver transplant recipients is evaluated. BACKGROUND: Growing populations of organ transplant recipients face increased risk of developing actinic keratosis (AK) and skin cancer secondary to continuous systemic immunosuppressive therapy. Imiquimod 5% cream is an effective option for the treatment of AK, but the safety of topical immune stimulation in immunocompromised patients has not been widely evaluated. METHODS: A total of 43 patients in six European transplant centres applied two sachets of topical imiquimod or vehicle cream three times per week to a 100 cm(2) field. Dosing continued for 16 weeks regardless of lesion clearance. Patients were assessed for safety variables that included adverse events, local skin reactions, laboratory results, vital signs, dosage of immunosuppressive medication and indication of graft rejection. A blinded independent expert committee was responsible for safety monitoring and final safety assessment. RESULTS: No graft rejections or trends for a deterioration of graft function were detected. No meaningful trends were observed in laboratory results. Among patients randomized to imiquimod, the complete clearance rate was 62.1% (18/29); for vehicle patients, the complete clearance rate was 0% (0/14). Clinical clearance was confirmed histologically in all cases. CONCLUSIONS: Imiquimod appears to be a safe alternative for the treatment of multiple actinic keratoses in patients with solid organ transplants. Efficacy was within the range previously observed in nontransplanted populations

Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients.

OBJECTIVE: In this study the safety and efficacy of imiquimod 5% cream for the treatments of actinic keratoses in kidney, heart and liver transplant recipients is evaluated. BACKGROUND: Growing populations of organ transplant recipients face increased risk of developing actinic keratosis (AK) and skin cancer secondary to continuous systemic immunosuppressive therapy. Imiquimod 5% cream is an effective option for the treatment of AK, but the safety of topical immune stimulation in immunocompromised patients has not been widely evaluated. METHODS: A total of 43 patients in six European transplant centres applied two sachets of topical imiquimod or vehicle cream three times per week to a 100 cm(2) field. Dosing continued for 16 weeks regardless of lesion clearance. Patients were assessed for safety variables that included adverse events, local skin reactions, laboratory results, vital signs, dosage of immunosuppressive medication and indication of graft rejection. A blinded independent expert committee was responsible for safety monitoring and final safety assessment. RESULTS: No graft rejections or trends for a deterioration of graft function were detected. No meaningful trends were observed in laboratory results. Among patients randomized to imiquimod, the complete clearance rate was 62.1% (18/29); for vehicle patients, the complete clearance rate was 0% (0/14). Clinical clearance was confirmed histologically in all cases. CONCLUSIONS: Imiquimod appears to be a safe alternative for the treatment of multiple actinic keratoses in patients with solid organ transplants. Efficacy was within the range previously observed in nontransplanted populations