Explanation and elaboration of the SQUIRE (Standards for Quality Improvement Reporting Excellence) Guidelines, V.2.0: examples of SQUIRE elements in the healthcare improvement literature

Since its publication in 2008, SQUIRE (Standards for Quality Improvement Reporting Excellence) has contributed to the completeness and transparency of reporting of quality improvement work, providing guidance to authors and reviewers of reports on healthcare improvement work. In the interim, enormous growth has occurred in understanding factors that influence the success, and failure, of healthcare improvement efforts. Progress has been particularly strong in three areas: the understanding of the theoretical basis for improvement work; the impact of contextual factors on outcomes; and the development of methodologies for studying improvement work. Consequently, there is now a need to revise the original publication guidelines. To reflect the breadth of knowledge and experience in the field, we solicited input from a wide variety of authors, editors and improvement professionals during the guideline revision process. This Explanation and Elaboration document (E&E) is a companion to the revised SQUIRE guidelines, SQUIRE 2.0. The product of collaboration by an international and interprofessional group of authors, this document provides examples from the published literature, and an explanation of how each reflects the intent of a specific item in SQUIRE. The purpose of the guidelines is to assist authors in writing clearly, precisely and completely about systematic efforts to improve the quality, safety and value of healthcare services. Authors can explore the SQUIRE statement, this E&E and related documents in detail at http://www.squire-statement.org

Androgenic suppression combined with radiotherapy for the treatment of prostate adenocarcinoma: a systematic review

<p>Abstract</p> <p>Background</p> <p>Locally advanced prostate cancer is often associated with elevated recurrence rates. Despite the modest response observed, external-beam radiotherapy has been the preferred treatment for this condition. More recent evidence from randomised trials has demonstrated clinical benefit with the combined use of androgen suppression in such cases. The aim of this meta-analysis is to compare the combination of distinct hormone therapy modalities versus radiotherapy alone for overall survival, disease-free survival and toxicity.</p> <p>Methods</p> <p>Databases (MEDLINE, EMBASE, LILACS, Cochrane databases and ClinicalTrials.gov) were scanned for randomised clinical trials involving radiotherapy with or without androgen suppression in local prostate cancer. The search strategy included articles published until October 2011. The studies were examined and the data of interest were plotted for meta-analysis. Survival outcomes were reported as a hazard ratio with corresponding 95% confidence intervals.</p> <p>Results</p> <p>Data from ten trials published from 1988 to 2011 were included, comprising 6555 patients. There was a statistically significant advantage to the use of androgen suppression, in terms of both overall survival and disease free survival, when compared to radiotherapy alone. The use of long-term goserelin (up to three years) was the strategy providing the higher magnitude of clinical benefit. In contrast to goserelin, there were no trials evaluating the use of other luteinizing hormone-releasing hormone (LHRH) analogues as monotherapy. Complete hormonal blockade was not shown to be superior to goserelin monotherapy.</p> <p>Conclusions</p> <p>Based on the findings of this systematic review, the evidence supports the use of androgen suppression with goserelin monotherapy as the standard treatment for patients with prostate cancer treated with radiotherapy, which are at high risk of recurrence or metastases.</p

Pathogenic Intestinal Bacteria Enhance Prostate Cancer Development via Systemic Activation of Immune Cells in Mice

A role for microbes has been suspected in prostate cancer but difficult to confirm in human patients. We show here that a gastrointestinal (GI) tract bacterial infection is sufficient to enhance prostate intraepithelial neoplasia (PIN) and microinvasive carcinoma in a mouse model. We found that animals with a genetic predilection for dysregulation of wnt signaling, Apc[superscript Min/+] mutant mice, were significantly susceptible to prostate cancer in an inflammation-dependent manner following infection with Helicobacter hepaticus. Further, early neoplasia observed in infected Apc[superscript Min/+] mice was transmissible to uninfected mice by intraperitoneal injection of mesenteric lymph node (MLN) cells alone from H. hepaticus-infected mutant mice. Transmissibility of neoplasia was preventable by prior neutralization of inflammation using anti-TNF-α antibody in infected MLN donor mice. Taken together, these data confirm that systemic inflammation triggered by GI tract bacteria plays a pivotal role in tumorigenesis of the prostate gland.RO1CA108854National Institute of Environmental Health Sciences (Massachusetts Institute of Technology. Center for Environmental Health Sciences Pilot Project Award P30-ES002109

Cataract-Causing Defect of a Mutant γ-Crystallin Proceeds through an Aggregation Pathway Which Bypasses Recognition by the α-Crystallin Chaperone

Background: The transparency of the eye lens depends upon maintenance of the native state of the γ- and β-crystallins, which is aided by the abundant chaperones αA- and αB-crystallin. Mature onset cataract, the leading cause of blindness worldwide, involves the polymerization of covalently damaged or partially unfolded crystallins into light-scattering aggregates. A number of single amino acid substitutions and truncations of γ-crystallins result in congenital cataract in both humans and mice, though in many cases the coupling between the protein alterations and the accumulation of aggregates is poorly defined. Methodology/Principal Findings: We have studied the aggregation properties and chaperone interactions of human γD-crystallin carrying substitutions of two buried core mutants, I90F and V75D, which cause congenital cataract in mice. The in vitro aggregation pathway competing with productive refolding was not altered by either substitution. Furthermore, this aggregation pathway for both mutant proteins–originating from a partially folded intermediate–was efficiently suppressed by αB-crystallin. Thus the cataract pathology was unlikely to be associated with a direct folding defect. The native state of wild-type human γD-crystallin exhibited no tendency to aggregate under physiological conditions. However both I90F and V75D native-like proteins exhibited slow (days) aggregation to high molecular weight aggregates under physiological conditions. The perturbed conformation of I90F was recognized and bound by both αA and αB chaperones. In contrast, the aggregation derived from the perturbed state of V75D was not suppressed by either chaperone, and the aggregating species were not bound by the chaperone. Conclusions/Significance: The cataract phenotype of I90F in mice may be due to premature saturation of the finite α- crystallin pool. The V75D aggregation pathway and its escape from chaperone surveillance and aggregation suppression can account for the congenital cataract pathology of this mutant. Failure of chaperone recognition may be an important source of pathology for many other protein folding defects.National Eye Institute (Grant no. EY015834 )National Institutes of Health (U.S.) (Grant no. GM17980

Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells

BACKGROUND: Recent observations indicate that human tumorous breast tissue metabolizes progesterone differently than nontumorous breast tissue. Specifically, 5α-reduced metabolites (5α-pregnanes, shown to stimulate cell proliferation and detachment) are produced at a significantly higher rate in tumorous tissue, indicating increased 5α-reductase (5αR) activity. Conversely, the activities of 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO enzymes appeared to be higher in normal tissues. The elevated conversion to 5α-pregnanes occurred regardless of estrogen (ER) or progesterone (PR) receptor levels. To gain insight into these differences, the activities and expression of these progesterone converting enzymes were investigated in a nontumorigenic cell line, MCF-10A (ER- and PR-negative), and the three tumorigenic cell lines, MDA-MB-231 (ER- and PR-negative), MCF-7 and T-47D (ER- and PR-positive). METHODS: For the enzyme activity studies, either whole cells were incubated with [(14)C]progesterone for 2, 4, 8, and 24 hours, or the microsomal/cytosolic fraction was incubated for 15–60 minutes with [(3)H]progesterone, and the metabolites were identified and quantified. Semi-quantitative RT-PCR was employed to determine the relative levels of expression of 5αR type1 (SRD5A1), 5αR type 2 (SRD5A2), 20α-HSO (AKR1C1), 3α-HSO type 2 (AKR1C3), 3α-HSO type 3 (AKR1C2) and 3β-HSO (HSD3B1/HSD3B2) in the four cell lines using 18S rRNA as an internal control. RESULTS: The relative 5α-reductase activity, when considered as a ratio of 5α-pregnanes/4-pregnenes, was 4.21 (± 0.49) for MCF-7 cells, 6.24 (± 1.14) for MDA-MB-231 cells, 4.62 (± 0.43) for T-47D cells and 0.65 (± 0.07) for MCF-10A cells, constituting approximately 6.5-fold, 9.6-fold and 7.1 fold higher conversion to 5α-pregnanes in the tumorigenic cells, respectively, than in the nontumorigenic MCF-10A cells. Conversely, the 20α-HSO and 3α-HSO activities were significantly higher (p < 0.001) in MCF-10A cells than in the other three cell types. In the MCF-10A cells, 20α-HSO activity was 8-14-fold higher and the 3α-HSO activity was 2.5-5.4-fold higher than in the other three cell types. The values of 5αR:20α-HSO ratios were 16.9 – 32.6-fold greater and the 5αR:3α-HSO ratios were 5.2 – 10.5-fold greater in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. RT-PCR showed significantly higher expression of 5αR1 (p < 0.001), and lower expression of 20α-HSO (p < 0.001), 3α-HSO2 (p < 0.001), 3α-HSO3 (p < 0.001) in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. CONCLUSION: The findings provide the first evidence that the 5αR activity (leading to the conversion of progesterone to the cancer promoting 5α-pregnanes) is significantly higher in the tumorigenic MCF-7, MDA-MB-231 and T-47D breast cell lines than in the nontumorigenic MCF-10A cell line. The higher 5αR activity coincides with significantly greater expression of 5αR1. On the other hand, the activities of 20α-HSO and 3α-HSO are higher in the MCF-10A cells than in MCF-7, MDA-MB-231 and T-47D cells; these differences in activity correlate with significantly higher expression of 20α-HSO, 3α-HSO2 and 3α-HSO3 in MCF-10A cells. Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for stimulating breast cancer by increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes

Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: Meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Hormone therapy plus radiotherapy significantly decreases recurrences and mortality of patients affected by locally advanced prostate cancer. In order to determine if difference exists according to the hormonal treatment duration, a literature-based meta-analysis was performed.</p> <p>Methods</p> <p>Relative risks (RR) were derived through a random-effect model. Differences in primary (biochemical failure, BF; cancer-specific survival, CSS), and secondary outcomes (overall survival, OS; local or distant recurrence, LR/DM) were explored. Absolute differences (AD) and the number needed to treat (NNT) were calculated. Heterogeneity, a meta-regression for clinic-pathological predictors and a correlation test for surrogates were conducted.</p> <p>Results</p> <p>Five trials (3,424 patients) were included. Patient population ranged from 267 to 1,521 patients. The longer hormonal treatment significantly improves BF (with significant heterogeneity) with an absolute benefit of 10.1%, and a non significant trend in CSS. With regard to secondary end-points, the longer hormonal treatment significantly decrease both the LR and the DM with an absolute difference of 11.7% and 11.5%. Any significant difference in OS was observed. None of the three identified clinico-pathological predictors (median PSA, range 9.5-20.35, Gleason score 7-10, 27-55% patients/trial, and T3-4, 13-77% patients/trial), did significantly affect outcomes. At the meta-regression analysis a significant correlation between the overall treatment benefit in BF, CSS, OS, LR and DM, and the length of the treatment was found (p≤0.03).</p> <p>Conclusions</p> <p>Although with significant heterogeneity (reflecting different patient' risk stratifications), a longer hormonal treatment duration significantly decreases biochemical, local and distant recurrences, with a trend for longer cancer specific survival.</p

Work satisfaction of professional nurses in South Africa: a comparative analysis of the public and private sectors

<p>Abstract</p> <p>Background</p> <p>Work satisfaction of nurses is important, as there is sufficient empirical evidence to show that it tends to affect individual, organizational and greater health and social outcomes. Although there have been several studies of job satisfaction among nurses in South Africa, these are limited because they relate to studies of individual organizations or regions, use small samples or are dated. This paper presents a national study that compares and contrasts satisfaction levels of nurses in both public and private sectors.</p> <p>Methods</p> <p>This was a cross-sectional survey of professional nurses conducted throughout South Africa using a pretested and self-administered questionnaire. Univariate and bivariate statistical models were used to evaluate levels of satisfaction with various facets of work and to elicit the differences in satisfaction levels between different groups of nurses. A total of 569 professional nurses participated in the study.</p> <p>Results</p> <p>Private-sector nurses were generally satisfied, while public-sector nurses were generally dissatisfied. Public-sector nurses were most dissatisfied with their pay, the workload and the resources available to them. They were satisfied only with the social context of the work. Private-sector nurses were dissatisfied only with their pay and career development opportunities. Professional nurses in the more rural provinces, those intending to change sectors and those more likely not to be in their current positions within the next five years were also more likely to be dissatisfied with all facets of their work.</p> <p>Conclusion</p> <p>This study highlighted the overall dissatisfaction among South African nurses and confirmed the disparity between the levels of job satisfaction between the public and private sectors. Health managers should address those factors that affect job satisfaction, and therefore retention, of nurses in South Africa. Improving the work environment so that it provides a context congruent with the aspirations and values systems of nurses is more likely to increase the satisfaction of nurses and consequently have a positive effect on individual, organizational and health outcomes.</p

STK35L1 Associates with Nuclear Actin and Regulates Cell Cycle and Migration of Endothelial Cells

BACKGROUND: Migration and proliferation of vascular endothelial cells are essential for repair of injured endothelium and angiogenesis. Cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors play an important role in vascular tissue injury and wound healing. Previous studies suggest a link between the cell cycle and cell migration: cells present in the G(1) phase have the highest potential to migrate. The molecular mechanism linking these two processes is not understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we explored the function of STK35L1, a novel Ser/Thr kinase, localized in the nucleus and nucleolus of endothelial cells. Molecular biological analysis identified a bipartite nuclear localization signal, and nucleolar localization sequences in the N-terminal part of STK35L1. Nuclear actin was identified as a novel binding partner of STK35L1. A class III PDZ binding domains motif was identified in STK35L1 that mediated its interaction with actin. Depletion of STK35L1 by siRNA lead to an accelerated G(1) to S phase transition after serum-stimulation of endothelial cells indicating an inhibitory role of the kinase in G(1) to S phase progression. Cell cycle specific genes array analysis revealed that one gene was prominently downregulated (8.8 fold) in STK35L1 silenced cells: CDKN2A alpha transcript, which codes for p16(INK4a) leading to G(1) arrest by inhibition of CDK4/6. Moreover in endothelial cells seeded on Matrigel, STK35L1 expression was rapidly upregulated, and silencing of STK35L1 drastically inhibited endothelial sprouting that is required for angiogenesis. Furthermore, STK35L1 depletion profoundly impaired endothelial cell migration in two wound healing assays. CONCLUSION/SIGNIFICANCE: The results indicate that by regulating CDKN2A and inhibiting G1- to S-phase transition STK35L1 may act as a central kinase linking the cell cycle and migration of endothelial cells. The interaction of STK35L1 with nuclear actin might be critical in the regulation of these fundamental endothelial functions