Improving a regional chemotherapy service by learning from deaths occurring within 30 days of treatment with systemic anti-cancer therapy.

Background: Outwith clinical trials, patient outcomes specifically related to SACT (systemic anti-cancer therapy) are not well reported despite a significant proportion of patients receiving active treatment at the end of life. The NCEPOD reviewing deaths within 30 days of SACT found SACT caused or hastened death in 27% of cases.

Method: Across the Northern Ireland cancer network, 95 patients who died within 30 days of SACT for solid tumours were discussed at the Morbidity and Mortality monthly meeting during 2013. Using a structured template, each case was independently reviewed, with particular focus on whether SACT caused or hastened death.

Results: Lung, GI and breast cancers were the most common sites. Performance status was recorded in 92% at time of final SACT cycle (ECOG PS 0-2 89%).

In 57% the cause of death was progressive disease. Other causes included thromboembolism (13%) and infection (5% neutropenic sepsis, 6% non-neutropenic sepsis). In 26% with death from progressive disease, the patient was first cycle of first line treatment for metastatic disease. In the majority discussion regarding treatment aims and risks was documented. Only one patient was receiving SACT with curative intent, who died from appropriately managed neutropenic sepsis.

A definitive decision regarding SACT's role in death was made in 60%: in 49% SACT was deemed non-contributory and in 11% SACT was deemed the cause of death. In 40% SACT did not play a major role, but a definitive negative association could not be made.

Conclusion: Development of a robust review process of 30-day mortality after SACT established a benchmark for SACT delivery for future comparisons and identified areas for SACT service organisation improvement. Moreover it encourages individual practice reflection and highlights the importance of balancing patients' needs and concerns with realistic outcomes and risks, particularly in heavily pre-treated patients or those of poor performance status.

Global Systemic Risk and International Regulatory Coordination: Squaring Sovereignty and Financial Stability

In recent years much attention has been given to systemic risk and maintaining financial stability. Much of the focus, rightly, has been on market failures and the role of regulation in addressing them. This article looks at the role of domestic policies and government actions as sources of global instability. The global financial system is built upon global markets controlled by national financial and macroeconomic policies. In this context, regulatory asymmetries, diverging policy preferences, and government failures add a further dimension to global systemic risk not present at the national level.
Systemic risk is a result of the interplay between two independent variables: an underlying trigger event, in this analysis a domestic policy measure, and a transmission channel. The solution to systemic risk requires tackling one of these variables. In a domestic setting, the centralization of regulatory power into one single authority makes it easier to balance the delicate equilibrium between enhancing efficiency and reducing instability. However, in a global financial system in which national financial policies serve to maximize economic welfare, regulators will be confronted with difficult policy and legal tradeoffs.
We investigate the role that financial regulation plays in addressing domestic policy failures and in controlling the danger of global financial interdependence. To do so we analyse global financial interconnectedness, and explain its role in transmitting instability; we investigate the political economy dynamics at the origin of regulatory asymmetries and government failures; and we discuss the limits of regulation.

Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry

Objective: To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma.
Design: Cross-sectional observational study.Setting The primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry.
Participants: Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)—severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control).
Main outcome measures: Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group.
Results: 748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified.

Conclusions: Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.

Fluid strategies and outcomes in patients with acute respiratory distress syndrome, systemic inflammatory response syndrome and sepsis: a protocol for a systematic review and meta-analysis

Background
Fluid administration to critically ill patients remains the subject of considerable controversy. While intravenous fluid given for resuscitation may be life-saving, a positive fluid balance over time is associated with worse outcomes in critical illness. The aim of this systematic review is to summarise the existing evidence regarding the relationship between fluid administration or balance and clinically important patient outcomes in critical illness.

Methods
We will search Medline, EMBASE, the Cochrane Central Register of Controlled Trials from 1980 to the present and key conference proceedings from 2009 to the present. We will include studies of critically ill adults and children with acute respiratory distress syndrome (ARDS), sepsis and systemic inflammatory response syndrome (SIRS). We will include randomised controlled trials comparing two or more fluid regimens of different volumes of fluid and observational studies reporting the relationship between volume of fluid administered or fluid balance and outcomes including mortality, lengths of intensive care unit and hospital stay and organ dysfunction. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal. We will conduct a narrative and/or meta-analysis as appropriate.

Discussion
While fluid management has been extensively studied and discussed in the critical care literature, no systematic review has attempted to summarise the evidence for post-resuscitation fluid strategies in critical illness. Results of the proposed systematic review will inform practice and the design of future clinical trials.

Systematic review registration
PROSPERO CRD42013005608. (http://​www.​crd.​york.​ac.​uk/​PROSPERO/​)

Role of oxidative stress-induced systemic and cavernosal molecular alterations in the progression of diabetic erectile dysfunction

Background Erectile dysfunction (ED) is a prevalent complication of diabetes, and oxidative stress is an important feature of diabetic ED. Oxidative stress-induced damage plays a pivotal role in the development of tissue alterations. However, the deleterious effects of oxidative stress in the corpus cavernosum with the progression of diabetes remain unclear. The aim of this study was to evaluate systemic and penile oxidative stress status in the early and late stages of diabetes. Methods Male Wistar streptozotocin-diabetic rats (and age-matched controls) were examined 2 (early) and 8 weeks (late) after the induction of diabetes. Systemic oxidative stress was evaluated by urinary H2O2 and the ratio of circulating reduced/oxidized glutathione (GSH/GSSG). Penile oxidative status was assessed by H2O2 production and 3-nitrotyrosine (3-NT) formation. Cavernosal endothelial nitric oxide synthase (eNOS) was analyzed by quantitative immunohistochemistry. Dual immunofluorescence was also performed for 3-NT and α-smooth muscle actin (α-SMA) and eNOS–α-SMA. Results There was a significant increase in urinary H2O2 levels in both diabetic groups. The plasma GSH/GSSG ratio was significantly augmented in late diabetes. In cavernosal tissue, H2O2 production was significantly increased in late diabetes. Reactivity for 3-NT was located predominantly in cavernosal smooth muscle (SM) and was significantly reduced in late diabetes. Quantitative immunohistochemistry revealed a significant decrease in eNOS levels in cavernosal SM and endothelium in late diabetes. Conclusions The findings indicate that the noxious effects of oxidative stress are more prominent in late diabetes. Increased penile protein oxidative modifications and decreased eNOS expression may be responsible for structural and/or functional deregulation, contributing to the progression of diabetes-associated ED.

Aortic and Tricuspid Endocarditis in Hemodialysis Patient with Systemic and Pulmonary Embolism

This is a case report of a 43-year-old Caucasian male with end-stage renal disease being treated with hemodialysis and infective endocarditis in the aortic and tricuspid valves. The clinical presentation was dominated by neurologic impairment with cerebral embolism and hemorrhagic components. A thoracoabdominal computerized tomography scan revealed septic pulmonary embolus. The patient underwent empirical antibiotherapy with ceftriaxone, gentamicin and vancomycin, and the therapy was changed to flucloxacilin and gentamicin after the isolation of S. aureus in blood cultures. The multidisciplinary team determined that the patient should undergo valve replacement after the stabilization of the intracranial hemorrhage; however, on the 8th day of hospitalization, the patient entered cardiac arrest due to a massive septic pulmonary embolism and died. Despite the risk of aggravation of the hemorrhagic cerebral lesion, early surgical intervention should be considered in high-risk patients.

Systemic risk for financial institutions in UK

Marginal Expected Shortfall (MES) is an approach used to measure the systemic risk financial institutions face. It estimates how significantly systemic events (poor market performance, out of 1.6 times Standard Deviation borders) are expected to affect market capitalization of a particular firm. The concept was developed in the late 2000s and is widely used for cross-country comparisons of financial firms. For the purposes of generalization of this technique it is often used with market data containing non-domestic currencies for some financial firms. That may lead to results having currency noise in them as it is shown for 77 UK financial firms in our analysis between 2001 and 2014.

Raising the Level of Moral Thinking among Managers Will Not Help. Kohlberg's Conventionality and Systemic Ethical Flaws in Business

Business ethicists often assume that unethical behavior arises when individuals deviate from the norms and responsibilities that are institutionalized to frame economic activities. People's greed motivates them to violate the rules of the game. In Kohlberg's terms, it is assumed that such actors make decisions in a preconventional way and act opportunistically. In this article, we propose an alternative interpretation of deviant behavior, arguing that such behavior does not result from a lack of conventional moral guidance but rather from the fact that characteristics attributed to preconventional morality by Kohlberg - the purely incentive and punishment driven opportunistic morality - have become the conventionalized morality. The prevailing norms that economic actors have internalized as their yardstick are those of the preconventional Homo economicus. Not the deviation from, but the compliance with the rules of the game explains many forms of harmful and illegal decisions made in corporations.

Sclérodermie et risques oncologiques [Systemic sclerosis and cancer]

The combination of skin induration with clinical features such as dyspnea, facial telangiectasia, digital infarctions and/or dysphagia supports the diagnosis of systemic sclerosis. The oesophageal dysmotility is associated with symptoms which may delay the diagnosis of gastro-oesophageal cancer. Herein we report a case of long standing systemic sclerosis with heartburn and dysphagia symptoms which were monitored closely. Unfortunately, these symptoms delayed the diagnosis of gastric adenocarcinoma. This case prompted us to review the evidence of the association of cancer and systemic sclerosis and if any oncologic evaluation is required during the follow-up of patients affected with systemic sclerosis.

Quantitative and qualitative research on brief systemic therapies carried out within the framework of an ambulatory consultation for couples and families

Abstract: This article presents both a brief systemic intervention method (IBS) consisting in 6 sessions developed in an ambulatory service for couples and families, and two research projects done in collaboration with the Institute for Psychotherapy of the University of Lausanne. The first project is quantitative and it aims at evaluating the effectiveness of ISB. One of its main feature is that outcomes are assessed at different levels of individual and family functioning: 1) symptoms and individual functioning; 2) quality of marital relationship; 3) parental and co-parental relationships; 4) familial relationships. The second project is a qualitative case study about a marital therapy which identifies and analyses significant moments of the therapeutic process from the patients' perspective. Methodology was largely inspired by Daniel Stem's work about "moments of meeting" in psychotherapy. Results show that patients' theories about relationship and change are important elements that deepen our understanding of the change process in couple and family therapy. The interest of associating clinicians and researchers for the development and validation of a new clinical model is discussed.

Adjuvant early breast cancer systemic therapies according to daily used technologies.

Prognosis of early breast cancer patients is significantly improved with the use of adjuvant therapies. Various guidelines have been proposed to select patients who will derive the most benefit from such treatments. However, classifications have limited usefulness in subsets of patients such as those with node negative breast cancer. The 2007 St. Paul de Vence Clinical Practice Recommendations proposed to consider adjuvant therapy in accordance with the 10-year relapse-free survival reduction estimated by Adjuvant! Online. However, many limitations remain regarding the use of Adjuvant! Online. Among them, adverse prognostic and/or predictive factors such as vascular invasion, mitotic activity, progesterone receptor negativity, and HER-2 expression are not incorporated in the routine clinical decision process. Our group has therefore issued guidelines based on the consideration of both Adjuvant! Online calculations and the prognostic and/or predictive effects of these markers. In addition, web-accessible comprehensive tables summarizing these recommendations are provided.

The Swiss Systemic lupus erythematosus Cohort Study (SSCS) - cross-sectional analysis of clinical characteristics and treatments across different medical disciplines in Switzerland.

OBJECTIVES: To describe disease characteristics and treatment modalities in a multidisciplinary cohort of systemic lupus erythematosus (SLE) patients in Switzerland. METHODS: Cross-sectional analysis of 255 patients included in the Swiss SLE Cohort and coming from centres specialised in Clinical Immunology, Internal Medicine, Nephrology and Rheumatology. Clinical data were collected with a standardised form. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), an integer physician's global assessment score (PGA) ranging from 0 (inactive) to 3 (very active disease) and the erythrocyte sedimentation rate (ESR). The relationship between SLE treatment and activity was assessed by propensity score methods using a mixed-effect logistic regression with a random effect on the contributing centre. RESULTS: Of the 255 patients, 82% were women and 82% were of European ancestry. The mean age at enrolment was 44.8 years and the median SLE duration was 5.2 years. Patients from Rheumatology had a significantly later disease onset. Renal disease was reported in 44% of patients. PGA showed active disease in 49% of patients, median SLEDAI was 4 and median ESR was 14 millimetre/first hour. Prescription rates of anti-malarial drugs ranged from 3% by nephrologists to 76% by rheumatologists. Patients regularly using anti-malarial drugs had significantly lower SELENA-SLEDAI scores and ESR values. CONCLUSION: In our cohort, patients in Rheumatology had a significantly later SLE onset than those in Nephrology. Anti-malarial drugs were mostly prescribed by rheumatologists and internists and less frequently by nephrologists, and appeared to be associated with less active SLE.

Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.

BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.