Faculty Bibliography

OBJECTIVE: Depressive symptoms, common in breast cancer patients, may increase, decrease, or remain stable over the course of treatment. Most longitudinal studies have reported mean symptom scores that tend to obscure interindividual heterogeneity in the symptom experience. The identification of different trajectories of depressive symptoms may help identify patients who require an intervention. This study aimed to identify distinct subgroups of breast cancer patients with different trajectories of depressive symptoms in the first six months after surgery. METHOD: Among 398 patients with breast cancer, growth mixture modeling was used to identify latent classes of patients with distinct depressive symptom profiles. These profiles were identified based on Center for Epidemiological Studies-Depression (CES-D) scale scores completed just prior to surgery, and 1, 2, 3, 4, 5, and 6 months after surgery. RESULTS: Four latent classes of breast cancer patients with distinct depressive symptom trajectories were identified: Low Decelerating (38.9%), Intermediate (45.2%), Late Accelerating (11.3%), and Parabolic (4.5%) classes. Patients in the Intermediate class were younger, on average, than those in the Low Decelerating class. The Intermediate, Late Accelerating, and Parabolic classes had higher mean baseline anxiety scores compared to the Low Decelerating class. CONCLUSIONS: Breast cancer patients experience different trajectories of depressive symptoms after surgery. Of note, over 60% of these women were classified into one of three distinct subgroups with clinically significant levels of depressive symptoms. Identification of phenotypic and genotypic predictors of these depressive symptom trajectories after cancer treatment warrants additional investigation.

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.

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.

BACKGROUND: Attentional fatigue is experienced as a decreased ability to concentrate, engage in purposeful activity, and maintain social relationships when there are competing demands on attention. Breast and prostate cancer are the 2 most common cancers in women and men, respectively. Most previous studies on self-reported attentional fatigue evaluated patients with breast cancer. OBJECTIVES: The objectives of the study were to determine if self-reported attentional fatigue differed in patients with breast cancer and prostate cancer before radiation therapy (RT) and to determine the relationships between attentional fatigue and other symptoms in these 2 groups. METHODS: Patients (n = 155) completed questionnaires before RT. Descriptive statistics, Pearson correlations, and analysis of covariance were used for data analyses. RESULTS: After controlling for age, patients with breast cancer reported significantly higher levels of attentional fatigue. In both groups, more attentional fatigue correlated significantly with more anxiety, depression, sleep disturbance, and physical fatigue. These correlations were stronger for patients with breast cancer. CONCLUSIONS: The present study is the first to identify differences in self-reported attentional fatigue between these 2 groups before RT. Additional research is warranted to determine factors that contribute to these differences, as well as mechanisms that underlie the development of attentional fatigue. IMPLICATIONS FOR PRACTICE: Clinicians should consider the capacity of their patients to direct attention when learning about RT and other treatments. It is important to simplify confusing healthcare terminology and reinforce teaching that is most important both verbally and in writing. Appropriate interventions for anxiety and depression may decrease attentional fatigue in these patients.

AIMS AND OBJECTIVES: Describe patterns of morning and evening fatigue in adults with HIV and examine their relationship to demographic and clinical factors and other symptoms. BACKGROUND: Most studies of HIV-related fatigue assess average levels of fatigue and do not address its diurnal fluctuations. Patterns of fatigue over the course of the day may have important implications for assessment and treatment. DESIGN: A cross-sectional, correlational design was used with six repeated measures over 72 hours. METHOD: A convenience sample of 318 HIV-infected adults was recruited in San Francisco. Socio-demographic, clinical and symptom data were collected with questionnaires. CD4+ T-cell count and viral load were obtained from medical records. Participants completed a four-item version of the Lee Fatigue Scale each morning and evening for three consecutive days. Participants were grouped based on their diurnal pattern of fatigue (high evening only, high morning only, high morning and evening and low morning and evening). Group comparisons and logistic regression were used to determine the unique predictors of each fatigue pattern. RESULTS: The high evening fatigue pattern was associated with anxiety and the high morning pattern was associated with anxiety and depression. The morning fatigue pattern showed very little fluctuation between morning and evening, the evening pattern showed the largest fluctuation. The high morning and evening pattern was associated with anxiety, depression and sleep disturbance and this group reported the most fatigue-related distress and interference in functioning. CONCLUSIONS: These results provide initial evidence for the importance of assessing the patient's daily pattern of fatigue fluctuation, as different patterns were associated with different symptom experiences and perhaps different aetiologies. RELEVANCE TO CLINICAL PRACTICE: Different fatigue patterns may benefit from tailored intervention strategies. Management of depressive symptoms could be tested in patients who experience high levels of morning fatigue.

CONTEXT: Little is known about the occurrence and severity of sleep disturbance and fatigue between patients with common cancer diagnoses. OBJECTIVES: Study purposes were to evaluate for differences in the occurrence rates of sleep disturbances and fatigue; evaluate for differences in the severity of sleep disturbance using both subjective and objective measures; and evaluate for differences in the severity of self-reported fatigue in patients with breast and prostate cancer at the initiation of radiation therapy (RT). METHODS: Patients with breast (n=78) and prostate (n=82) cancer were evaluated before the initiation of RT using the Pittsburgh Sleep Quality Index, General Sleep Disturbance Scale, Lee Fatigue Scale, and wrist actigraphy. Differences in sleep disturbance and fatigue between groups were evaluated using independent sample t-tests and Chi-square analyses. RESULTS: Occurrence rates for sleep disturbance (P<0.0001) and fatigue (P=0.03) were significantly higher in patients with breast compared with prostate cancer. Patients with breast cancer self-reported significantly higher levels of sleep disturbance (P=0.008) and fatigue (P=0.005) than patients with prostate cancer. However, using actigraphy, patients with prostate cancer had poorer sleep efficiency (P=0.02) than patients with breast cancer. CONCLUSION: Based on self-report, patients with breast cancer experience sleep disturbance more frequently and with greater severity than patients with prostate cancer. Objective measures of sleep disturbance suggest that prostate cancer patients have more severe sleep disturbance than breast cancer patients. All the patients experienced poor sleep quality and fatigue, which suggests that oncology patients need to be assessed for these symptoms.

BACKGROUND: Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study. METHODS: Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls. RESULTS: Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 x 10(-7)), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 x 10(-8); Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 x 10(-4); OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 x 10(-2), OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 x 10(-3), OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 x 10(-3), OR = 1.13, 95% CI:1.042, 1.215). CONCLUSION: We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.

BACKGROUND: Little is known about the relationships between sleep parameters and fatigue in patients at the initiation of radiation therapy (RT). 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 objective parameters and subjective ratings of sleep disturbance and fatigue severity, in a sample of patients at the initiation of RT. METHODS: Patients (n = 185) with breast, prostate, lung, or brain cancer 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 a total of 48 hours prior to beginning RT. Actigraphy data were analyzed using the Cole-Kripke algorithm. Spearman rank correlations were calculated between variables. RESULTS: Approximately 30% to 50% of patients experienced sleep disturbance, depending on whether clinically significant cutoffs for the subjective or objective measures were used to calculate occurrence rates. In addition, these patients 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 the subjective, but not the objective measures of sleep disturbance and fatigue. CONCLUSIONS: A significant percentage of oncology patients experience significant disturbances in sleep-wake circadian activity rhythms at the initiation of RT. The disturbances occur in both sleep initiation and sleep maintenance. IMPLICATIONS FOR PRACTICE: Patients need to be assessed at the initiation of RT for sleep disturbance, so appropriate treatment is initiated.

Symptom burden has been identified as a predictor of medication adherence, but little is known about which symptoms are most strongly implicated. This study examines self-reported medical adherence in relation to demographic, clinical, and symptom characteristics among 302 adults living with HIV. Only 12% reported missing medication during the 3-day assessment, but 75% gave at least one reason for missing it in the previous month. Poor adherence was associated with higher viral load and greater symptom burden. Trouble sleeping and difficulty concentrating were strongly associated with poor adherence. Given that "forgetting" was the most common reason for missing medication and nearly one third reported sleeping through dose time, future research should examine the influence of sleep disturbance on adherence. Effective management of common symptoms, such as sleep disturbance, fatigue, and gastrointestinal side-effects of medications may result in better adherence, as well as improved clinical outcomes and quality of life.

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). Twenty-seven 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.