Survival expectations of the obese: Is excess mortality reflected in perceptions?

OBJECTIVE: This study compared self-reported subjective life expectancy (i.e., probability of living to age 75) for normal-weight, overweight, and obese weight groups to examine whether individuals are internalizing information about the health risks due to excessive weight. RESEARCH METHODS AND PROCEDURES: Using data from the Health and Retirement Study, a total of 9035 individuals 51 to 61 years old were analyzed by BMI category. The primary outcome measure was individuals' reports about their own expectations of survival to age 75. Absolute and relative risks of survival were compared with published estimates of survival to age 75. RESULTS: Consistently, higher levels of BMI were associated with lower self-estimated survival probabilities. Differences relative to normal weight ranged from 4.9% (p < 0.01) for male nonsmokers to 8.8% (p < 0.001) for female nonsmokers. However, these differences were substantially less than those obtained from published survival curve estimates, suggesting that obese individuals tended to underestimate mortality risks. DISCUSSION: Individuals appeared to underestimate the mortality risks of excessive weight; thus, knowledge campaigns about the risks of obesity should remain a top priority.

Researcher practices on returning genetic research results.

BACKGROUND/AIMS: as genetic and genomic research proliferates, debate has ensued about returning results to participants. In addition to consideration of the benefits and harms to participants, researchers must also consider the logistical and financial feasibility of returning research results. However, little data exist of actual researcher practices. METHODS: we conducted an online survey of 446 corresponding authors of genetic/genomic studies conducted in the United States and published in 2006-2007 to assess the frequency with which they considered, offered to, or actually returned research results, what factors influenced these decisions, and the method of communicating results. RESULTS: the response rate was 24% (105/446). Fifty-four percent of respondents considered the issue of returning research results to participants, 28% offered to return individual research results, and 24% actually returned individual research results. Of those who considered the issue of returning research results during the study planning phase, the most common factors considered were whether research results were deemed clinically useful (18%) and respect for participants (13%). Researchers who had a medical degree and conducted studies on children were significantly more likely to offer to return or actually return individual results compared to those with a Ph.D. only. CONCLUSIONS: we speculate that issues associated with clinical validity and respect for participants dominated concerns of time and expense given the prominent and continuing ethical debates surrounding genetics and genomics research. The substantial number of researchers who did not consider returning research results suggests that researchers and institutional review boards need to devote more attention to a topic about which research participants are interested.

Anti-cholinergic load, health care utilization, and survival in people with advanced cancer: a pilot study.

INTRODUCTION: Anti-cholinergic medications have been associated with increased risks of cognitive impairment, premature mortality and increased risk of hospitalisation. Anti-cholinergic load associated with medication increases as death approaches in those with advanced cancer, yet little is known about associated adverse outcomes in this setting. METHODS: A substudy of 112 participants in a randomised control trial who had cancer and an Australia modified Karnofsky Performance Scale (AKPS) score (AKPS) of 60 or above, explored survival and health service utilisation; with anti-cholinergic load calculated using the Clinician Rated Anti-cholinergic Scale (modified version) longitudinally to death. A standardised starting point for prospectively calculating survival was an AKPS of 60 or above. RESULTS: Baseline entry to the sub-study was a mean 62 +/- 81 days (median 37, range 1-588) days before death (survival), with mean of 4.8 (median 3, SD 4.18, range 1 - 24) study assessments in this time period. Participants spent 22% of time as an inpatient. There was no significant association between anti-cholinergic score and time spent as an inpatient (adjusted for survival time) (p = 0.94); or survival time. DISCUSSION: No association between anti-cholinergic load and survival or time spent as an inpatient was seen. Future studies need to include cognitively impaired populations where the risks of symptomatic deterioration may be more substantial.

Communication practices in physician decision-making for an unstable critically ill patient with end-stage cancer.

BACKGROUND: Shared decision-making has become the standard of care for most medical treatments. However, little is known about physician communication practices in the decision making for unstable critically ill patients with known end-stage disease. OBJECTIVE: To describe communication practices of physicians making treatment decisions for unstable critically ill patients with end-stage cancer, using the framework of shared decision-making. DESIGN: Analysis of audiotaped encounters between physicians and a standardized patient, in a high-fidelity simulation scenario, to identify best practice communication behaviors. The simulation depicted a 78-year-old man with metastatic gastric cancer, life-threatening hypoxia, and stable preferences to avoid intensive care unit (ICU) admission and intubation. Blinded coders assessed the encounters for verbal communication behaviors associated with handling emotions and discussion of end-of-life goals. We calculated a score for skill at handling emotions (0-6) and at discussing end of life goals (0-16). SUBJECTS: Twenty-seven hospital-based physicians. RESULTS: Independent variables included physician demographics and communication behaviors. We used treatment decisions (ICU admission and initiation of palliation) as a proxy for accurate identification of patient preferences. Eight physicians admitted the patient to the ICU, and 16 initiated palliation. Physicians varied, but on average demonstrated low skill at handling emotions (mean, 0.7) and moderate skill at discussing end-of-life goals (mean, 7.4). We found that skill at discussing end-of-life goals was associated with initiation of palliation (p = 0.04). CONCLUSIONS: It is possible to analyze the decision making of physicians managing unstable critically ill patients with end-stage cancer using the framework of shared decision-making.

Daily intake of antioxidants in relation to survival among adult patients diagnosed with malignant glioma.

BACKGROUND: Malignant glioma is a rare cancer with poor survival. The influence of diet and antioxidant intake on glioma survival is not well understood. The current study examines the association between antioxidant intake and survival after glioma diagnosis. METHODS: Adult patients diagnosed with malignant glioma during 1991-1994 and 1997-2001 were enrolled in a population-based study. Diagnosis was confirmed by review of pathology specimens. A modified food-frequency questionnaire interview was completed by each glioma patient or a designated proxy. Intake of each food item was converted to grams consumed/day. From this nutrient database, 16 antioxidants, calcium, a total antioxidant index and 3 macronutrients were available for survival analysis. Cox regression estimated mortality hazard ratios associated with each nutrient and the antioxidant index adjusting for potential confounders. Nutrient values were categorized into tertiles. Models were stratified by histology (Grades II, III, and IV) and conducted for all (including proxy) subjects and for a subset of self-reported subjects. RESULTS: Geometric mean values for 11 fat-soluble and 6 water-soluble individual antioxidants, antioxidant index and 3 macronutrients were virtually the same when comparing all cases (n=748) to self-reported cases only (n=450). For patients diagnosed with Grade II and Grade III histology, moderate (915.8-2118.3 mcg) intake of fat-soluble lycopene was associated with poorer survival when compared to low intake (0.0-914.8 mcg), for self-reported cases only. High intake of vitamin E and moderate/high intake of secoisolariciresinol among Grade III patients indicated greater survival for all cases. In Grade IV patients, moderate/high intake of cryptoxanthin and high intake of secoisolariciresinol were associated with poorer survival among all cases. Among Grade II patients, moderate intake of water-soluble folate was associated with greater survival for all cases; high intake of vitamin C and genistein and the highest level of the antioxidant index were associated with poorer survival for all cases. CONCLUSIONS: The associations observed in our study suggest that the influence of some antioxidants on survival following a diagnosis of malignant glioma are inconsistent and vary by histology group. Further research in a large sample of glioma patients is needed to confirm/refute our results.

Targeting A20 decreases glioma stem cell survival and tumor growth.

Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.

Epigenetic regulation of the nitrosative stress response and intracellular macrophage survival by extraintestinal pathogenic Escherichia coli.

Extraintestinal pathogenic Escherichia coli (ExPEC) reside in the enteric tract as a commensal reservoir, but can transition to a pathogenic state by invading normally sterile niches, establishing infection and disseminating to invasive sites like the bloodstream. Macrophages are required for ExPEC dissemination, suggesting the pathogen has developed mechanisms to persist within professional phagocytes. Here, we report that FimX, an ExPEC-associated DNA invertase that regulates the major virulence factor type 1 pili (T1P), is also an epigenetic regulator of a LuxR-like response regulator HyxR. FimX regulated hyxR expression through bidirectional phase inversion of its promoter region at sites different from the type 1 pili promoter and independent of integration host factor (IHF). In vitro, transition from high to low HyxR expression produced enhanced tolerance of reactive nitrogen intermediates (RNIs), primarily through de-repression of hmpA, encoding a nitric oxide-detoxifying flavohaemoglobin. However, in the macrophage, HyxR produced large effects on intracellular survival in the presence and absence of RNI and independent of Hmp. Collectively, we have shown that the ability of ExPEC to survive in macrophages is contingent upon the proper transition from high to low HyxR expression through epigenetic regulatory control by FimX.

Environmental management for malaria control: knowledge and practices in Mvomero, Tanzania.

Environmental conditions play an important role in the transmission of malaria; therefore, regulating these conditions can help to reduce disease burden. Environmental management practices for disease control can be implemented at the community level to complement other malaria control methods. This study assesses current knowledge and practices related to mosquito ecology and environmental management for malaria control in a rural, agricultural region of Tanzania. Household surveys were conducted with 408 randomly selected respondents from 10 villages and qualitative data were collected through focus group discussions and in-depth interviews. Results show that respondents are well aware of the links between mosquitoes, the environment, and malaria. Most respondents stated that cleaning the environment around the home, clearing vegetation around the home, or draining stagnant water can reduce mosquito populations, and 63% of respondents reported performing at least one of these techniques to protect themselves from malaria. It is clear that many respondents believe that these environmental management practices are effective malaria control methods, but the actual efficacy of these techniques for controlling populations of vectors or reducing malaria prevalence in the varying ecological habitats in Mvomero is unknown. Further research should be conducted to determine the effects of different environmental management practices on both mosquito populations and malaria transmission in this region, and increased participation in effective techniques should be promoted.

Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.

Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of betaARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of betaARK1 (betaARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca(2+)-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 +/- 1 weeks). In contrast, CSQ/betaARKct mice exhibited a significant increase in mean survival age (15 +/- 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/betaARKct, left ventricular end diastolic dimension 5.60 +/- 0.17 mm vs. 4.19 +/- 0.09 mm, P < 0.005; % fractional shortening, 15 +/- 2 vs. 36 +/- 2, P < 0.005). The enhancement of the survival rate in CSQ/betaARKct mice was substantially potentiated by chronic treatment with the betaAR antagonist metoprolol (CSQ/betaARKct nontreated vs. CSQ/betaARKct metoprolol treated, 15 +/- 1 weeks vs. 25 +/- 2 weeks, P < 0.0001). Thus, overexpression of the betaARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with beta-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of betaARK1 inhibition.

Neuronal Survival of the Fittest: The Importance of Aerobic Capacity in Exercise-Induced Neurogenesis and Cognition

It is commonly accepted that aerobic exercise increases hippocampal neurogenesis, learning and memory, as well as stress resiliency. However, human populations are widely variable in their inherent aerobic fitness as well as their capacity to show increased aerobic fitness following a period of regimented exercise. It is unclear whether these inherent or acquired components of aerobic fitness play a role in neurocognition. To isolate the potential role of inherent aerobic fitness, we exploited a rat model of high (HCR) and low (LCR) inherent aerobic capacity for running. At a baseline, HCR rats have two- to three-fold higher aerobic capacity than LCR rats. We found that HCR rats also had two- to three- fold more young neurons in the hippocampus than LCR rats as well as rats from the heterogeneous founder population. We then asked whether this enhanced neurogenesis translates to enhanced hippocampal cognition, as is typically seen in exercise-trained animals. Compared to LCR rats, HCR rats performed with high accuracy on tasks designed to test neurogenesis-dependent pattern separation ability by examining investigatory behavior between very similar objects or locations. To investigate whether an aerobic response to exercise is required for exercise-induced changes in neurogenesis and cognition, we utilized a rat model of high (HRT) and low (LRT) aerobic response to treadmill training. At a baseline, HRT and LRT rats have comparable aerobic capacity as measured by a standard treadmill fit test, yet after a standardized training regimen, HRT but not LRT rats robustly increase their aerobic capacity for running. We found that sedentary LRT and HRT rats had equivalent levels of hippocampal neurogenesis, but only HRT rats had an elevation in the number of young neurons in the hippocampus following training, which was positively correlated with accuracy on pattern separation tasks. Taken together, these data suggest that a significant elevation in aerobic capacity is necessary for exercise-induced hippocampal neurogenesis and hippocampal neurogenesis-dependent learning and memory. To investigate the potential for high aerobic capacity to be neuroprotective, doxorubicin chemotherapy was administered to LCR and HCR rats. While doxorubicin induces a progressive decrease in aerobic capacity as well as neurogenesis, HCR rats remain at higher levels on those measures compared to even saline-treated LCR rats. HCR and LCR rats that received exercise training throughout doxorubicin treatment demonstrated positive effects of exercise on aerobic capacity and neurogenesis, regardless of inherent aerobic capacity. Overall, these findings demonstrate that inherent and acquired components of aerobic fitness play a crucial role not only in the cardiorespiratory system but also the fitness of the brain.

Gene selection using iterative feature elimination random forests for survival outcomes.

Although many feature selection methods for classification have been developed, there is a need to identify genes in high-dimensional data with censored survival outcomes. Traditional methods for gene selection in classification problems have several drawbacks. First, the majority of the gene selection approaches for classification are single-gene based. Second, many of the gene selection procedures are not embedded within the algorithm itself. The technique of random forests has been found to perform well in high-dimensional data settings with survival outcomes. It also has an embedded feature to identify variables of importance. Therefore, it is an ideal candidate for gene selection in high-dimensional data with survival outcomes. In this paper, we develop a novel method based on the random forests to identify a set of prognostic genes. We compare our method with several machine learning methods and various node split criteria using several real data sets. Our method performed well in both simulations and real data analysis.Additionally, we have shown the advantages of our approach over single-gene-based approaches. Our method incorporates multivariate correlations in microarray data for survival outcomes. The described method allows us to better utilize the information available from microarray data with survival outcomes.

Nurse-led behavioral management of diabetes and hypertension in community practices: a randomized trial.

BACKGROUND: Several trials have demonstrated the efficacy of nurse telephone case management for diabetes (DM) and hypertension (HTN) in academic or vertically integrated systems. Little is known about the real-world potency of these interventions. OBJECTIVE: To assess the effectiveness of nurse behavioral management of DM and HTN in community practices among patients with both diseases. DESIGN: The study was designed as a patient-level randomized controlled trial. PARTICIPANTS: Participants included adult patients with both type 2 DM and HTN who were receiving care at one of nine community fee-for-service practices. Subjects were required to have inadequately controlled DM (hemoglobin A1c [A1c] ≥ 7.5%) but could have well-controlled HTN. INTERVENTIONS: All patients received a call from a nurse experienced in DM and HTN management once every two months over a period of two years, for a total of 12 calls. Intervention patients received tailored DM- and HTN- focused behavioral content; control patients received non-tailored, non-interactive information regarding health issues unrelated to DM and HTN (e.g., skin cancer prevention). MAIN OUTCOMES AND MEASURES: Systolic blood pressure (SBP) and A1c were co-primary outcomes, measured at 6, 12, and 24 months; 24 months was the primary time point. RESULTS: Three hundred seventy-seven subjects were enrolled; 193 were randomized to intervention, 184 to control. Subjects were 55% female and 50% white; the mean baseline A1c was 9.1% (SD = 1%) and mean SBP was 142 mmHg (SD = 20). Eighty-two percent of scheduled interviews were conducted; 69% of intervention patients and 70% of control patients reached the 24-month time point. Expressing model estimated differences as (intervention--control), at 24 months, intervention patients had similar A1c [diff = 0.1 %, 95 % CI (-0.3, 0.5), p = 0.51] and SBP [diff = -0.9 mmHg, 95% CI (-5.4, 3.5), p = 0.68] values compared to control patients. Likewise, DBP (diff = 0.4 mmHg, p = 0.76), weight (diff = 0.3 kg, p = 0.80), and physical activity levels (diff = 153 MET-min/week, p = 0.41) were similar between control and intervention patients. Results were also similar at the 6- and 12-month time points. CONCLUSIONS: In nine community fee-for-service practices, telephonic nurse case management did not lead to improvement in A1c or SBP. Gains seen in telephonic behavioral self-management interventions in optimal settings may not translate to the wider range of primary care settings.

Polymorphisms at the microRNA binding-site of the stem cell marker gene CD133 modify susceptibility to and survival of gastric cancer.

CD133 is one of the most common stem cell markers, and functional single nucleotide polymorphisms (SNPs) of CD133 may modulate its gene functions and thus cancer risk and patient survival. We hypothesized that potentially functional CD133 SNPs are associated with gastric cancer (GC) risk and survival. To test this hypothesis, we conducted a case-control study of 371 GC patients and 313 cancer-free controls frequency-matched by age, sex, and ethnicity. We genotyped four selected, potentially functional CD133 SNPs (rs2240688A>C, rs7686732C>G, rs10022537T>A, and rs3130C>T) and used logistic regression analysis for associations of these SNPs with GC risk and Cox hazards regression analysis for survival. We found that compared with the miRNA binding site rs2240688 AA genotype, AC + CC genotypes were associated with significantly increased GC risk (adjusted OR = 1.52, 95% CI = 1.09-2.13); for another miRNA binding site rs3130C>T SNP, the TT genotype was associated with significantly reduced GC risk (adjusted OR = 0.68, 95% CI = 0.48-0.97), compared with CC + CT genotypes. In all patients, the risk rs3130 TT variant genotype was significantly associated with overall survival (OS) (adjusted P(trend) = 0.016 and 0.007 under additive and recessive models, respectively). These findings suggest that these two CD133 miRNA binding site variants, rs2240688 and rs3130, may be potential biomarkers for genetic susceptibility to GC and possible predictors for survival in GC patients but require further validation by larger studies.

Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma.

BACKGROUND: The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients. METHODS: We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset. Multivariate and stepwise Cox proportional hazards regression and false-positive report probability corrections were performed to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific survival. Receiver operating characteristic curve was constructed, and area under the curve was used to assess the classification performance of the model. RESULTS: Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients. The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73-4.23; Ptrend = 9.62 × 10(-7)), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating characteristic analysis revealed that area under the curve was significantly increased after adding the combined unfavorable genotype score to the model containing the known clinicopathologic factors. CONCLUSIONS: Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival. IMPACT: Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients.

Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC.

INTRODUCTION: Platinum agents can cause the formation of DNA adducts and induce apoptosis to eliminate tumor cells. The aim of the present study was to investigate the influence of genetic variants of MDM2 on chemotherapy-related toxicities and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We recruited 663 patients with advanced NSCLC who had been treated with first-line platinum-based chemotherapy. Five tagging single nucleotide polymorphisms (SNPs) in MDM2 were genotyped in these patients. The associations of these SNPs with clinical toxicities and outcomes were evaluated using logistic regression and Cox regression analyses. RESULTS: Two SNPs (rs1470383 and rs1690924) showed significant associations with chemotherapy-related toxicities (ie, overall, hematologic, and gastrointestinal toxicity). Compared with the wild genotype AA carriers, patients with the GG genotype of rs1470383 had an increased risk of overall toxicity (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.34-8.02; P = .009) and hematologic toxicity (OR, 4.10; 95% CI, 1.73-9.71; P = .001). Likewise, patients with the AG genotype of rs1690924 showed more sensitivity to gastrointestinal toxicity than did those with the wild-type homozygote GG (OR, 2.32; 95% CI, 1.30-4.14; P = .004). Stratified survival analysis revealed significant associations between rs1470383 genotypes and overall survival in patients without overall or hematologic toxicity (P = .007 and P = .0009, respectively). CONCLUSION: The results of our study suggest that SNPs in MDM2 might be used to predict the toxicities of platinum-based chemotherapy and overall survival in patients with advanced NSCLC. Additional validations of the association are warranted.