Lifestyle Risk Score: handling missingness of individual lifestyle components in meta-analysis of gene-by-lifestyle interactions

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to “benchmark” results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered due to lower sample size, and the Naïve Approach, which utilized all available data and ignored the missingness, was slightly inflated. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to “benchmark” results. In conclusion, we generally recommend the Safe Approach, a straightforward and non-inflated approach, to handle heterogeneity among cohorts in the LRS based genome-wide interaction meta-analyses.Subject terms: Genetics, Risk factors     

Substantial pain burden in frequency,intensity, interference and chronicity among children and adults with neurofibromatosis Type 1

Tumor growths, migraine headaches, and other health‐related complications reported in patients with neurofibromatosis type 1 (NF1) are often associated with pain. Thus, this study sought to describe and quantify the pain experience in children and young adults with NF1. Surveys were administered to 49 participants (28 children and 21 adults), ages 8 through 40 years. The survey included the Numeric Rating Scale 11 (NRS11) to assess pain intensity and the Patient Reported Outcomes Measurement Information System (PROMIS) to assess pain interference. A supplemental survey was created to measure pain frequency, chronicity, quality, and location. Results suggest pain is not only present in 55% of the cohort, but that it can begin at early ages. Pain was chronic in 35% of participants, with 41% reporting the use of medication to manage pain symptoms. Common sources of pain included migraine headaches and NF‐related tumors. Pain was described as having neuropathic features (i.e., burning, tingling, numbness, or itching), and was localized to the head, back, and extremities. Further, subsets of participants reported moderate‐to‐severe pain intensity, high frequency of pain, and interference of pain in daily activities. Continued investigation of the pain experience in a multisystem disorder, such as NF1, remains essential to providing guidance in the setting of complex pain management.     

Identification of neural pathways involved in genital reflexes in the female: a combined anterograde and retrograde tracing study

The medial preoptic area (MPOA) is important for reproductive behavior in females. However, the descending pathways mediating these responses to the spinal motor output are unknown. The MPOA does not directly innervate the spinal cord. Therefore, pathways mediating MPOA-induced changes in sexual behavior must relay in the brain. The nucleus paragigantocellularis (nPGi) projects heavily to spinal circuits involved in female sexual reflexes and is involved in the tonic inhibition of genital reflexes. However, the periaqueductal gray (PAG) is also important for female sexual behavior. The present study examined the hypothesis that the MPOA output relays through PAG and the nPGi before descending to the spinal cord. We used anterograde and retrograde tracing techniques to examine the descending pathways and relay sites from the MPOA to the spinal cord and the nPGi in the female rat. Injection of biotinylated dextran amine into the MPOA produced dense labeling in specific regions of the PAG and Barrington's nucleus; anterogradely labeled fibers terminated close to neurons retrogradely labeled from the spinal cord in the PAG, Barrington's nucleus, nPGi, lateral hypothalamus and paraventricular nucleus (PVN). Anterogradely labeled fibers and varicosities were also found close to neurons retrogradely labeled from the nPGi in the PAG, lateral hypothalamus and PVN. These results suggest that the major MPOA output relays in the PAG and nPGi before descending to innervate spinal circuits regulating female genital reflexes and that the MPOA plays a multifaceted role in female reproductive behavior through its modulation of PAG output systems.     

Error behaviors associated with loss of competency in Alzheimer's disease

OBJECTIVE: To investigate qualitative behavioral changes associated with declining medical decision-making capacity (competency) in patients with AD. BACKGROUND: Qualitative measures can yield clinical information about functional changes in neurologic disease not available through quantitative measures. METHODS: Normal older controls (n = 21) and patients with mild and moderate probable AD (n = 72) were compared using a standardized competency measure and neuropsychological measures. A system of 16 qualitative error scores representing conceptual domains of language, executive dysfunction, affective dysfunction, and compensatory responses was used to analyze errors produced on the competency measure. Patterns of errors were examined across groups. Relationships between error behaviors and competency performance were determined, and neurocognitive correlates of specific error behaviors were identified. RESULTS: AD patients demonstrated more miscomprehension, factual confusion, intrusions, incoherent responses, nonresponsive answers, loss of task, and delegation than controls. Errors in the executive domain (loss of task, nonresponsive answer, and loss of detachment) were key predictors of declining competency performance by AD patients. Neuropsychological analyses in the AD group generally confirmed the conceptual domain assignments of the qualitative scores. CONCLUSIONS: Loss of task, nonresponsive answers, and loss of detachment were key behavioral changes associated with declining competency of AD patients and with neurocognitive measures of executive dysfunction. These findings support the growing linkage between executive dysfunction and competency loss.     

Executive dysfunction and loss of capacity to consent to medical treatment in patients with Alzheimer's disease

Loss of medical decision making capacity (competency) is an inevitable consequence of Alzheimer's disease (AD) and is an important subject for neuropsychological investigation. Consent capacity involves a complex set of comprehension, encoding, information processing, decision making, and communication abilities, which ultimately must have an explicit neurological basis. This article examines the role of executive dysfunction in loss of consent capacity in patients with AD. The authors first describe a cognitive neuropsychological model for understanding loss of consent capacity in AD. The article also reviews neuropsychological studies that have used a psychometric instrument to test consent capacity under different legal standards (Capacity to Consent to Treatment Instrument). These studies indicate that when multiple cognitive functions are associated with declining competency of AD patients on the Capacity to Consent to Treatment Instrument legal standards, measures of simple executive function are the predominant predictors. These empirical findings are discussed and related to the conceptual model. The findings support the growing body of literature linking frontal neural systems and executive cognitive functions to competency and to higher order functional capacities.     

Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma

BACKGROUND: For patients with borderline resectable pancreatic cancer, preoperative chemoradiation and standalone chemotherapy may allow for R0 resection and improved survival. METHODS: A retrospective review of patients with borderline resectable pancreatic cancer treated with preoperative chemoradiation and standalone chemotherapy was undertaken. Clinical variables, including disease-free and overall survival, were collected. Univariate analysis was used to identify factors impacting survival. RESULTS: Thirteen patients with borderline resectable pancreatic cancer were treated with preoperative chemoradiation and chemotherapy. Morbidity and mortality were 38% and 0. There were 2 R1 and 11 R0 resections. Nine patients are alive with a median follow-up of 20 months. Five patients recurred at a median of 4 months. Tumor fibrosis < or = 60% was associated with recurrence and poor survival. CONCLUSIONS: Preoperative chemoradiation and chemotherapy allow a select group of patients with borderline resectable pancreatic cancer to undergo an R0 or R1 resection with acceptable morbidity and mortality. Tumor response may be associated with survival.     

Usual Intake of Flavonoids Is Inversely Associated with Metabolic Syndrome in African American and White Males but Not Females in Baltimore City,Maryland, USA

Despite research that suggests flavonoids protect against metabolic syndrome (MetS) and evidence that intake of these compounds differs by race, knowledge about whether flavonoid–MetS associations vary among racial groups is limited. This study sought to estimate usual total flavonoid intake in African American and White adults and assess its sex- and sex/race-specific associations with MetS and its risk factors. Analysis of cross-sectional data from 1837 adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study were analyzed. Usual total flavonoid intake was estimated using the NCI Method, and logistic regression measured its linkages with health outcomes. Among males overall and when stratified by race, odds of MetS and its risk factors low high-density lipoprotein cholesterol (HDL-C) and elevated glucose were lower at the 75th percentile of usual total flavonoid intake than at the 25th percentile (OR for MetS = 0.62; 95% CI = 0.53, 0.71). However, low HDL-C and elevated glucose were positively associated with usual flavonoid intake among females. The comparable associations by race within sex imply that the relationships between flavonoid and health outcomes may be evident across an array of intakes.