Bradley E. Aouizerat

Abstract

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 × 10-7), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 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 × 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 × 10-2, OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10-3, OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 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.

Abstract

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.

Abstract

Multiple concurrent symptoms are highly prevalent in patients with cancer. However, little is known about the relationships among these symptoms and their underlying mechanisms. A number of cytokines that are involved in the development of sickness behavior are hypothesized to be a mechanism for symptom clusters. Measurement of these cytokines would provide valuable information that could be used to elucidate mechanisms underlying the development of symptom clusters and the identification of potential targets for intervention studies. In this article, the authors explore several issues that warrant careful consideration when designing a research study involving the use of a cytokine as a biomarker in symptom cluster research. These issues include which molecules to measure, which specimens to collect, the timing of specimen collection and processing, and which technologies to use to measure the biomarker and the sensitivity and specificity of the assay system. The article begins with a brief discussion of cytokines and sickness behavior and the role of the cytokines in cancer-related symptoms.

Abstract

UNLABELLED: The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS ≥5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH Clinical Research Network (CRN) studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and "not SH" in 22%. The NAS was ≥5 in 50% and ≤4 in 49%; in this cohort only 75% of biopsies with definite SH had an NAS ≥5, whereas 28% of borderline SH and 7% of "not SH" biopsies had NAS ≥5. Of biopsies with an NAS ≥5, 86% had SH and 3% "not SH". NAS ≤4 did not indicate benign histology; 29% had SH and only 42% had "not SH." Higher values of the NAS were associated with higher levels of alanine aminotransferase and aspartate aminotransferase, whereas the diagnosis of SH was associated with features of the metabolic syndrome.CONCLUSION: The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account.

Abstract

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 72hours. 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.

Abstract

OBJECTIVES: Factors that determine disease severity in nonalcoholic fatty liver disease (NAFLD) are unclear, but exercise is a recommended treatment. We evaluated the association between physical activity intensity and histological severity of NAFLD.METHODS: We conducted a retrospective analysis of adults with biopsy-proven NAFLD enrolled in the NASH CRN (Nonalcoholic Steatohepatitis Clinical Research Network). Using self-reported time spent in physical activity, we classified participants as inactive or as meeting the US guidelines for either moderate or vigorous exercise. Histology was reviewed by a central pathology committee. Frequency and odds of steatohepatitis (NASH) and advanced fibrosis were compared between subjects who either met or did not meet exercise recommendations, and by the total amount of exercise per week.RESULTS: A total of 813 adults (males=302, females=511) with NAFLD were included, with a mean age of 48 years. Neither moderate-intensity exercise nor total exercise per week was associated with NASH or stage of fibrosis. Meeting vigorous recommendations was associated with a decreased adjusted odds of having NASH (odds ratio (OR): 0.65 (0.43-0.98)). Doubling the recommended time spent in vigorous exercise, as is suggested for achieving additional health benefits, was associated with a decreased adjusted odds of advanced fibrosis (OR: 0.53 (0.29-0.97)).CONCLUSIONS: These data support an association of vigorous but not moderate or total exercise with the severity of NAFLD. Optimal doses of exercise by duration and intensity for the prevention or treatment of NASH have not been established; however, intensity may be more important than duration or total volume.

Abstract

Study Objectives: To examine how self-reported ratings of sleep disturbance changed from the time of the simulation visit to four months after the completion of radiation therapy (RT) and to investigate whether specific patient, disease, and symptom characteristics predicted the initial levels of sleep disturbance and/or characteristics of the trajectories of sleep disturbance. Design: Prospective longitudinal study. Setting: Two radiation therapy centers. Patients: Patients (n = 82) who underwent primary or adjuvant RT for prostate cancer. Measurements and Results: Changes in self-reported sleep disturbance were measured using the General Sleep Disturbance Scale (GSDS). Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression Scale. Trait and state anxiety were measured using the Spielberger State-Trait Anxiety Inventory. Hierarchical linear modeling was used to answer the study aims. Self-reported sleep disturbance increased during the course of RT and then decreased following the completion of RT. Predictors of higher levels of sleep disturbance included younger age, higher levels of trait anxiety, higher levels of depressive symptoms, and higher levels of sleep disturbance at the initiation of RT. Conclusions: Sleep disturbance is a significant problem in patients with prostate cancer who undergo RT. Younger men with co-occurring depression and anxiety may be at greatest risk for sleep disturbance during RT.

Abstract

Objective: The findings from several studies suggest that palliative care patients with advanced cancer experience multiple symptoms, and that these symptoms may be related to demographic and clinical factors as well as to patient outcomes. However, no systematic review has summarized the findings from studies that assessed multiple symptoms, predictors, and outcomes in these patients. The purposes of this review, focused on palliative care patients with advanced cancer, are to: 1) describe the relationships among multiple symptoms; 2) describe the predictors of multiple symptoms; and 3) describe the relationships between multiple symptoms and patient outcomes. Method: Comprehensive literature searches were completed using the following databases: PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsychInfo. The key words: cancer or advanced cancer or neoplasm, AND palliative care or terminal care or hospice or end-of-life, AND symptoms or multiple symptoms or symptom clusters were combined.Results: Twenty-two studies met the inclusion criteria and examined at least one of our purposes. The majority of these studies were descriptive and used one of four common symptom assessment scales. Fifty-six different signs and symptoms were evaluated across various dimensions (i.e., prevalence, severity, distress, frequency, control). Pain, dyspnea, and nausea were the only symptoms measured in all 22 studies. Relationships among concurrent symptoms were examined in nine studies. Relationships among symptoms and predictors (i.e., demographics, cancer type, healthcare delivery environment) were examined in seven studies. Relationships among symptoms and outcomes (i.e., functional status, psychological status, quality-of-life, survival time) were examined in 14 studies. Significant methodological variation was found among these studies.Significance of results: It is difficult to draw conclusions about the relationships among multiple symptoms, predictors, and outcomes due to the heterogeneity of these studies. Future research is needed to determine which symptoms and symptom dimensions to assess in order to better understand how multiple symptoms relate to each other as well to as predictors and outcomes in palliative care patients with advanced cancer.