Bradley E. Aouizerat

Abstract

Hereditary haemorrhagic telangiectasia (HTT) is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HTT shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng+/- and Tgfb1-/- mice provides further support for genetic modification of transforming growth factor-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1-/- mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HTT, as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HTT in particular and to angiogenesis in general.

Abstract

UNLABELLED: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01).CONCLUSION: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.

Abstract

Background. Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. Methods. We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. Results. Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. Conclusions. This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.

Abstract

Background: Little is known about the relationships between sleep/wake circadian activity rhythms and fatigue in family caregivers (FCs) of oncology patients. Objectives: The objectives of this study were to describe values for nocturnal sleep/rest, daytime wake/activity, and circadian activity rhythm parameters measured using actigraphy and to evaluate the relationships between these subjective and objective measures of sleep disturbance and self-reported fatigue severity, in a sample of FCs of oncology patients. Methods: Family caregivers (n = 103) completed self-report measures for sleep disturbance (ie, Pittsburgh Sleep Quality Index, General Sleep Disturbance Scale) and fatigue (Lee Fatigue Scale) and wore wrist actigraphs for 48 hours prior to beginning radiation therapy. Spearman rank correlations were calculated between variables. Results: Approximately 40% to 60% of FCs experienced sleep disturbance depending on whether clinically significant cutoffs for the subjective or objective measures were used to calculate occurrence rates. In addition, these FCs reported moderate levels of fatigue. Only a limited number of significant correlations were found between the subjective and objective measures of sleep disturbance. Significant positive correlations were found between fatigue and subjective, but not objective measures of sleep disturbance. The amplitude of circadian activity rhythm was not related to any objective sleep measure but was correlated with self-report of longer sleep-onset latency. Conclusions: A significant percentage of FCs experience clinically meaningful disturbances in sleep-wake circadian activity rhythms. These disturbances occur primarily in sleep maintenance. Implications for Practice: Family caregivers need to be assessed, along with patients, for sleep disturbance, and appropriate interventions initiated for them and for the patient.

Abstract

Purpose: Anxiety is common in patients undergoing radiation therapy (RT) and in their family caregivers (FCs). Little is known about individual differences in anxiety trajectories during and after RT. This study aimed to identify distinct latent classes of oncology patients and their FCs based on self-reported anxiety symptoms from the beginning to four months after the completion of RT. Method: Using growth mixture modeling (GMM), longitudinal changes in Spielberger State Anxiety Inventory (STAI-S) scores among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 FCs were evaluated to determine distinct anxiety symptom profiles. STAI-S scores were assessed just prior to, throughout the course of, and for four months following RT (total of 7 assessments). Baseline trait anxiety and depressive symptoms (during and after RT) were also assessed. Results: The GMM analysis identified three latent classes of oncology patients and FCs with distinct trajectories of state anxiety: Low Stable (n = 93, 36.9%), Intermediate Decelerating (n = 82, 32.5%), and High (n = 77, 30.6%) classes. Younger participants, women, ethnic minorities, and those with children at home were more likely to be classified in the High anxiety class. Higher levels of trait anxiety and depressive symptoms, at the initiation of RT, were associated with being in the High anxiety class. Conclusions: Subgroups of patients and FCs with high, intermediate, and low mean levels of anxiety during and after RT were identified with GMM. Additional research is needed to better understand the heterogeneity of symptom experiences as well as comorbid symptoms in patients and FCs.

Abstract

Context. Radiation therapy (RT) is a common treatment for prostate cancer. Despite available research, prostate cancer patients report that information about side effects is their most important unmet need. Additional research is needed that focuses on specific dimensions of the patient's symptom experience. Objectives. The study's purposes were to evaluate the trajectories of occurrence, severity, and distress of the six most prevalent symptoms reported by patients undergoing RT for prostate cancer and the effects of selected demographic and clinical characteristics on these trajectories. Methods. Patients completed the Memorial Symptom Assessment Scale 11 times before, during, and after RT. For problems with urination, pain, lack of energy, feeling drowsy, difficulty sleeping, and diarrhea, the trajectories of occurrence, severity, and distress were evaluated using multilevel generalized linear models. Results. Across all three dimensions, pain, lack of energy, feeling drowsy, and difficulty sleeping followed a decreasing linear trend. Problems with urination and diarrhea demonstrated more complex patterns of change over time. Conclusion. Although longitudinal data on pain, lack of energy, feeling drowsy, and difficulty sleeping are limited, they are highly prevalent symptoms in these patients. In addition, diarrhea becomes a significant problem for these patients over the course of RT. A number of demographic and clinical characteristics affect the trajectories of these common symptoms differentially.

Abstract

Objective: To characterize specific types of sleep problems experienced by adults with HIV. Method: The design was cross-sectional involving sleep questionnaires, diaries, and wrist actigraphy. The convenience sample included 290 adults living with HIV, 22-77 years of age. Measures included self-report for sleep onset latency, and wrist actigraphy estimates of total sleep time at night, wake after sleep onset, and daytime sleep. Results: Nearly half (45%) of the sample slept < 6 h per night. Difficulty falling asleep was reported by 34%, and 56% had fragmented sleep according to actigraphy; 20% had both problems, and 30% were good sleepers. Participants reporting difficulty falling asleep had actigraphy and clinical measures similar to the good sleepers, but subjectively they experienced greater sleep disturbance and symptom burden (particularly anxiety and morning fatigue) and reported more use of sleep medication. Participants with fragmented sleep reported low levels of sleep disturbance and symptom burden similar to the good sleepers, despite actigraphy measures indicating they obtained less sleep both at night and during the day. Sleep fragmentation was also associated with sociodemographic factors and slightly lower CD4+ T-cell counts. Participants reporting both sleep problems had actigraphy and clinical profiles similar to those who had only fragmented sleep, but their symptom experience was similar to participants with only sleep initiation difficulties. Conclusions: Findings support the need for targeting efforts to improve sleep for the majority of adults living with HIV/AIDS and tailoring interventions to the specific type of sleep problem regardless of the person's clinical and demographic profile.

Abstract

OBJECTIVE: CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene. DESIGN: The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study. METHODS: Five putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n=91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers. RESULTS: Rs3745274 was significantly associated with virologic suppression [odds ratio=3.61, 95% confidence interval (CI) 1.16-11.22, P trend=0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend=0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response. CONCLUSION: The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.

Abstract

Purpose: To examine the psychometric properties of the 9-item Fatigue Severity Scale (FSS) using a Rasch model application. Methods: A convenience sample of HIV-infected adults was recruited, and a subset of the sample was assessed at 6-month intervals for 2 years. Socio-demographic, clinical, and symptom data were collected by self-report questionnaires. CD4 T-cell count and viral load measures were obtained from medical records. The Rasch analysis included 316 participants with 698 valid questionnaires. Results: FSS item 2 did not advanced monotonically, and items 1 and 2 did not show acceptable goodness-of-fit to the Rasch model. A reduced FSS 7-item version demonstrated acceptable goodness-of-fit and explained 61.2% of the total variance in the scale. In the FSS-7 item version, no uniform Differential Item Functioning was found in relation to time of evaluation or to any of the socio-demographic or clinical variables. Conclusion This study demonstrated that the FSS-7 has better psychometric properties than the FSS-9 in this HIV sample and that responses to the different items are comparable over time and unrelated to socio-demographic and clinical variables.

Abstract

Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs) in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109) and Cape Mixed Ancestry (CMA) (n = 67) groups. The minor allele frequencies (MAFs) of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1]) were significantly different between the Xhosa and CMA populations (Bonferroni p < 0.05). Twentyseven haplotypes were inferred in four genes (CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1) between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations.