Aberrant association of misfolded SOD1 with Na+/K+ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS.

Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na+/K+ATPase-α3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na+/K+ATPase-α3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na+/K+ATPase-α3 onto a 10 amino acid stretch that is unique to Na+/K+ATPase-α3 but not found in the closely related Na+/K+ATPase-α1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na+/K+ATPase-α3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na+/K+ATPase-α3 restored Na+/K+ATPase-α3 activity in the spinal cord, delayed pathological alterations and prolonged survival of SOD1G93A mice. Additionally, altered Na+/K+ATPase-α3 expression was observed in the spinal cord of individuals with sporadic and familial ALS. A fraction of sporadic ALS cases also presented B8H10 positive misfSOD1 immunoreactivity, suggesting that similar mechanism might contribute to the pathology.

Modelling the impact of deferring HCV treatment on liver-related complications in HIV coinfected men who have sex with men

BACKGROUND AND AIMS Hepatitis C (HCV) is a leading cause of morbidity and mortality in people who live with HIV. In many countries, access to direct acting antiviral agents to treat HCV is restricted to individuals with advanced liver disease (METAVIR stage F3 or F4). Our goal was to estimate the long term impact of deferring HCV treatment for men who have sex with men (MSM) who are coinfected with HIV and often have multiple risk factors for liver disease progression. METHODS We developed an individual-based model of liver disease progression in HIV/HCV coinfected men who have sex with men. We estimated liver-related morbidity and mortality as well as the median time spent with replicating HCV infection when individuals were treated in liver fibrosis stages F0, F1, F2, F3 or F4 on the METAVIR scale. RESULTS The percentage of individuals who died of liver-related complications was 2% if treatment was initiated in F0 or F1. It increased to 3% if treatment was deferred until F2, 7% if it was deferred until F3 and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5 years if treatment was initiated in F2 to almost 15 years if it was deferred until F4. CONCLUSIONS Deferring HCV therapy until advanced liver fibrosis is established could increase liver-related morbidity and mortality in HIV/HCV coinfected individuals, and substantially prolong the time individuals spend with replicating HCV infection.

Estimated current patterns of food consumption and perceived changes among patients with lymphoma

Usual food choices during the past year, self-reported changes in consumption of three important food groups, and weight changes or stability were the questions addressed in this cross-sectional survey and retrospective review. The subjects were 141 patients with Hodgkin's disease or other B-cell types of lymphoma within their first three years following completion of initial treatments for lymphoma at the University of Texas M. D. Anderson Cancer Center in Houston, Texas. ^ The previously validated Block-98 Food Frequency Questionnaire was used to estimate usual food choices during the past year. Supplementary questions asked about changes breads and cereals (white or whole grain) and relative amounts of fruits and vegetables compared with before diagnosis and treatment. Over half of the subjects reported consuming more whole grains, fruits, and/or vegetables and almost three quarters of those not reporting such changes had been consuming whole grains before diagnosis and treatment. ^ Various dietary patterns were defined in order to learn whether proportionately more patients who changed in healthy directions fulfilled recognized nutritional guidelines such as 5-A-day fruits and vegetables and Dietary Reference Intakes (DRIB) for selected nutrients. ^ Small sizes of dietary pattern sub-groups limited the power of this study to detect differences in meeting recommended dietary guidelines. Nevertheless, insufficient and excessive intakes were detected among individuals with respect to fruits and vegetables, fats, calcium, selenium, iron, folate, and Vitamin A. The prevalence of inadequate or excess intakes of foods or nutrients even among those who perceived that they had increased or continued to eat whole grains and/or fruits and vegetables is of concern because of recognized effects upon general health and potential cancer related effects. ^ Over half of the subjects were overweight or obese (by BMI category) on their first visit to this cancer center and that proportion increased to almost three-quarters by their last follow-up visits. Men were significantly heavier than women, but no other significant differences in BMI measures were found even after accounting for prescribed steroids and dietary patterns. ^

Factors associated with diabetes in tuberculosis patients in Harris County, Texas 1995--2004

Objective. To determine the prevalence and factors associated with diabetes in tuberculosis patients in Harris County, Texas. ^ Background. Tuberculosis and diabetes mellitus are two diseases of immense public health significance. Various epidemiologic studies have established an association between the two conditions. While many studies have identified factors associated with the conditions individually, few have looked at factors associated with their co-occurrence particularly in the United States. Furthermore, most of those studies are hospital-based and may not be representative of the population. The aim of this study was to determine the prevalence and distribution of diabetes among tuberculosis patients in Harris County, Texas and to identify the factors associated with diabetes in tuberculosis. ^ Methods. A population-based case control study was performed using secondary data from the Houston Tuberculosis Initiative (HTI) collected from October 1995 to September 2004. Socio-demographic characteristics and clinical variables were compared between tuberculosis patients with diabetes and non-diabetic tuberculosis patients. Logistic regression analysis was performed to identify associations. Survival at 180 days post tuberculosis diagnosis was assessed by Cox regression. ^ Results. The prevalence of diabetes among the tuberculosis (TB) population was 14.4%. The diabetics (cases) with a mean age 53 ± 13.3 years were older than the non-diabetics (controls) with a mean age of 39 ± 18.5 years (p<0.001). Socio-demographic variables that were independently associated with the risk of diabetes were age (OR 1.04, p<0.001) and Hispanic ethnicity (OR 2.04, p<0.001). Diabetes was associated with an increased risk of pulmonary tuberculosis disease (OR 1.33, p<0.028). Among individuals with pulmonary TB, diabetes was associated with positive sputum acid-fast bacilli (AFB) smear (OR 1.47, p<0.005) and culture (OR 1.83, p<0.018). Diabetics were more likely to have cavitary lung disease than non-diabetics (OR 1.50, p<0.002). After adjustment for age and HIV status, the risk of dying within 180 days of TB diagnosis was significantly increased in the diabetics (HR 1.51, p<0.002). ^ Conclusion. Diabetes mellitus was more prevalent in our tuberculosis patients than in the general population. The tuberculous diabetic may be more infectious and has a higher risk of death. It is therefore imperative to screen diabetics for TB and TB patients for diabetes. ^

Spirituality of Thai Buddhists with chronic cardiovascular disease

Background. Advances in medical technology contribute to the survival rate of a growing number of persons with chronic illnesses. Individuals with chronic cardiovascular disease (chronic CVD) are among other chronically ill persons who add to the need for healthcare services. They need to cope and live with the chronic conditions and find a new balance to make sense of their lives. Thai Buddhists with chronic CVD may use their religious resources to cope with their illnesses because religious beliefs are reflected in patterns of living. The aims of the study were to: (a) explore how Thai Buddhists with chronic CVD construct the spiritual aspects of the illness experience, (b) explore how Thai Buddhists with chronic CVD may use their spiritual/religious resources as a means of coping with the illness, and (c) explore the impacts of spiritual/religious beliefs and/or practices on the daily lives of Thai Buddhists with chronic CVD. ^ Methods. Ethnography was employed and data were collected from December 1, 2007 to May 31, 2008 using in-depth interviews with 20 participants. Field notes were also recorded. ^ Findings. Three categories emerged from the study data: set of spiritual and biomedical beliefs and practices, integrated meanings, and positive consequences of the integration of spiritual and biomedical beliefs and practices. ^ Conclusions. The findings of the study suggest the importance of understanding and integrating spiritual needs into care of patients with chronic CVD. The findings revealed that the participants constructed ideas of their illness and meanings for living and coping with the illness, and integrated spiritual and biomedical beliefs and practices, resulting in positive outcomes. Further research could test interventions which facilitate such coping; for example, using reflective thinking and group support. Other studies might explore how age affects Buddhist views of the illness. ^

Occupational performance of Mexican Americans with end-stage-renal-disease living on dialysis in the lower Rio Grande Valley

The number of people with end-stage-renal-disease (ESRD) and living with dialysis is a growing public health concern. Most studies about the impact of ESRD on people’s lives have placed attention on the medical and clinical dimension of ESRD. Very few have given attention to the environmental and cultural context in which people with ESRD live, the adaptation that these individuals must make to adjust to living with ESRD and dialysis, or the occupations in which they engage. Additionally these studies have not focused on Mexican Americans who are disproportionately affected by this illness and condition. This qualitative study explores the needs, perceptions, and issues facing Mexican Americans with ESRD living with dialysis as well as their families. Participants were residents of the Lower Rio Grande Valley and included individuals with ESRD, family members, and the healthcare providers who give care to them. The Health Belief Model and Lifestyle Performance Model served as the theoretical frameworks. The study also explored the daily occupations of this population. ^ In-depth interviews were conducted on 15 Mexican Americans with ESRD living with dialysis, 15 family members, and six dialysis healthcare providers. A video documentary of the day-to-day life of three individuals with ESRD and their families was produced. Such data do not currently exist and will greatly enhance the understanding of the human experience of living with ESRD. The results suggest that a collective effort of the family unit is at work to deal with the demands of dialysis. An imbalance and disharmony exist among the occupational activities, which creates occupational deprivation and disruption for both the individuals and family members. Implications for practice and recommendations for further research are described. ^

Use of pneumococcal vaccine in people with chronic disease in United States

Objective. The risk of complications and deaths related to pneumococcal infections is high among high risk population (i.e. those with chronic diseases such as diabetes or asthma), despite current immunization recommendations. The aim of this study is to evaluate the use of pneumonia vaccine in adults with and without diabetes or asthma by year of age and whether immunization practices conform to policy recommendations. ^ Methods. Data were drawn from 2005 Behavioral Risk Factor Surveillance Study. Age specific estimated counts and proportions of pneumonia vaccination status were computed. The association of socio-demographic factors with vaccination status was estimated from multiple logistic regression and results were presented for adults (18-64yrs) and elderly (65 or older). ^ Results. Overall 12.3% of the adults and 61.5% of elderly reported ever received pneumonia vaccine. 66.8% of diabetics and 72.6% of asthmatics received the vaccine among elderly. 33.4% of diabetics and 21.6% of asthmatics received the vaccine among adults. These numbers are far away from Healthy people 2010 objective coverage rates of 90% for elderly and 60% for high risk adults. Though diabetes was one of the recommendations for the pneumonia vaccine still the status was less than 70% even at older ages. Although asthma was not an indication for pneumonia vaccine, asthmatics still achieved 50% level by an early age of 60 and reached up to 80% at as early as 75 years. In those having both asthma and diabetes, although the curve reaches to 50% level at a very early age of 40yrs, it is not stable until the age of 55 and percentages reached to as high as 90% in older ages. Odds of receiving pneumonia vaccine were high in individuals with diabetes or asthma in both the age groups. But the odds were stronger for diabetics in adults compared to those in the elderly [2.24 CI (2.08-2.42) and 1.32 CI (1.18-1.47)]. The odds were slightly higher in adults than in elderly for asthmatics [1.92 CI (1.80-2.04) and 1.73 CI (1.50-2.00)].The likelihood of vaccination also differed by gender, ethnicity, marital status, income category, having a health insurance, current employment, physician visit in last year, reporting of good to excellent health and flu vaccine status. ^ Conclusion. There is a very high proportion of high risk adults and elderly that remain unvaccinated. Given the proven efficacy and safety of vaccine there is a need for interventions targeting the barriers for under-vaccination with more emphasis on physician knowledge and practice as well as the recipient attitudes.^

Comparing experience of diabetes care with chronic illness care in the primary care clinic using the Patient Assessment of Chronic Illness Care (PACIC)

Purpose. The overall purpose of the study was to evaluate the patient experience relevant to the Chronic Care Model as measured by the PACIC. Chronic illness care of patients with diabetes was compared to those with other chronic illnesses. In addition, chronic illness care of Hispanics was compared to those of other race/ethnicity. ^ Methods. The setting of this study was 20 primary care practices located in San Antonio, TX. The subjects in this study were consecutive adult patients age >18 yrs. Data was collected via a survey (PACIC) administered to 40-60 consecutive adult patients in each primary care clinic who presented for a scheduled appointment. ^ Results. Patient experience of the Chronic Care Model is different among those with diabetes than those with other chronic diseases: those with diabetes report a higher PACIC score. (P = 0.012) Although Hispanic patients report a higher PACIC score, patient experience of the Chronic Care Model among Hispanic patients is not significantly different than that of patients of other race/ethnicity regardless of chronic disease. (P = 0.053) After controlling for the patient characteristics of age, education, health status, and race/ethnicity, the diabetes status of the patient remains significantly associated with the outcome, the PACIC score. (P = 0.033) ^ Conclusions. Diabetes is associated with a greater experience of the Chronic Care model. Contributing factors to diabetes patients’ greater experience of the Chronic Care Model include the greater heath care use and higher self-care needs unique to individuals with diabetes. Special consideration must be given to the specific needs diabetic patients to ensure effective interventions, higher patient education, greater patient compliance, and lower health care costs. ^

Critical indicators associated with negative performance in a selectively manned unit

Introduction. Selectively manned units have a long, international history, both military and civilian. Some examples include SWAT teams, firefighters, the FBI, the DEA, the CIA, and military Special Operations. These special duty operators are individuals who perform a highly skilled and dangerous job in a unique environment. A significant amount of money is spent by the Department of Defense (DoD) and other federal agencies to recruit, select, train, equip and support these operators. When a critical incident or significant life event occurs, that jeopardizes an operator's performance; there can be heavy losses in terms of training, time, money, and potentially, lives. In order to limit the number of critical incidents, selection processes have been developed over time to “select out” those individuals most likely to perform below desired performance standards under pressure or stress and to "select in" those with the "right stuff". This study is part of a larger program evaluation to assess markers that identify whether a person will fail under the stresses in a selectively manned unit. The primary question of the study is whether there are indicators in the selection process that signify potential negative performance at a later date. ^ Methods. The population being studied included applicants to a selectively manned DoD organization between 1993 and 2001 as part of a unit assessment and selection process (A&S). Approximately 1900 A&S records were included in the analysis. Over this nine year period, seventy-two individuals were determined to have had a critical incident. A critical incident can come in the form of problems with the law, personal, behavioral or family problems, integrity issues, and skills deficit. Of the seventy-two individuals, fifty-four of these had full assessment data and subsequent supervisor performance ratings which assessed how an individual performed while on the job. This group was compared across a variety of variables including demographics and psychometric testing with a group of 178 individuals who did not have a critical incident and had been determined to be good performers with positive ratings by their supervisors.^ Results. In approximately 2004, an online pre-screen survey was developed in the hopes of preselecting out those individuals with items that would potentially make them ineligible for selection to this organization. This survey has aided the organization to increase its selection rates and save resources in the process. (Patterson, Howard Smith, & Fisher, Unit Assessment and Selection Project, 2008) When the same prescreen was used on the critical incident individuals, it was found that over 60% of the individuals would have been flagged as unacceptable. This would have saved the organization valuable resources and heartache.^ There were some subtle demographic differences between the two groups (i.e. those with critical incidents were almost twice as likely to be divorced compared with the positive performers). Upon comparison of Psychometric testing several items were noted to be different. The two groups were similar when their IQ levels were compared using the Multidimensional Aptitude Battery (MAB). When looking at the Minnesota Multiphasic Personality Inventory (MMPI), there appeared to be a difference on the MMPI Social Introversion; the Critical Incidence group scored somewhat higher. When analysis was done, the number of MMPI Critical Items between the two groups was similar as well. When scores on the NEO Personality Inventory (NEO) were compared, the critical incident individuals tended to score higher on Openness and on its subscales (Ideas, Actions, and Feelings). There was a positive correlation between Total Neuroticism T Score and number of MMPI critical items.^ Conclusions. This study shows that the current pre-screening process is working and would have saved the organization significant resources. ^ If one was to develop a profile of a candidate who potentially could suffer a critical incident and subsequently jeopardize the unit, mission and the safety of the public they would look like the following: either divorced or never married, score high on the MMPI in Social Introversion, score low on MMPI with an "excessive" amount of MMPI critical items; and finally scores high on the NEO Openness and subscales Ideas, Feelings, and Actions.^ Based on the results gleaned from the analysis in this study there seems to be several factors, within psychometric testing, that when taken together, will aid the evaluators in selecting only the highest quality operators in order to save resources and to help protect the public from unfortunate critical incidents which may adversely affect our health and safety.^

A movement from traditional malarial chemoprophylaxis to the use of intermittent preventive treatment as a method of protection for children diagnosed with sickle-cell disease: A proposal for consideration based on a systematic review of the literature

Approximately 200,000 African children are born with sickle-cell anemia each year. Research has shown that individuals with hemoglobin disorders, particularly sickle-cell anemia, have increased susceptibility to contracting malaria. Currently it is recommended that patients diagnosed with sickle-cell anemia undergo malaria chemoprophylaxis in order to decrease their chances of malarial infection. However, studies have shown that routine administration of these drugs increases the risk of drug resistance and could possibly impair the development of naturally acquired immunity. Clinical trials have shown intermittent preventive treatment (IPT) to be an effective method of protection against malaria. The objective of this report was to review previously conducted clinical trials that study the effects of intermittent preventive treatment on malaria and anemia in infants and children. Based on the review, implications for its appropriateness as a protective measure against malaria for infants and children diagnosed with sickle-cell disease were provided.^ The 18 studies reviewed were randomized controlled trials that focused on IPT’s effect on malaria (7 studies), anemia (1 study), or both (8 studies). In addition to these 16, one study looks at IPT’s effect on molecular resistance to malaria, and another study is a follow-up to a study in order to review IPT’s potential to cause a rebound effect. The 18 th study in this review specifically looks at IPT’s protective efficacy in children with SCA. The studies in this report were restricted to randomized controlled trials that have been performed from 2000 to 2010. Reports on anemia were included to illustrate possible added benefits of the use of IPT specific to burdens associated with SCA other than malaria susceptibility. The outcomes of these studies address several issues of concern involving the administration of IPT: protective efficacy (in reference to age, seasonal versus perennial malaria regions, and overall effectiveness against malaria and anemia), drug resistance, drug rebound effect, drug side-effects, and long-term effects. Overall, these showed that IPT has a significant level of protective efficacy against malaria and/or anemia in children. More specifically, the IPT study evaluating children diagnosed with sickle-cell anemia proved IPT to be a more effective method of protection than traditional chemoprophylaxis. ^

Mitral valve prolapse and its relationship with stroke

The purpose of this study was to elucidate the relationship between mitral valve prolapse and stroke. A population-based historical cohort investigation was conducted among residents of Olmsted County, Minnesota who had an initial echocardiographic diagnosis of mitral valve prolapse from 1975 through 1989. This cohort (N = 1085) was followed for stroke outcomes using the resources of an operational medical record linkage system. There was an overall two-fold increase in the incidence of stroke among individuals with mitral valve prolapse relative to a standard population (standardized morbidity ratio = 2.12, 95% confidence limits = 1.33-3.21). When the data were partitioned by duration of follow-up from the diagnosis of mitral valve prolapse, or by the calendar years at echocardiographic diagnosis, respectively, the association between mitral valve prolapse and stroke was not modified. Mitral valve prolapse subjects 85 years and older were at highest increased risk of developing strokes relative to the general population (standardized morbidity ratio = 5.47, 95% confidence limits = 2.20-11.24). Coronary heart disease, atrial fibrillation, diabetes mellitus and hypertension, were unlikely to have confounded the association between mitral valve prolapse and stroke.^ The cumulative risk of first stroke among individuals initially diagnosed with mitral valve prolapse age 15 to 64 years, given survival to 15.2 years of follow-up, was 4.0%. The cumulative risk of first stroke among individuals initially diagnosed with mitral valve prolapse age 65 to 74 years, given survival to 11.2 years of follow-up, was 13.2%. The cumulative risk of first stroke among individuals initially diagnosed with mitral valve prolapse age 75 years and older, given survival to 6.7 years of follow-up, was 30.6%.^ Among individuals with mitral valve prolapse, age, diabetes, and atrial fibrillation were associated with an increased risk of stroke. Atrial fibrillation was associated with a four-fold rate of stroke and diabetes associated with a seven-fold rate of stroke.^ Findings from this research support the hypothesis that mitral valvular heart prolapse is linked with a stroke sequela. ^

Macular edema in Hispanics with non-insulin dependent diabetes mellitus in Starr County, Texas: Prevalence, incidence and risk factors

This project is based on secondary analyses of data collected in Starr County, Texas from 1981 till 1991 to determine the prevalence, incidence and risk factors for macular edema in Hispanics with non-insulin-dependent diabetes in Starr County, Texas. Two studies were conducted. The first study examined the prevalence of macular edema in this population. Of the 310 diabetics that were included in the study 22 had macular edema. Of these 22 individuals 9 had clinically significant macular edema. Fasting blood glucose was found to be significantly associated with macular edema. For each 10 mg/dl increase in fasting blood glucose there was a 1.07 probability of an increase in the risk of having macular edema. Individuals with fasting blood glucose $\ge$200 mg/dl were found to be more than three times at risk of having macular edema compared to those with fasting blood glucose $<$200 mg/dl.^ In the second study the incidence and the risk factors that could cause macular edema in this Hispanic population were examined. 240 Hispanics with non-insulin-dependent diabetes mellitus and without macular edema were followed for 1223 person-years. During the follow-up period 27 individuals developed macular edema (2.21/100 person-years). High fasting blood glucose and glycosylated hemoglobin were found to be strong and independent risk factors for macular edema. Participants taking insulin were 3.9 times more at risk of developing macular edema compared to those not taking insulin. Systolic blood pressure was significantly related to macular edema, where each 10 mmHg increase in systolic blood pressure was associated with a 1.3 increase in the risk of macular edema.^ In summary, this study suggests that hyperglycemia is the main underlying factor for retinal pathological changes in this diabetic population, and that macular edema probably is not the result of sudden change in the blood glucose level. It also determined that changes in blood pressure, particularly systolic blood pressure, could trigger the development of macular edema.^ Based on the prevalence reported in this study, it is estimated that 35,500 Hispanic diabetics in the US have macular edema. This imposes a major public health challenge particularly in areas with high concentration of Mexican Americans. It also highlights the importance of public health measures directed to Mexican Americans such as health education, improved access to medical care, and periodic and careful ophthalmologic examination by ophthalmologists knowledgeable and experienced in the management of diabetic macular edema. ^

Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of survival and clinical response in women with ovarian cancer

Background. The mTOR pathway is commonly altered in human tumors and promotes cell survival and proliferation. Preliminary evidence suggests this pathway's involvement in chemoresistance to platinum and taxanes, first line therapy for epithelial ovarian cancer. A pathway-based approach was used to identify individual germline single nucleotide polymorphisms (SNPs) and cumulative effects of multiple genetic variants in mTOR pathway genes and their association with clinical outcome in women with ovarian cancer. ^ Methods. The case-series was restricted to 319 non-Hispanic white women with high grade ovarian cancer treated with surgery and platinum-based chemotherapy. 135 SNPs in 20 representative genes in the mTOR pathway were genotyped. Hazard ratios (HRs) for death and Odds ratios (ORs) for failure to respond to primary therapy were estimated for each SNP using the multivariate Cox proportional hazards model and multivariate logistic regression model, respectively, while adjusting for age, stage, histology and treatment sequence. A survival tree analysis of SNPs with a statistically significant association (p<0.05) was performed to identify higher order gene-gene interactions and their association with overall survival. ^ Results. There was no statistically significant difference in survival by tumor histology or treatment regimen. The median survival for the cohort was 48.3 months. Seven SNPs were significantly associated with decreased survival. Compared to those with no unfavorable genotypes, the HR for death increased significantly with the increasing number of unfavorable genotypes and women in the highest risk category had HR of 4.06 (95% CI 2.29–7.21). The survival tree analysis also identified patients with different survival patterns based on their genetic profiles. 13 SNPs on five different genes were found to be significantly associated with a treatment response, defined as no evidence of disease after completion of primary therapy. Rare homozygous genotype of SNP rs6973428 showed a 5.5-fold increased risk compared to the wild type carrying genotypes. In the cumulative effect analysis, the highest risk group (individuals with ≥8 unfavorable genotypes) was significantly less likely to respond to chemotherapy (OR=8.40, 95% CI 3.10–22.75) compared to the low risk group (≤4 unfavorable genotypes). ^ Conclusions. A pathway-based approach can demonstrate cumulative effects of multiple genetic variants on clinical response to chemotherapy and survival. Therapy targeting the mTOR pathway may modify outcome in select patients.^

Association of p21/p27 polymorphisms with risk of HPV16-associated oral squamous cell carcinoma

The increasing incidence of oral squamous cell carcinoma (OSCC) among young adults has been associated with sexually transmitted infection of human papillomavirus (HPV), particularly HPV16. Given the roles of p21 (WAF1/Cip1/CDKN1A) and p27 (Kip1/CDKNIB) in cell-cycle regulation and of HPV16 E6 and E7 oncoproteins in p53 degradation and pRb inactivation, the effect of HPV16 L1 seropositivity and three putatively functional single-nucleotide polymorphisms (SNPs) of p21 (p21 C70T and p21 C98A) and p27 (p27 T109G), individually and in combination, on the risk of OSCC was evaluated in a hospital-based case-control study of 327 cases and 401 cancer-free controls who were frequency-matched on age, gender and smoking status. Individuals with HPV16 L1 seropositivity had an overall 3-fold increased risk of having OSCC than those with HPV16 seronegativity. The increased risk of HPV16-associated OSCC was particularly found among younger people (aged ≤ 50 years), males, never smokers, never drinkers and oropharynx cancer patients. None of three p21 and p27 polymorphisms alone was significantly associated with risk of OSCC. Individuals with variant genotypes for both p21 polymorphisms were more likely to have OSCC than individuals with wild-type genotypes or variant genotypes for either one of the p21 polymorphisms (adjusted OR, 1.4; 95% CI, 0.9-2.1). There was a borderline significant or significant interaction between the p21 C70T, combined p21 and combined p21/p27 genotypes and HPV16 L1 seropositivity on risk of OSCC. The three studied p21 and p27 polymorphisms, individually or in combination, did not appear to have an effect on HPV16-related clinical outcomes (overall and disease-free survival and tumor recurrence). Despite the fact that the exact biological mechanism remains to be explored, these findings suggest possible involvement of p21variants, particularly the p21 C70T variant genotypes (CT/TT), in the etiology of HPV16-associated OPSCC. Further large and functional studies are required to validate the findings.^

Childhood cancer survivor satisfaction with characteristics of clinical care

This study investigated the characteristics of a clinic that affect how satisfied survivors of childhood cancer are with their medical care. Questionnaire and interview data from the Passport for Care: Texas Implementation project collected between January 2011 to April 2012 were analyzed. Eleven clinics in Texas participated. Questionnaire respondents were childhood cancer survivor patients who had been off therapy for at least 2 years, or their parents. Interview respondents were clinical providers or research staff at the participating clinics. The outcomes evaluated were answers to a single question on satisfaction with care and a composite Percent Satisfaction Score created from seven other questionnaire items that were correlated (Spearman Rho >0.3) with the question on satisfaction. The following characteristics were also evaluated: sex, age, race, education, and type of cancer. The following clinic indicators were evaluated: type of clinic (general vs. dedicated cancer survivor clinics), number of providers, number of survivors, ratio of survivors/providers, distribution of handouts, distribution of treatment summaries, and use of Children's Oncology Group (COG) guidelines. ^ The only demographic characteristic that affected satisfaction was race. A Kruskal-Wallis test showed a statistically significant difference (Chi-square 6.129, 2 d.f., p = 0.0467). To analyze this further, Wilcoxon Rank Sum test of pairings of the three groups were performed. A Bonferroni correction for multiple testing was applied, with p = 0.017 indicating significance at alpha = 0.05. There was no significant difference between the White and Hispanic groups or between the Hispanic and "Other" groups. For the White and "Other" groups there was a significant difference for the satisfaction item (p = 0.0123) but not for the Percent Satisfaction Score (p = 0.0289). These results suggest that race may influence satisfaction and should be evaluated further in future studies. ^ None of the clinic indicators affected the Percent Satisfaction Score. Going to a clinic that distributed patient information handouts (Wilcoxon Rank Sum p = 0.048) and going to a clinic with >=100 survivors (Wilcoxon Rank Sum p = 0.021) were associated with increased satisfaction. The population of childhood cancer survivors is a growing group of individuals with special health needs. In the future survivors will likely seek medical care in a variety of clinical settings, so it is important to investigate features to improve patient satisfaction with clinical care.^