Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

Personality dimensions in persons symptomatically at risk of psychosis: pronounced but lacking a characteristic profile

AIM Personality dimensions are frequently abnormal in psychosis. We examined if these abnormalities form a personality profile that is characteristic for patients symptomatically at risk of psychosis. METHODS Four higher order personality dimensions were assessed in 104 at-risk patients, 67 clinical and 97 healthy controls with the 'Dimensional Assessment of Personality Pathology', and analysed by two-step cluster procedure to detect personality profiles. Logistic regression was used to test for predictors of profile assignment. RESULTS Low and high scorers were distinguished by two profiles. Patients were more likely high scorers. The presence of clinically relevant depression, though equally frequent in clinical groups, best predicted high scorers among patients. CONCLUSIONS Though at-risk patients were significantly more often high scorers, this seemed to be a general reflection of the level of psychopathology rather than a group characteristic. Thus, personality dimensions might be of little value for facilitating early detection but might be important to consider in early intervention approaches.

Apolipoprotein E genotypes and cognitive functions in healthy elderly persons

Objectives- We investigated whether apoE genotypes correlate with cognitive functions in clinically healthy persons. Methods - In 1993 and 1995, we measured information processing speed, delayed free recall and semantic aspects of long-term memory in 227 men and 105 women aged 65 and over, a randomly selected subsample of the prospective Basel Study. Cardiovascular risk factors and education were assessed. Results -E2 were more prevalent in old-old (>75 years, 23.5% vs 15%) compared to E4 than in young-old (<75 years, 19.3% vs 23.5%). Taking into account age and education, subjects with ɛ3/ɛ4 or ɛ4/ɛ4 alleles (E4) performed lowest in all 3 tests compared to those homozygous for ɛ3 (E3) or carriers of one or two ɛ2 alleles (E2) (reaction time P=0.009, free recall P=0.05, WAIS-R vocabulary P<0.05). In old-old there was a significant difference between E2 and E4 for reaction time (P=0.02) and free recall (P<0.02) but not for vocabulary (P=0.086). In all 3 groups there were no significant changes after 2 years. The subgroup with the genotype ɛ2/ɛ4 performed consistently best in the cognitive tests. Cholesterol was significantly increased in the E4 and E3 group compared to the E2 group. Conclusion - ApoE genotype correlates with cognitive performance. The increased prevalence of E2 in the old-old and the significantly lower plasma cholesterol levels suggest differential morbidity and mortality as important factors influencing the prevalence of cognitive disorders in late life.

Psychological adaptation to marital breakup in middle-aged persons: the role of gender and time

Marital breakup is among the most incisive stressors in adult life. While the negative effects of divorce on well-being are well documented in research literature, the large interindividual differences in psychological adaptation to marital dissolution are still not well understood. One major controversially discussed question is, whether marital dissolution represents a temporary crisis or rather a chronic strain. But also with regard of the role of gender results are mixed. The aim of the present study is to investigate the psychological adaptation (depression, perceived stress and life satisfaction) to marital breakup in a sample of 980 middle-aged persons (M = 51.8 years) who were partnered on average 19.4 years. We compared four time groups: one with a separation within the last 12 months (84 women, 36 men), another within the last 13-24 months (75 women, 19 men), a third within 25-60 months (121 women, 49 men), and one with a separation more than 60 months ago (189 women, 144 men). A group of 348 age-matched married people served as control group (189 women, 159 men). Findings from ANOVA with the outcome depression as well as with the outcome perceived stress yielded a significant main effect for both factors (gender and time). The group who had experienced a separation within the last 12 months differed significantly from all other groups (higher depression score and higher perceived stress). No significant main effect for the factor time was found for the outcome life satisfaction. Regarding gender differences, females from all time groups displayed higher depression scores and higher perceived stress but lower life satisfaction than males. These results give important insights into the process of adaptation to marital breakup, which can be used for counselling.

The prevalence and predictive value of dipstick urine protein in HIV-positive persons in Europe.

INTRODUCTION Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m(2). PATIENTS AND METHODS Baseline was defined as the first of two consecutive dipstick urine protein (DPU) measurements during prospective follow-up >1/6/2011 (when systematic data collection began). PTU was defined as two consecutive DUP >1+ (>30 mg/dL) >3 months apart; persons with eGFR <60 at either DPU measurement were excluded. Logistic regression investigated factors associated with PTU. RESULTS A total of 1,640 persons were included, participants were mainly white (n=1,517, 92.5%), male (n=1296, 79.0%) and men having sex with men (n=809; 49.3%). Median age at baseline was 45 (IQR 37-52 years), and CD4 was 570 (IQR 406-760/mm(3)). The median baseline date was 2/12 (IQR 11/11-6/12), and median eGFR was 99 (IQR 88-109 mL/min/1.73 m(2)). Sixty-nine persons had PTU (4.2%, 95% CI 3.2-4.7%). Persons with diabetes had increased odds of PTU, as were those with a prior non-AIDS (1) or AIDS event and those with prior exposure to indinavir. Among females, those with a normal eGFR (>90) and those with prior abacavir use had lower odds of PTU (Figure 1). CONCLUSIONS One in 25 persons with eGFR>60 had confirmed proteinuria at baseline. Factors associated with PTU were similar to those associated with CKD. The lack of association with antiretrovirals, particularly tenofovir, may be due to the cross-sectional design of this study, and additional follow-up is required to address progression to PTU in those without PTU at baseline. It may also suggest other markers are needed to capture the deteriorating renal function associated with antiretrovirals may be needed at higher eGFRs. Our findings suggest PTU is an early marker for impaired renal function.

Why does placement of persons with Alzheimer's disease into long-term care improve caregivers' well-being? Examination of psychological mediators.

Caregiving for individuals with Alzheimer's disease is associated with chronic stress and elevated symptoms of depression. Placement of the care receiver (CR) into a long-term care setting may be associated with improved caregiver well-being; however, the psychological mechanisms underlying this relationship are unclear. This study evaluated whether decreases in activity restriction and increases in personal mastery mediated placement-related reductions in caregiver depressive symptoms. In a 5-year longitudinal study of 126 spousal Alzheimer's disease caregivers, we used multilevel models to evaluate placement-related changes in depressive symptoms (short form of the Center for Epidemiologic Studies Depression scale), activity restriction (Activity Restriction Scale), and personal mastery (Pearlin Mastery Scale) in 44 caregivers who placed their spouses into long-term care relative to caregivers who never placed their CRs. The Monte Carlo method for assessing mediation was used to evaluate the significance of the indirect effect of activity restriction and personal mastery on postplacement changes in depressive symptoms. Placement of the CR was associated with significant reductions in depressive symptoms and activity restriction and was also associated with increased personal mastery. Lower activity restriction and higher personal mastery were associated with reduced depressive symptoms. Furthermore, both variables significantly mediated the effect of placement on depressive symptoms. Placement-related reductions in activity restriction and increases in personal mastery are important psychological factors that help explain postplacement reductions in depressive symptoms. The implications for clinical care provided to caregivers are discussed.

Effect of Cognitive Impairment on Driving-Relevant Cognition in Older Persons

Intact cognitive abilities are fundamental for driving. Driving-relevant cognition may be affected in older drivers due to aging or cognitive impairment. The aim of this study was to investigate the effects of cognitive impairment on driving-relevant cognition in older persons. Performance in selective and divided attention, eye-hand-coordination, executive functions and the ability to regulate distance and speed of 18 older persons with CI-Group (cognitive impairment group) was compared to performance of older control group (18 age and gender-matched cognitively normal subjects) and young control group (18 gender-matched young subjects). The CI-Group showed poorer performance than the other two control groups in all cognitive tasks (significance level (p) < 0.001, effect size (partial η2) = 0.63). Differences between cognitively impaired and cognitively normal subjects were still significant after controlling for age (effect sizes from 0.14 to 0.28). Dual tasking affected performance of cognitively impaired subjects more than performance of the other two groups (p = 0.016, partial η2 = 0.14). Results show that cognitive impairment has age-independent detrimental effects on selective and divided attention, eye-hand-coordination, executive functions and the ability to regulate distance and speed. Largest effect sizes are found for reaction times in attention tasks.

High Hepatic and Extrahepatic Mortality and Low Treatment Uptake in HCV-coinfected Persons in the Swiss HIV Cohort Study between 2001 and 2013

BACKGROUND & AIMS The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV-therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.

HBV genotypes and response to tenofovir disoproxil fumarate in HIV/HBV-coinfected persons

BACKGROUND Hepatitis B virus (HBV) genotypes can influence treatment outcome in HBV-monoinfected and human immunodeficiency virus (HIV)/HBV-coinfected patients. Tenofovir disoproxil fumarate (TDF) plays a pivotal role in antiretroviral therapy (ART) of HIV/HBV-coinfected patients. The influence of HBV genotypes on the response to antiviral drugs, particularly TDF, is poorly understood. METHODS HIV/HBV-co-infected participants with detectable HBV DNA prior to TDF therapy were selected from the Swiss HIV Cohort Study. HBV genotypes were identified and resistance testing was performed prior to antiviral therapy, and in patients with delayed treatment response (>6 months). The efficacy of TDF to suppress HBV (HBV DNA <20 IU/mL) and the influence of HBV genotypes were determined. RESULTS 143 HIV/HBV-coinfected participants with detectable HBV DNA were identified. The predominant HBV genotypes were A (82 patients, 57 %); and D (35 patients, 24 %); 20 patients (14 %) were infected with multiple genotypes (3 % A + D and 11 % A + G); and genotypes B, C and E were each present in two patients (1 %). TDF completely suppressed HBV DNA in 131 patients (92 %) within 6 months; and in 12 patients (8 %), HBV DNA suppression was delayed. No HBV resistance mutations to TDF were found in patients with delayed response, but all were infected with HBV genotype A (among these, 5 patients with genotype A + G), and all had previously been exposed to lamivudine. CONCLUSION In HIV/HBV-coinfected patients, infection with multiple HBV genotypes was more frequent than previously reported. The large majority of patients had an undetectable HBV viral load at six months of TDF-containing ART. In patients without viral suppression, no TDF-related resistance mutations were found. The role of specific genotypes and prior lamivudine treatment in the delayed response to TDF warrant further investigation.