Faculty Bibliography

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.

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.

Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-beta/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] 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-beta 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 HHT, [corrected] 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 HHT [corrected] in particular and to angiogenesis in general.

OBJECTIVES: This study assessed the prevalence of insomnia symptoms among women with and without HIV-infection and examined factors associated with insomnia. DESIGN: Participants (n = 1682) were enrolled in the Women's Interagency HIV Study (WIHS); 69% were infected with HIV. This was a cross-sectional analysis of data from standardized interviewer-administered instruments and physical/gynecological exams. Analysis focused on sociodemographics, sleep measures, depressive symptoms, drug use, alcohol consumption, medications, and HIV-related clinical variables. Women were classified as having symptoms of insomnia if they reported either difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening >/= 3 times a week in the past 2 weeks. RESULTS: Overall, HIV-infected women were 17% more likely to endorse insomnia symptoms than uninfected women (OR = 1.17, 95% CI: 1.04-1.34, P < 0.05). The adjusted prevalence of insomnia symptoms varied by HIV status and age groups. Among women ages 31-40 years, those with HIV infection were 26% more likely to endorse insomnia symptoms than their counterparts (OR = 1.26, 95% CI: 1.01-1.59, P < 0.05). No significant differences were observed in the likelihood of reporting insomnia symptoms based on HIV treatment type. Multivariate-adjusted regression analyses showed that depression was the most consistent and significant independent predictor of the likelihood of reporting insomnia symptoms across all age strata. CONCLUSIONS: Insomnia symptoms are common among both HIV-infected and uninfected women. Prevalence of insomnia did not vary significantly by HIV status, except among younger women. Younger women with HIV infection are at greater risk for experiencing insomnia symptoms.

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.

Vitamin E was recently shown to improve hepatic histology in a randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS). The current study utilized samples collected in the PIVENS trial to identify: (1) baseline metabolomic profiles that could identify who would respond to vitamin E treatment and (2) end of treatment metabolomic profiles reflective of histologic improvement. A comprehensive analysis of metabolomics profiles (n = 547) quantified by mass spectrometry was performed in vitamin E responders (n = 16), vitamin E non-responders (n = 15), and placebo responders (n = 15). At baseline, phenyl-propionic acid (Odds ratio: 29.4, p<0.01), indole-propionic acid levels (Odds ratio: 16.2, p<0.01) were directly associated with a subsequent histologic response to vitamin E treatment whereas gamma-carboxyethylhydroxychroman (CEHC) levels were inversely related to histologic response. Adjusting for baseline values by analysis of covariance, the end of treatment levels of gamma-glutamyl leucine (Fold change: 0.82, p<0.02) and gamma-glutamyl valine (Fold change: 0.8, p<0.03) were significantly lower in vitamin E responders compared to non-responders. The levels of gamma-glutamyl transpeptidase were not significantly different across the two groups. Subjects receiving placebo who demonstrated a histologic improvement also demonstrated lower levels of gamma-glutamylated amino acids (leucine, valine and isoleucine) compared to vitamin E non-responders. These data provide exploratory proof that there are measurable differences in the metabolic profile of subjects who are likely (vs unlikely) to respond to vitamin E treatment for NASH and in those experiencing histologic improvement (vs no improvement) on treatment and support further studies to validate these biomarkers.

The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM) was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS) obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs) and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5%) and higher sleep disturbance (11.5%). Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB) predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories.