Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness.

BACKGROUND: Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of BRCA-like tumour features (BRCAness) in these familial breast cancers where germline BRCA1 or BRCA2 mutations have not been identified is to a large extent unknown. METHODS: We performed whole-genome sequencing on matched tumour and normal samples from high-risk non-BRCA1/BRCA2 breast cancer families to understand the germline and somatic mutational landscape and mutational signatures. We measured BRCAness using HRDetect. As a comparator, we also analysed samples from BRCA1 and BRCA2 germline mutation carriers. RESULTS: We noted for non-BRCA1/BRCA2 tumours, only a small proportion displayed high HRDetect scores and were characterized by concomitant promoter hypermethylation or in one case a RAD51D splice variant previously reported as having unknown significance to potentially explain their BRCAness. Another small proportion showed no features of BRCAness but had mutationally active tumours. The remaining tumours lacked features of BRCAness and were mutationally quiescent. CONCLUSIONS: A limited fraction of high-risk familial non-BRCA1/BRCA2 breast cancer patients is expected to benefit from treatment strategies against homologue repair deficient cancer cells.

Review of gestational diabetes mellitus effects on vascular structure and function.

Vascular dysfunction has been described in women with a history of gestational diabetes mellitus. Furthermore, previous gestational diabetes mellitus increases the risk of developing Type 2 diabetes mellitus, a risk factor for cardiovascular disease. Factors contributing to vascular changes remain uncertain. The aim of this review was to summarize vascular structure and function changes found to occur in women with previous gestational diabetes mellitus and to identify factors that contribute to vascular dysfunction. A systematic search of electronic databases yielded 15 publications from 1998 to March 2014 that met the inclusion criteria. Our review confirmed that previous gestational diabetes mellitus contributes to vascular dysfunction, and the most consistent risk factor associated with previous gestational diabetes mellitus and vascular dysfunction was elevated body mass index. Heterogeneity existed across studies in determining the relationship of glycaemic levels and insulin resistance to vascular dysfunction.

Women with a history of gestational diabetes on long-term follow up have normal vascular function despite more dysglycemia, dyslipidemia and adiposity.

AIMS: Previous gestational diabetes (GDM) is a risk factor for type 2 diabetes and increased metabolic risk, but the link with vascular dysfunction is not clear. This study examined vascular function in women 4-10 years after a diagnosis of GDM who had a normal oral glucose tolerance test (OGTT) in the first postpartum year. METHODS: We studied 90 women with a history of GDM and 59 age-matched controls, examining differences in insulin resistance as measured by the Homeostatic Model Assessment (HOMA-IR) and glucose responses during an OGTT, adiposity, lipid profile and C-reactive protein (CRP). Using pulse wave analysis, we also measured cardiac function, vascular compliance, and systemic vascular resistance. RESULTS: Women with a history of GDM had higher measures of adiposity (body mass index 28.9 ± 6.5 vs. 26.6 ± 6.9 kg/m(2), P=0.04, waist-hip ratio 0.85 ± 0.06 vs. 0.79 ± 0.07, P<0.001), dyslipidemia (LDL cholesterol 2.78 ± 0.64 vs. 2.41 ± 0.56 mmol/L, P<0.001, total cholesterol: HDL cholesterol 3.93 ± 1.2 vs. 3.21 ± 0.82 mmol/L, P<0.001) and abnormal glucose metabolism (50% vs. 12%, P<0.001). However, there was no difference in CRP, HOMA-IR, or measures of cardiovascular function including pulse rate, pulse pressure, mean arterial pressure, cardiac output, systemic vascular resistance, small and large artery elasticity index. After controlling for adiposity, blood pressure, lipids and CRP, glycemic status did not contribute to vascular function. CONCLUSION: Despite a higher incidence of adiposity, dyslipidemia, and impaired glycemia, women with a history of GDM who had a normal postpartum OGTT did not have impaired vascular function 4-10 years postpartum, when compared to healthy controls.

The development of an electronic database for Acute Pain Service outcomes.

BACKGROUND: Quality assurance is increasingly important in the current health care climate. An electronic database can be used for tracking patient information and as a research tool to provide quality assurance for patient care. OBJECTIVE: An electronic database was developed for the Acute Pain Service, University of Alberta Hospital (Edmonton, Alberta) to record patient characteristics, identify at-risk populations, compare treatment efficacies and guide practice decisions. METHOD: Steps in the database development involved identifying the goals for use, relevant variables to include, and a plan for data collection, entry and analysis. Protocols were also created for data cleaning quality control. The database was evaluated with a pilot test using existing data to assess data collection burden, accuracy and functionality of the database.  RESULTS: A literature review resulted in an evidence-based list of demographic, clinical and pain management outcome variables to include. Time to assess patients and collect the data was 20 min to 30 min per patient. Limitations were primarily software related, although initial data collection completion was only 65% and accuracy of data entry was 96%. CONCLUSIONS: The electronic database was found to be relevant and functional for the identified goals of data storage and research.

Alcohol use while on the liver transplant waiting list: a single-center experience.

Alcoholic liver disease (ALD) is a leading indication for liver transplantation. Our center has randomly checked blood alcohol levels (BALs) in ALD patients on the waiting list since 2004. We aimed to identify the incidence and predictors of inactivation on the transplant list due to alcohol use and to determine the utility of BAL-screening in this process. We conducted a retrospective review of patients with ALD listed for liver transplantation with at least 3 months of postlisting follow-up. Alcohol use while on the transplant list was defined as a positive BAL, an admission of alcohol use, or refusal to perform screening within 12 hours of request. Cox proportional hazards regression was used to estimate risk ratios (RRs). Of 134 patients meeting eligibility criteria, 78% were male, and mean age was 52 years. Alcohol use was documented in 23 patients (17%). Of these, 12 refused to have a random screen, 8 had detectable serum ethanol levels, and 3 had self-reported alcohol use. On multivariable analysis, a higher number of random BAL-checks [RR = 0.63(0.52, 0.76), P = 0.001] and a longer duration of prelisting abstinence [RR = 0.88(0.83, 0.94), P = 0.001] independently reduced the risk of alcohol use by patients while on the waiting list. None of the patients with >24 months of prelisting abstinence had a positive screen. In conclusion, this study supports random BAL-screening before transplantation and reinforces the importance of abstinence duration as a predictor of relapse. For patients with <24 months of prelisting abstinence, our center will increase the frequency of random BAL screening and increase the rehabilitation requirements to include an intensive 3-week rehabilitation program. We hope that these measures will reduce the rate of relapse to alcohol use post-transplantation.

Efficacy of N-acetylcysteine and hydration versus placebo and hydration in decreasing contrast-induced renal dysfunction in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention.

OBJECTIVE: Contrast-induced renal dysfunction is an iatrogenic complication that occurs more frequently in patients with preexisting renal dysfunction. A prospective, double-blind, randomized, placebo, controlled trial was completed to assess the efficacy of N-acetylcysteine in decreasing the incidence of contrast-induced renal dysfunction in patients with an acute coronary syndrome and renal insufficiency who underwent coronary angiography with or without percutaneous coronary intervention. METHODS: With similar intravenous hydration protocols, 20 patients received N-acetylcysteine (treatment group) and 20 patients received placebo (control group) in a twice per day dosing regimen with one dose before and three doses after contrast media exposure. RESULTS: The two groups were similar at baseline on demographic and clinical characteristics, and preexisting renal insufficiency. Contrast-induced renal dysfunction, defined as an increase in serum creatinine greater than 44 micromol/L (.5 mg/dL) and/or 25% above baseline within 48 hours, occurred in 7.5% of the cohort, with 2.5% in the treatment group, and 5% in the control group, for an absolute difference of 2.5%. There was no difference in serum creatinine or creatinine clearance at 24 hours or at 48 hours between the treatment and control groups. CONCLUSION: These results suggest that this cohort gained no added protection to renal function with the use of N-acetylcysteine.

Arctic vegetation damage by winter-generated coal mining pollution released upon thawing.

Acid mine drainage (known as AMD) is a well-known environmental problem resulting from the oxidation of sulfidic mine waste. In cold regions, AMD is often considered limited by low temperatures most of the year and observed environmental impact is related to pollution generated during the warm summer period. Here we show that heat generation within an oxidizing, sulfidic, coal-mining waste-rock pile in Svalbard (78 degrees N) is high enough to keep the pile warm (roughly 5 degrees C throughout the year) despite mean annual air temperatures below -5 degrees C. Consequently, weathering processes continue year-round within the waste-rock pile. During the winter, weathering products accumulate within the pile because of a frozen outer layer on the pile and are released as a flush within 2 weeks of soil thawing in the spring. Consequently, spring runoff water contains elevated concentrations of metals. Several of these metals are taken up and accumulated in plants where they reach phytotoxic levels, including aluminum and manganese. Laboratory experiments document that uptake of Al and Mn in native plant species is highly correlated with dissolved concentrations. Therefore, future remedial actions to control the adverse environmental impacts of cold region coal-mining need to pay more attention to winter processes including AMD generation and accumulation of weathering products.

Improving adherence to a mechanical ventilation weaning protocol for critically ill adults: outcomes after an implementation program.

BACKGROUND: Despite multiple reminders, education sessions, and multidisciplinary team involvement, adherence to an evidence-based mechanical ventilation weaning protocol had been less than 1% in a general systems intensive care unit since implementation. OBJECTIVE: To assess the effectiveness of using an implementation program, the Model for Accelerating Improvement, to improve adherence and clinical outcomes after restarting a mechanical ventilation weaning protocol in an adult general systems intensive care unit. METHODS: A prospective comparative design, before and after implementation of the Model for Accelerating Improvement, was used with a consecutive sample of 129 patients and 112 multidisciplinary team members. Clinical outcomes were rate of unsuccessful extubations, rate of ventilator-associated pneumonia, and duration of mechanical ventilation; practice outcomes were staff's understanding of the mechanical ventilation weaning protocol, perceptions of the practice safety climate, and adherence to the weaning protocol. RESULTS: After the intervention, the rate of unsuccessful extubations decreased, and staff's understanding of and adherence to the weaning protocol increased significantly. The rate of ventilator-associated pneumonia, duration of mechanical ventilation, and staff's perceptions of the practice safety climate did not change significantly. CONCLUSION: Implementing the Model for Accelerating Improvement improved understanding of and adherence to protocol-directed weaning and reduced the rate of unsuccessful extubations.

Women with coronary artery disease report worse health-related quality of life outcomes compared to men.

BACKGROUND: Although there have been substantial medical advances that improve the outcomes following cardiac ischemic events, gender differences in the treatment and course of recovery for patients with coronary artery disease (CAD) continue to exist. There is a general paucity of data comparing the health related quality of life (HRQOL) in men and women undergoing treatment for CAD. The purpose of this study was to compare HRQOL outcomes of men and women in Alberta, at one-year following initial catheterization, after adjustment for known demographic, co-morbid, and disease severity predictors of outcome. METHOD: The HRQOL outcome data were collected by means of a self-reported questionnaire mailed to patients on or near the one-year anniversary of their initial cardiac catheterization. Using the Seattle Angina Questionnaire (SAQ), 5 dimensions of HRQOL were measured: exertional capacity, anginal stability, anginal frequency, quality of life and treatment satisfaction. Data from the APPROACH registry were used to risk-adjust the SAQ scale scores. Two analytical strategies were used including general least squares linear modeling, and proportional odds modeling sometimes referred to as the "ordinal logistic modeling". RESULTS: 3392 (78.1%) patients responded to the follow-up survey. The adjusted proportional odds ratios for men relative to women (PORs > 1 = better) indicated that men reported significantly better HRQOL on all 5 SAQ dimensions as compared to women. (PORs: Exertional Capacity 3.38 (2.75-4.15), Anginal Stability 1.23 (1.03-1.47), Anginal Frequency 1.70 (1.43-2.01), Treatment Satisfaction 1.27 (1.07-1.50), and QOL 1.74 (1.48-2.04). CONCLUSIONS: Women with CAD consistently reported worse HRQOL at one year follow-up compared to men. These findings underline the fact that conclusions based on research performed on men with CAD may not be valid for women and that more gender-related research is needed. Future studies are needed to further examine gender differences in psychosocial adjustment following treatment for CAD, as adjustment for traditional clinical variables fails to explain sex differences in health related quality of life outcomes.

Referral rate and outcomes of cardiac rehabilitation after cardiac catheterization in a large Canadian city.

PURPOSE: The benefits of cardiac rehabilitation (CR) for patients with coronary artery disease are extensive and compelling, demonstrating reductions in mortality. However, some reports suggest that only 10% to 20% of eligible patients currently participate in formal CR programs. The purpose of this study was to identify the proportion of patients referred to CR in a large Canadian city, and to determine their statistically adjusted survival rates relative to patients not referred to CR. METHODS: Subjects eligible for this study included all adult residents with coronary artery disease from 1995 to 1999 in the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry. All 5,081 patients who survived 6 months or more after catheterization were included in the analysis. Survival data were adjusted using a Cox proportional hazards model. RESULTS: Referral to a CR program (28.9% of patients) was significantly more likely for young male patients who had undergone a prior revascularization procedure, presented with an ejection fraction exceeding 50%, and did not report cerebrovascular, peripheral vascular, or renal disease. Crude hazard ratios indicated that referral to a CR program remained significantly associated with lower mortality after control was used for clinical, anatomic, treatment and comorbid conditions recorded at catheterization (hazard ratio, 0.68; 95% confidence interval, 0.51-0.90; P = .005). CONCLUSIONS: Despite the proven efficacy of CR in clinical trials, fewer than one third of the patients undergoing cardiac catheterization are referred to a CR program. The better survival outcomes noted for patients referred to CR suggests that there is an opportunity to improve care and outcomes through increased referral of patients to such programs.

The notion of evidence in evidence-based practice by the Nursing Philosophy Working Group.

Questions concerning the nature of evidence in evidence-based practice have kindled debate within nursing and other health care disciplines. Such questions include the ends for which evidence is sought, the form(s) of evidence, and the values underlying evidence-based practice. In this article, some of the issues, contradictions, and tensions implicit in these questions are highlighted. It is imperative that the nursing profession continue to explore the philosophic perspectives that underscore evidence-based practice and their implications for decision making in nursing practice.