Copy number aberrations (CNAs) in cancer affect disease outcomes by regulating molecular phenotypes, such as gene expressions, that drive important biological processes. To gain comprehensive ...insights into molecular biomarkers for cancer, it is critical to identify key groups of CNAs, the associated gene modules, regulatory modules, and their downstream effect on outcomes.
In this paper, we demonstrate an innovative use of sparse canonical correlation analysis (sCCA) to effectively identify the ensemble of CNAs, and gene modules in the context of binary and censored disease endpoints. Our approach detects potentially orthogonal gene expression modules which are highly correlated with sets of CNA and then identifies the genes within these modules that are associated with the outcome.
Analyzing clinical and genomic data on 1,904 breast cancer patients from the METABRIC study, we found 14 gene modules to be regulated by groups of proximally located CNA sites. We validated this finding using an independent set of 1,077 breast invasive carcinoma samples from The Cancer Genome Atlas (TCGA). Our analysis of 7 clinical endpoints identified several novel and interpretable regulatory associations, highlighting the role of CNAs in key biological pathways and processes for breast cancer. Genes significantly associated with the outcomes were enriched for early estrogen response pathway, DNA repair pathways as well as targets of transcription factors such as E2F4, MYC, and ETS1 that have recognized roles in tumor characteristics and survival. Subsequent meta-analysis across the endpoints further identified several genes through the aggregation of weaker associations.
Our findings suggest that sCCA analysis can aggregate weaker associations to identify interpretable and important genes, modules, and clinically consequential pathways.
Abstract Objective Physician suicide is an important public health problem as the rate of suicide is higher among physicians than the general population. Unfortunately, few studies have evaluated ...information about mental health comorbidities and psychosocial stressors which may contribute to physician suicide. We sought to evaluate these factors among physicians versus non-physician suicide victims. Methods We used data from the United States National Violent Death Reporting System to evaluate demographics, mental health variables, recent stressors and suicide methods among physician versus non-physician suicide victims in 17 states. Results The data set included 31,636 suicide victims of whom 203 were identified as physicians. Multivariable logistic regression found that having a known mental health disorder or a job problem which contributed to the suicide significantly predicted being a physician. Physicians were significantly more likely than non-physicians to have antipsychotics, benzodiazepines and barbiturates present on toxicology testing but not antidepressants. Conclusions Mental illness is an important comorbidity for physicians who complete a suicide but postmortem toxicology data shows low rates of medication treatment. Inadequate treatment and increased problems related to job stress may be potentially modifiable risk factors to reduce suicidal death among physicians.
Use of Magnesium in Traumatic Brain Injury Sen, Ananda P.; Gulati, Anil
Neurotherapeutics,
January 2010, 1-2010, 2010-Jan, 2010-01-00, 20100101, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Open access
Depletion of magnesium is observed in animal brain and in human blood after brain injury. Treatment with magnesium attenuates the pathological and behavioral changes in rats with brain injury; ...however, the therapeutic effect of magnesium has not been consistently observed in humans with traumatic brain injury (TBI). Secondary brain insults are observed in patients with brain injury, which adversely affect clinical outcome. Systemic administration studies in rats have shown that magnesium enters the brain; however, inducing hypermagnesemia in humans did not concomitantly increase magnesium levels in the CSF. We hypothesize that the neuroprotective effects of magnesium in TBI patients could be observed by increasing its brain bioavailability with mannitol. Here, we review the role of magnesium in brain injury, preclinical studies in brain injury, clinical safety and efficacy studies in TBI patients, brain bioavailability studies in rat, and pharmacokinetic studies in humans with brain injury. Neurodegeneration after brain injury involves multiple biochemical pathways. Treatment with a single agent has often resulted in poor efficacy at a safe dose or toxicity at a therapeutic dose. A successful neuroprotective therapy needs to be aimed at homeostatic control of these pathways with multiple agents. Other pharmacological agents, such as dexanabinol and progesterone, and physiological interventions, with hypothermia and hyperoxia, have been studied for the treatment of brain injury. Treatment with magnesium and hypothermia has shown favorable outcome in rats with cerebral ischemia. We conclude that coadministration of magnesium and mannitol with pharmacological and physiological agents could be an effective neuroprotective regimen for the treatment of TBI.
Background Patients receiving long-term dialysis have among the highest mortality and hospitalization rates. In the nonrenal literature, functional dependence is recognized as a contributor to ...subsequent disability, recurrent hospitalization, and increased mortality. A higher burden of functional dependence with progressive worsening of kidney function has been observed in several studies, suggesting that functional dependence may contribute to both morbidity and mortality in dialysis patients. Study Design Prospective cohort study. Setting & Participants 7,226 hemodialysis patients from 12 countries in the DOPPS (Dialysis Outcomes and Practice Patterns Study) phase 4 (2009-2011) with self-reported data for functional status. Predictor Patients’ ability to perform 13 basic and instrumental activities of daily living was summarized to create an overall functional status score (range, 1.25 most dependent to 13 functionally independent). Outcome Cox regression was used to estimate the association between functional status and all-cause mortality, adjusting for several demographic and clinical risk factors for mortality. Median follow-up was 17.2 months. Results The proportion of patients who could perform each activity of daily living task without assistance ranged from 97% (eating) to 47% (doing housework). 36% of patients could perform all 13 tasks without assistance (functional status = 13), and 14% of patients had high functional dependence (functional status < 8). Functionally independent patients were younger and had many indicators of better health status, including higher quality of life. Compared with functionally independent patients, the adjusted HR for mortality was 2.37 (95% CI, 1.92-2.94) for patients with functional status < 8. Limitations Possible nonresponse bias and residual confounding. Conclusions We found a high burden of functional dependence across all age groups and across all DOPPS countries. When adjusting for several known mortality risk factors, including age, access type, cachexia, and multimorbidity, functional dependence was a strong consistent predictor of mortality.
Background
The majority of breast cancer patients use complementary and/or integrative therapies during and beyond cancer treatment to manage symptoms, prevent toxicities, and improve quality of ...life. Practice guidelines are needed to inform clinicians and patients about safe and effective therapies.
Methods
Following the Institute of Medicine’s guideline development process, a systematic review identified randomized controlled trials testing the use of integrative therapies for supportive care in patients receiving breast cancer treatment. Trials were included if the majority of participants had breast cancer and/or breast cancer patient results were reported separately, and outcomes were clinically relevant. Recommendations were organized by outcome and graded based upon a modified version of the US Preventive Services Task Force grading system.
Results
The search (January 1, 1990–December 31, 2013) identified 4900 articles, of which 203 were eligible for analysis. Meditation, yoga, and relaxation with imagery are recommended for routine use for common conditions, including anxiety and mood disorders (Grade A). Stress management, yoga, massage, music therapy, energy conservation, and meditation are recommended for stress reduction, anxiety, depression, fatigue, and quality of life (Grade B). Many interventions (n = 32) had weaker evidence of benefit (Grade C). Some interventions (n = 7) were deemed unlikely to provide any benefit (Grade D). Notably, only one intervention, acetyl-l-carnitine for the prevention of taxane-induced neuropathy, was identified as likely harmful (Grade H) as it was found to increase neuropathy. The majority of intervention/modality combinations (n = 138) did not have sufficient evidence to form specific recommendations (Grade I).
Conclusions
Specific integrative therapies can be recommended as evidence-based supportive care options during breast cancer treatment. Most integrative therapies require further investigation via well-designed controlled trials with meaningful outcomes.
Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in ...rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.
Background Predialysis serum sodium concentrations recently have been linked to patient characteristics and outcomes in hemodialysis patients and may have implications for the dialysate sodium ...prescription. Study Design Prospective cohort study. Participants 11,555 patients from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS), phases I (1996-2001) and III (2005-2008). Predictors Demographics, comorbid conditions, laboratory measurements (model 1); mean serum sodium level, dialysate sodium concentration (model 2). Outcomes Serum sodium level, using adjusted linear mixed models (model 1); all-cause mortality, using Cox proportional hazards models (model 2). Results Median follow-up was 12 months, with 1,727 deaths (15%) occurring during the study period (12,274 patient-years). Mean serum sodium level in the DOPPS countries was 138.5 ± 2.8 mEq/L. Japan had the highest (139.1 ± 2.6 mEq/L) and Australia/New Zealand had the lowest mean serum sodium level (137.4 ± 2.8 mEq/L). Serum sodium level was associated positively with male sex, black race, body mass index, serum albumin level, and creatinine level and negatively with neurologic and psychiatric disease, white blood cell count, and intradialytic weight loss (0.16 mEq/L lower per 1% loss). Higher serum sodium level was associated with lower adjusted all-cause mortality in a continuous model (HR, 0.95 per 1 mEq/L higher; 95% CI, 0.93-0.97). Dialysate sodium prescription was not associated with serum sodium level. Mortality analyses restricted to the serum sodium tertile with the highest mortality (serum sodium <137 mEq/L) showed lower mortality risk in patients with dialysate sodium prescriptions >140 mEq/L. Limitations Causality cannot be established in this observational study, which does not consider potential effects of dialysate sodium level on postdialysis thirst, dietary salt and water intake, interdialytic weight gain, and cardiovascular stability. Conclusions Lower serum sodium levels are associated with certain hemodialysis patient characteristics and higher adjusted risk of death. The lower mortality observed in our adjusted analyses in patients with serum sodium levels <137 mEq/L dialyzed against dialysate sodium prescriptions >140 mEq/L is intriguing, may be related to intradialytic cardiovascular stability, and deserves further study.
The linearity (or lack thereof) of association between sample mean and sample variance is explored in this note with the intent of providing new insights. Of particular interest is a well-known ...inequality involving the measures of skewness and kurtosis that is derived as a consequence of an identity involving the correlation between sample mean and sample variance. The nature of association between the two is explored further by means of the conditional expectation of the sample variance given the mean. We present several characterization results where the specific relationship of this conditional expectation and sample mean uniquely determines the parent population. The note is presented at a level accessible to graduate or upper-level undergraduate students with several illustrative examples included as teaching aid.
Communication and language barriers isolate Deaf American Sign Language (ASL) users from mass media, health care messages, and health care communication, which, when coupled with social ...marginalization, places them at a high risk for inadequate health literacy. Our objectives were to translate, adapt, and develop an accessible health literacy instrument in ASL and to assess the prevalence and correlates of inadequate health literacy among Deaf ASL users and hearing English speakers using a cross-sectional design. A total of 405 participants (166 Deaf and 239 hearing) were enrolled in the study. The Newest Vital Sign was adapted, translated, and developed into an ASL version (ASL-NVS). We found that 48% of Deaf participants had inadequate health literacy, and Deaf individuals were 6.9 times more likely than hearing participants to have inadequate health literacy. The new ASL-NVS, available on a self-administered computer platform, demonstrated good correlation with reading literacy. The prevalence of Deaf ASL users with inadequate health literacy is substantial, warranting further interventions and research.
Objective The objective of the study was to determine the prevalence and characteristics of vulvodynia among women in southeast Michigan. Study design A population-based study of adult women was ...conducted, using telephone recruitment and completion of a self-administered survey. Weighted estimates of vulvodynia prevalence and characteristics were determined. Results Over a year, 2542 women were recruited and 2269 (89.3%) completed the self-administered survey. The weighted prevalence of vulvodynia was 8.3% (95% confidence interval, 7.0–9.8) or approximately 101,000 women in the targeted population. Prevalence remained stable through age 70 years and declined thereafter. Among sexually active women, the prevalence was similar at all ages. Of 208 women meeting vulvodynia criteria, 101 (48.6%) had sought treatment, and only 3 (1.4%) had been diagnosed with vulvodynia (unweighted values). Previous vulvodynia symptoms had resolved in 384 women (16.9%) after a mean duration of 12.5 years. Conclusion Vulvodynia is common, although rarely diagnosed. Prevalence remains high among sexually active women of any age.
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