Breast cancer histologic grading using digital microscopy: concordance and outcome association

Aims: Virtual microscopy utilising digital whole slide imaging (WSI) is increasingly used in breast pathology. Histologic grade is one of the strongest prognostic factors in breast cancer (BC). This study aims at investigating the agreement between BC grading using traditional light microscopy (LM) and digital whole slide imaging (WSI) with consideration of reproducibility and impact on outcome prediction. Methods: A large (n=1675) well-characterised cohort of BC originally graded by LM was re-graded using WSI. Two separate virtual-based grading sessions (V1 and V2) were performed with a three months washout period. Outcome was assessed using breast cancer specific and distant metastasis free survival. Results: The concordance between LM grading and WSI was strong (LM/SWI Cramer’s V: V1=0.576, and V2=0.579). The agreement regarding grade components was as follows: Tubule formation=0.538, Pleomorphism=0.422 and Mitosis=0.514. Greatest discordance was observed between adjacent grades whereas high/low grade discordance was uncommon (1.5%). The intra-observer agreement for the two WSI sessions was substantial for grade (V1/V2 Cramer’s V=0.676; kappa=0.648) and grade components (Cramer’s V T=0.628, P=0.573 and M=0.580). Grading using both platforms showed strong association with outcome (All p-value <0.001). Although mitotic scores assessed using both platforms were strongly associated with outcome, WSI tends to underestimate mitotic counts. Conclusions: Virtual microscopy is a reliable and reproducible method for assessing BC histologic grade. Regardless of the observer or assessment platform, histologic grade is a significant predictor of outcome. Continuing advances in imaging technology could potentially provide improved performance of WSI BC grading and in particular mitotic count assessment

CoQ10 Deficient Endothelial Cell Culture Model for the Investigation of CoQ10 Blood–Brain Barrier Transport

Primary coenzyme Q10 (CoQ10) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ10 supplements are given in the early stages of the disease.While supplements improve peripheral abnormalities, neurological symptoms are only partially or temporarily ameliorated. The reasons for this refractory response to CoQ10 supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ10 across the blood–brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ10 transport across the BBB, using normal and pathophysiological (CoQ10 deficient) cell culture models. The study identifies lipoprotein-associated CoQ10 transcytosis in both directions across the in vitro BBB. Uptake via SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation Endproducts), is matched by efflux via LDLR (Low Density Lipoprotein Receptor) transporters, resulting in no “net” transport across the BBB. In the CoQ10 deficient model, BBB tight junctions were disrupted and CoQ10 “net” transport to the brain side increased. The addition of anti-oxidants did not improve CoQ10 uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ10 deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ10 distribution across the BBB. The results imply that the uptake of exogenous CoQ10 into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters

How ethnic are African parties really? Evidence from Francophone Africa

Though African party systems are said to be ethnic, there is little evidence for this claim. The few empirical studies rarely rely on individual data and are biased in favour of Anglophone Africa. This paper looks at four Francophone countries, drawing on representative survey polls. Results reveal that ethnicity matters, but that its impact is generally rather weak and differs with regard to party systems and individual parties. ‘Ethnic parties’ in the strict sense are virtually absent. In particular, the voters’ location seems more important than ethnic affiliation. Other determinants such as regional ties, elite strategies, cross-cutting cleavages, and rational preferences deserve more attention in the future study of voting behaviour in Africa

Assessment of cardiovascular risk factors prior to NHS Health Checks in an urban setting: cross-sectional study

OBJECTIVES: To assess the completeness of cardiovascular disease (CVD) risk factor recording and levels of risk factors in patients eligible for the NHS Health Check. DESIGN: Cross-sectional study. SETTING: Twenty-eight general practices located in Hammersmith and Fulham, London, UK. PARTICIPANTS: 42,306 patients aged 40 to 74 years without existing cardiovascular disease or diabetes. MAIN OUTCOME MEASURES: MEASUREMENT AND LEVEL OF CVD RISK FACTORS: blood pressure, cholesterol, body mass index (BMI), blood glucose and smoking status. RESULTS: There was a high recording of smoking status (86.1%) and blood pressure (82.5%); whilst BMI, cholesterol and glucose recording was lower. There was large variation in BMI, cholesterol, glucose recording between practices (29.7-91.5% for BMI). Women had significantly better risk factor recording than men (AOR = 1.70 [1.61-1.80] for blood pressure). All risk factors were better recorded in the least deprived patient group (AOR = 0.79 [0.73-0.85] for blood pressure) and patients with diagnosed hypertension (AOR = 7.24 [6.67-7.86] for cholesterol). Risk factor recording varied considerably between practices but was more strongly associated with patient than practice level characteristics. Age-adjusted levels of cholesterol and BMI were not significantly different between men and women. More men had raised blood glucose, blood pressure and BMI than women (29.7% [29.1-30.4] compared to 19.8% [19.3-20.3] for blood pressure). CONCLUSIONS: Before the NHS Health Check, CVD risk factor recording varied considerably by practice and patient characteristics. We identified significant elevated levels of raised CVD risk factors in the population eligible for a Health Check, which will require considerable work to manage

Lessons learned from England's Health Checks Programme : Using qualitative research to identify and share best practice

Background: This study aimed to explore the challenges and barriers faced by staff involved in the delivery of the National Health Service (NHS) Health Check, a systematic cardiovascular disease (CVD) risk assessment and management program in primary care. Methods: Data have been derived from three qualitative evaluations that were conducted in 25 General Practices and involved in depth interviews with 58 staff involved all levels of the delivery of the Health Checks. Analysis of the data was undertaken using the framework approach and findings are reported within the context of research and practice considerations. Results: Findings indicated that there is no ‘one size fits all’ blueprint for maximising uptake although success factors were identified: evolution of the programme over time in response to local needs to suit the particular characteristics of the patient population; individual staff characteristics such as being proactive, enthusiastic and having specific responsibility; a supportive team. Training was clearly identified as an area that needed addressing and practitioners would benefit from CVD specific baseline training and refresher courses to keep them up to date with recent developments in the area. However there were other external factors that impinged on an individual’s ability to provide an effective service, some of these were outside the control of individuals and included cutbacks in referral services, insufficient space to run clinics or general awareness of the Health Checks amongst patients. Conclusions: The everyday experiences of practitioners who participated in this study suggest that overall, Health Check is perceived as a worthwhile exercise. But, organisational and structural barriers need to be addressed. We also recommend that clear referral pathways be in place so staff can refer patients to appropriate services (healthy eating sessions, smoking cessation, and exercise referrals). Local authorities need to support initiatives that enable data sharing and linkage so that GP Practices are informed when patients take up services such as smoking cessation or alcohol harm reduction programmes run by social services

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics

Hepatitis E Virus Seroprevalence among Blood Donors in Southwest Switzerland

Aim: The aim of this study was to determine the seroprevalence of Hepatitis E virus (HEV) among blood donors in southwest Switzerland.Background: HEV is recognized as a food-borne disease in industrialized countries, transmitted mainly through pork meat. Cases of transmission through blood transfusion have also been reported. Recent studies have revealed seroprevalence rates of 13.5%, 16.6% and 20.6% among blood donors in England, France and Denmark, respectively.Methods: We analyzed 550 consecutive blood donor samples collected in the region of Lausanne, canton of Vaud, Switzerland, for the presence of anti-HEV IgG, using the MP Diagnostics HEV ELISA kit. For each donor, we documented age, sex and alanine aminotransferase (ALT) value.Results: The study panel was composed of 332 men (60.4%) and 218 women (39.6%). Overall, anti-HEV IgG was found in 27 of 550 samples (4.9%). The seroprevalence was 5.4% (18/332) in men and 4.1% (9/218) in women. The presence of anti-HEV IgG was not correlated with age, gender or ALT values. However, we observed a peak in seroprevalence of 5.3% in individuals aged 51 to 70 years old.Conclusions: Compared with other European countries, HEV seroprevalence among blood donors in southwest Switzerland is low. The low seroprevalence may be explained by the sensitivity of commercial tests used and/or the strict regulation of animal and meat imports. Data regarding HEV prevalence in Swiss livestock are lacking and merit exploration

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism forcell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR inclinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications. © 2014 The Authors

Sternal plating for primary and secondary sternal closure; can it improve sternal stability?

<p>Abstract</p> <p>Background</p> <p>Sternal instability with mediastinitis is a very serious complication after median sternotomy. Biomechanical studies have suggested superiority of rigid plate fixation over wire cerclage for sternal fixation. This study tests the hypothesis that sternal closure stability can be improved by adding plate fixation in a human cadaver model.</p> <p>Methods</p> <p>Midline sternotomy was performed in 18 human cadavers. Four sternal closure techniques were tested: (1) approximation with six interrupted steel wires; (2) approximation with six interrupted cables; (3) closure 1 (wires) or 2 (cables) reinforced with a transverse sternal plate at the sixth rib; (4) Closure using 4 sternal plates alone. Intrathoracic pressure was increased in all techniques while sternal separation was measured by three pairs of sonomicrometry crystals fixed at the upper, middle and lower parts of the sternum until 2.0 mm separation was detected. Differences in displacement pressures were analyzed using repeated measures ANOVA and Regression Coefficients.</p> <p>Results</p> <p>Intrathoracic pressure required to cause 2.0 mm separation increased significantly from 183.3 ± 123.9 to 301.4 ± 204.5 in wires/cables alone vs. wires/cables plus one plate respectively, and to 355.0 ± 210.4 in the 4 plates group (p < 0.05). Regression Coefficients (95% CI) were 120 (47–194) and 142 (66–219) respectively for the plate groups.</p> <p>Conclusion</p> <p>Transverse sternal plating with 1 or 4 plates significantly improves sternal stability closure in human cadaver model. Adding a single sternal plate to primary closure improves the strength of sternal closure with traditional wiring potentially reducing the risk of sternal dehiscence and could be considered in high risk patients.</p