Deficits in mitochondrial TCA cycle and OXPHOS precede rod photoreceptor degeneration during chronic HIF activation

Background: Major retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and retinal detachment, are associated with a local decrease in oxygen availability causing the formation of hypoxic areas affecting the photoreceptor (PR) cells. Here, we addressed the underlying pathological mechanisms of PR degeneration by focusing on energy metabolism during chronic activation of hypoxia-inducible factors (HIFs) in rod PR. Methods: We used two-photon laser scanning microscopy (TPLSM) of genetically encoded biosensors delivered by adeno-associated viruses (AAV) to determine lactate and glucose dynamics in PR and inner retinal cells. Retinal layer-specific proteomics, in situ enzymatic assays and immunofluorescence studies were used to analyse mitochondrial metabolism in rod PRs during chronic HIF activation. Results: PRs exhibited remarkably higher glycolytic flux through the hexokinases than neurons of the inner retina. Chronic HIF activation in rods did not cause overt change in glucose dynamics but an increase in lactate production nonetheless. Furthermore, dysregulation of the oxidative phosphorylation pathway (OXPHOS) and tricarboxylic acid (TCA) cycle in rods with an activated hypoxic response decelerated cellular anabolism causing shortening of rod photoreceptor outer segments (OS) before onset of cell degeneration. Interestingly, rods with deficient OXPHOS but an intact TCA cycle did not exhibit these early signs of anabolic dysregulation and showed a slower course of degeneration. Conclusion: Together, these data indicate an exceeding high glycolytic flux in rods and highlight the importance of mitochondrial metabolism and especially of the TCA cycle for PR survival in conditions of increased HIF activity

ABCB5-Targeted chemoresistance reversal inhibits merkel cell carcinoma growth

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin- and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy. © 2016 The Author

Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

Background & AimsPatients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.MethodsIn a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation.ResultsSixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%).ConclusionsAdministration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844

Ethical frameworks for quality improvement activities: An analysis of international practice

Purpose: To examine international approaches to the ethical oversight and regulation of quality improvement and clinical audit in healthcare systems. Data sources: We searched grey literature including websites of national research and ethics regulatory bodies and health departments of selected countries. Study selection: National guidance documents were included from six countries: Ireland, England, Australia, New Zealand, the United States of America and Canada. Data extraction: Data were extracted from 19 documents using an a priori framework developed from the published literature. Results: We organised data under five themes: ethical frameworks; guidance on ethical review; consent, vulnerable groups and personal health data. Quality improvement activity tended to be outside the scope of the ethics frameworks in most countries. Only New Zealand had integrated national ethics standards for both research and quality improvement. Across countries, there is consensus that this activity should not be automatically exempted from ethical review, but requires proportionate review or organisational oversight for minimal risk projects. In the majority of countries, there is a lack of guidance on participant consent, use of personal health information and inclusion of vulnerable groups in routine quality improvement. Conclusion: Where countries fail to provide specific ethics frameworks for quality improvement, guidance is dispersed across several organisations which may lack legal certainty. Our review demonstrates a need for appropriate oversight and responsive infrastructure for quality improvement underpinned by ethical frameworks that build equivalence with research oversight. It outlines aspects of good practice, especially The New Zealand framework that integrates research and quality improvement ethics

An international perspective on definitions and terminology used to describe serious reportable patient safety incidents: A systematic review

Objectives: Patients are unintentionally, yet frequently, harmed in situations that are deemed preventable. Incident reporting systems help prevent harm, yet there is considerable variability in how patient safety incidents are reported. This may lead to inconsistent or unnecessary patterns of incident reporting and failures to identify serious patient safety incidents. This systematic review aims to describe international approaches in relation to defining serious reportable patient safety incidents. Methods: Multiple electronic and gray literature databases were searched for articles published between 2009 and 2019. Empirical studies, reviews, national reports, and policies were included. A narrative synthesis was conducted because of study heterogeneity. Results: A total of 50 articles were included. There was wide variation in the terminology used to represent serious reportable patient safety incidents. Several countries defined a specific subset of incidents, which are considered sufficiently serious, yet preventable if appropriate safety measures are taken. Terms such as “never events,” “serious reportable events,” or “always review and report” were used. The following dimensions were identified to define a serious reportable patient safety incident: (1) incidents being largely preventable; (2) having the potential for significant learning; (3) causing serious harm or have the potential to cause serious harm; (4) being identifiable, measurable, and feasible for inclusion in an incident reporting system; and (5) running the risk of recurrence. Conclusions: Variations in terminology and reporting systems between countries might contribute to missed opportunities for learning. International standardized definitions and blame-free reporting systems would enable comparison and international learning to enhance patient safety

Gender Gap in Parental Leave Intentions: Evidence from 37 Countries

Despite global commitments and efforts, a gender-based division of paid and unpaid work persists. To identify how psychological factors, national policies, and the broader sociocultural context contribute to this inequality, we assessed parental-leave intentions in young adults (18–30 years old) planning to have children (N = 13,942; 8,880 identified as women; 5,062 identified as men) across 37 countries that varied in parental-leave policies and societal gender equality. In all countries, women intended to take longer leave than men. National parental-leave policies and women’s political representation partially explained cross-national variations in the gender gap. Gender gaps in leave intentions were paradoxically larger in countries with more gender-egalitarian parental-leave policies (i.e., longer leave available to both fathers and mothers). Interestingly, this cross-national variation in the gender gap was driven by cross-national variations in women’s (rather than men’s) leave intentions. Financially generous leave and gender-egalitarian policies (linked to men’s higher uptake in prior research) were not associated with leave intentions in men. Rather, men’s leave intentions were related to their individual gender attitudes. Leave intentions were inversely related to career ambitions. The potential for existing policies to foster gender equality in paid and unpaid work is discussed.Gender Gap in Parental Leave Intentions: Evidence from 37 CountriespublishedVersio

Gender Gap in Parental Leave Intentions: Evidence from 37 Countries

Despite global commitments and efforts, a gender-based division of paid and unpaid work persists. To identify how psychological factors, national policies, and the broader sociocultural context contribute to this inequality, we assessed parental-leave intentions in young adults (18–30 years old) planning to have children (N = 13,942; 8,880 identified as women; 5,062 identified as men) across 37 countries that varied in parental-leave policies and societal gender equality. In all countries, women intended to take longer leave than men. National parental-leave policies and women’s political representation partially explained cross-national variations in the gender gap. Gender gaps in leave intentions were paradoxically larger in countries with more gender-egalitarian parental-leave policies (i.e., longer leave available to both fathers and mothers). Interestingly, this cross-national variation in the gender gap was driven by cross-national variations in women’s (rather than men’s) leave intentions. Financially generous leave and gender-egalitarian policies (linked to men’s higher uptake in prior research) were not associated with leave intentions in men. Rather, men’s leave intentions were related to their individual gender attitudes. Leave intentions were inversely related to career ambitions. The potential for existing policies to foster gender equality in paid and unpaid work is discussed

HER-2/neu gene amplification in esophageal adenocarcinoma and its influence on survival

The original publication is available at the Annals website at www.springerlink.com/content/1534-4681.Background: HER-2/neu (c-erbB-2, HER2) gene amplification and protein overexpression have been associated with poor prognosis in several solid tumors, including breast and gastric cancer. Its incidence and significance in esophageal adenocarcinoma is unknown. Materials and Methods: Tissue microarrays were successfully constructed from 89 paraffin-embedded archival specimens of esophageal adenocarcinomas for HER2 gene amplification by silver-enhanced in situ hybridization (SISH). No patients had undergone neoadjuvant therapy. Protein overexpression was tested with immunohistochemistry (IHC) using automated immunostaining (Ventana Benchmark). Incidence of HER2 positivity, correlation to clinicopathological variables in esophageal cancer patients, and concordance between SISH and IHC were determined. Results: True HER2 gene amplification was detected in 14 esophageal cancer specimens (16%), and 92% of those with high-level HER2 amplification showed positive HER2 protein overexpression. No significant associations were found among gene amplification and clinicopathological factors. The 5-year survival rates were 57% for esophageal cancer patients with HER2 amplification compared with 32% without, but the difference in overall survival was not significant (P = .37). The correlation between SISH and IHC was statistically significant (P < .0001). Conclusion: While molecular targeting may be possible for approximately 16% of esophageal adenocarcinoma patients, HER2 oncogene amplification did not influence survival in this study.Sarah K. Thompson, Thomas R. Sullivan, Ruth Davies and Andrew R. Ruszkiewic