Returning integrated genomic risk and clinical recommendations: The eMERGE study.

PURPOSE: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk. METHODS: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results. RESULTS: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022. CONCLUSION: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

HPV and HPV Vaccination Knowledge and Attitudes Among Medical Students in Alabama.

In addition to being the most common sexually transmitted infection, the human papillomavirus (HPV) is associated with six types of cancer in men and women. The HPV vaccine provides long-lasting, effective protection from high-risk HPV infection, thus serving as a means of cancer prevention. An effective healthcare provider recommendation is well-established as the most significant influence on HPV vaccine uptake, and, as emerging providers, it is critical that medical students receive comprehensive training in this area. However, the type and extent of such training for current medical students in the USA is unclear. An online survey assessing HPV and HPV vaccine knowledge, attitudes, and vaccine status was distributed to all medical students at an Alabama university. Scales were developed to assess composite HPV and HPV knowledge scores and HPV vaccination intentions. Of those age-eligible, 32.1% reported completion of the HPV vaccine series while 15.2% reported partial completion. Knowledge of both HPV and HPV vaccination significantly increased with program year (p < 0.0001 and p = 0.0069, respectively); however, there were knowledge gaps across all years regarding HPV-associated cancers. Attitudes and intentions showed a similar association, with more advanced students demonstrating more positive attitudes toward HPV vaccination (p = 0.0003). There is a need within the current curriculum to include more education and training on HPV, HPV vaccination, and counseling-particularly for students in the first 2 years of their program. Implementation of a classroom module or interactive workshop would likely improve knowledge and attitudes, better preparing students for their future role as potential immunizers.

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study.

OBJECTIVE: To determine if routine electroencephalography (EEG) in seizure-naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes. METHODS: Forty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1-hour awake and asleep video-EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland-II) were completed at 6, 12, and 24 months of age. RESULTS: Of 40 infants enrolled (mean age of 82.4 days), 32 completed the study. Two were lost to follow-up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation [SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control. SIGNIFICANCE: IEDs identify impending epilepsy in the majority (77%) of seizure-naive infants with TSC. The use of a 1-hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well-controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

Gastrointestinal bleeding and pro-angiogenic shift in the angiopoietin axis with continuous flow left ventricular assist device implantation.

BACKGROUND: Gastrointestinal bleeding (GIB) affects up to 40% of continuous-flow left ventricular assist device (CF-LVAD) recipients. A higher risk of GIB is seen in CF-LVAD recipients with lower device pulsatility without a known mechanism. One hypothesis is that the novel hemodynamics in CF-LVAD recipients affect angiogenesis signaling. We aimed to (1) measure serum levels of angiopoietin (Ang)-1, Ang-2, and VEGF-A in CF-LVAD recipients with and without GIB and in healthy controls and (2) evaluate correlations of those levels with hemodynamics. METHODS: We recruited 12 patients with CF-LVADs (six who developed GIB after device implantation) along with 12 age-matched controls without heart failure or GIB and measured Ang-1, Ang-2, and VEGF-A levels in serum samples from each patient. RESULTS: CF-LVAD recipients had significantly higher Ang-2 and lower Ang-1 levels compared to controls with no difference in VEGF-A levels. CF-LVAD recipients with GIB had lower Ang-1 levels than those without GIB. There were trends for pulse pressure to be positively correlated with Ang-1 levels and negatively correlated with Ang-2 levels in CF-LVAD recipients with no correlation observed in healthy controls. CONCLUSION: CF-LVAD recipients demonstrated a shift toward a pro-angiogenic phenotype in the angiopoietin axis that is significantly associated with GIB and may be linked to low pulse pressure.

The correlation in echocardiogram to right heart catheterization in identifying pulmonary hypertension as a barrier to liver transplantation.

BACKGROUND: Pulmonary hypertension (PH) and portopulmonary hypertension (POPH) can be limitations towards listing for liver transplantation (LT). Our study evaluates the correlation of right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) on transthoracic echocardiogram (TTE) compared to mPAP on right heart catheterization (RHC). METHODS: We performed a retrospective review of 723 patients who underwent LT evaluation at our institution between 2012 and 2020. Our cohort consisted of patients with RVSP and mPAP measured on TTE. A Wald t-test and area under the curve analysis were used for statistical analyses. RESULTS: Patients with higher mPAP values on TTE (N=33) did not correlate with mPAP ≥ 35 mmHg on RHC, while patients with higher RVSP values (N=147) on TTE were associated with mPAP ≥ 35 mmHg on RHC. The cutoff value of RVSP ≥ 48 mmHg on TTE was associated with mPAP ≥ 35 mmHg on RHC. CONCLUSIONS: Our data suggest that RVSP compared to mPAP on TTE is a better indicator for mPAP ≥ 35 mmHg on RHC. RVSP can be used as a marker on echocardiography for identifying patients with a higher likelihood of PH being a barrier to LT listing.

Risk of Postdischarge Bleeding From Dual Antiplatelet Therapy After Percutaneous Coronary Intervention Among US Black and White Adults.

Background Dual antiplatelet therapy after percutaneous coronary intervention reduces myocardial infarctions but increases bleeding. The risk of bleeding may be higher among Black patients for unknown reasons. Bleeding risk scores have not been validated among Black patients. We assessed the difference in bleeding risk between Black and White patients along with the performance of the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy, Patterns of Nonadherence to Antiplatelet Regimens in Stented Patients, and Academic Research Consortium for High Bleeding Risk scores among both groups. Methods and Results This was a single-center prospective study of patients who underwent percutaneous coronary intervention (2014-2019) and were followed for 1 year. The outcome was postdischarge Bleeding Academic Research Consortium 2 to 5 bleeding. Incidence rates were reported. Cox proportional hazards models measured the effect of self-reported Black race on bleeding and determined the predictors of bleeding among 19 a priori variables. The 3 risk scores were assessed among Black and White patients separately using the Harrell concordance index. Of 1529 included patients, 342 (22.4%) self-reported as being Black race. Unadjusted bleeding rates were 22.7 per 100 person-years among Black patients versus 16.3 among White patients (hazard ratio, 1.41 [95% CI, 1.00-2.00], P=0.052). Predictors of bleeding were age, glomerular filtration rate <30 mL/min per 1.73 m2, prior bleeding, ticagrelor or prasugrel use, and anticoagulant use. Among Black and White patients, respectively, the C-indexes were the following: 0.644 versus 0.600 for Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy (P<0.001 for both), 0.620 versus 0.612 for Patterns of Nonadherence to Antiplatelet Regimens in Stented Patients (P=0.003 and P<0.001, respectively), and 0.600 versus 0.598 for Academic Research Consortium for High Bleeding Risk (P=0.006 and P<0.001, respectively). Conclusions The risk of dual antiplatelet therapy-associated postdischarge Bleeding Academic Research Consortium 2 to 5 bleeding was not significantly different between self-reported Black and White patients. Bleeding risk scores performed similarly among both groups.

Factors associated with HPV vaccination initiation among United States college students.

Human papillomavirus (HPV) remains the most common sexually transmitted infection (STI) in the U.S. despite widespread availability of a safe, effective vaccine. Although young adults are at greatest risk of HPV infection, extensive vaccine promotion and intervention efforts has been directed toward 11-12-year-olds. College students represent an ideal audience for HPV vaccine "catch-up;" however, research indicates inconsistent HPV vaccination rates within this demographic. An online survey assessing HPV and HPV vaccine knowledge and behaviors was distributed to all undergraduate college students at a large, public university in the Deep South region of the U.S. The primary outcome was receipt of HPV vaccination (binary response options of Yes/No). Logistic regression analyses were performed to determine predictors of HPV vaccination. Of the 1,725 who completed the survey, 47.0% reported having received at least one dose of HPV vaccine; overall series completion (series = 3 doses for this population) was 17.4%. The primary outcome was HPV initiation among college students, defined as having received at least one dose of the HPV vaccine. Results indicated substantial gaps in participants' knowledge of their vaccination status. Provider and parental recommendations as well as social influences were shown to significantly impact student vaccination status, emphasizing the importance of incorporating these elements in future interventions, potentially as multi-level strategies. Future college interventions should address HPV and vaccination knowledge and the importance of provider and parental recommendations.

Outcomes of Individuals With and Without Heart Failure Presenting With Acute Coronary Syndrome.

Major adverse cardiac event (MACE) and bleeding risks following percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are not well defined in individuals with heart failure (HF). We followed 1,145 individuals in the Pharmacogenomic Resource to improve Medication Effectiveness Genotype Guided Antiplatelet Therapy cohort for MACE and bleeding events following PCI for ACS. We constructed Cox proportional hazards models to compare MACE and bleeding in those with versus without HF, adjusting for sociodemographics, comorbidities, and medications. We also determined predictors of MACE and bleeding events in both groups. 370 (32%) individuals did and 775 (68%) did not have HF prior to PCI. Mean age was 61.7 ± 12.2 years, 31% were female, and 24% were African American. After a median follow-up of 0.78 years, individuals with HF had higher rates of MACE compared to those without HF (48 vs. 24 events per 100 person years) which remained significant after multivariable adjustment (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.00 to 1.72). Similarly, bleeding was higher in those with versus without HF (22 vs. 11 events per 100 person years), although this was no longer statistically significant after multivariable adjustment (HR 1.29, 95% CI 0.86 to 1.93). Diabetes and peripheral vascular disease were predictors of MACE, and end-stage renal disease was a predictor of bleeding among participants with HF. MACE risk is higher in individuals with versus without HF following PCI for ACS. However, the risk of bleeding, especially among those with end-stage renal disease , must be considered when determining post-PCI anticoagulant strategies.

Trauma Communications Center Coordinated Severity-Based Stroke Triage: Protocol of a Hybrid Type 1 Effectiveness-Implementation Study.

Background: Mechanical thrombectomy (MT) can improve the outcomes of patients with large vessel occlusion (LVO), but a minority of patients with LVO are treated and there are disparities in timely access to MT. In part, this is because in most regions, including Alabama, the emergency medical service (EMS) transports all patients with suspected stroke, regardless of severity, to the nearest stroke center. Consequently, patients with LVO may experience delayed arrival at stroke centers with MT capability and worse outcomes. Alabama's trauma communications center (TCC) coordinates EMS transport of trauma patients by trauma severity and regional hospital capability. Our aims are to develop a severity-based stroke triage (SBST) care model based on Alabama's trauma system, compare the effectiveness of this care pathway to current stroke triage in Alabama for improving broad, equitable, and timely access to MT, and explore stakeholder perceptions of the intervention's feasibility, appropriateness, and acceptability. Methods: This is a hybrid type 1 effectiveness-implementation study with a multi-phase mixed methods sequential design and an embedded observational stepped wedge cluster trial. We will extend TCC guided stroke severity assessment to all EMS regions in Alabama; conduct stakeholder interviews and focus groups to aid in development of region and hospital specific prehospital and inter-facility stroke triage plans for patients with suspected LVO; implement a phased rollout of TCC Coordinated SBST across Alabama's six EMS regions; and conduct stakeholder surveys and interviews to assess context-specific perceptions of the intervention. The primary outcome is the change in proportion of prehospital stroke system patients with suspected LVO who are treated with MT before and after implementation of TCC Coordinated SBST. Secondary outcomes include change in broad public health impact before and after implementation and stakeholder perceptions of the intervention's feasibility, appropriateness, and acceptability using a mixed methods approach. With 1200 to 1300 total observations over 36 months, we have 80% power to detect a 15% improvement in the primary endpoint. Discussion: This project, if successful, can demonstrate how the trauma system infrastructure can serve as the basis for a more integrated and effective system of emergency stroke care.

The role of European genetic admixture in the etiology of the insulin resistance syndrome in children: are the effects mediated by fat accumulation?

OBJECTIVES: To evaluate the contribution of European genetic admixture (EUADM) to insulin resistance syndrome (IRS) in a multiethnic sample of children age 7-12 years, and to explore whether body fat affects this relationship. STUDY DESIGN: Anthropometric measurements and blood pressure were assessed in 243 children. After an overnight fast, an intravenous glucose tolerance test was conducted, and measures of fasting insulin/glucose, lipids, insulin sensitivity (SI), and acute insulin response to glucose (AIRg) were obtained. The proportion of EUADM was determined by maximum likelihood estimation using 140 ancestry informative markers. Subjects were stratified into tertiles according to the proportion of EUADM for analyses. Subjects were categorized as lean or obese using body fat percentage cutpoints (25% in boys, 30% in girls). RESULTS: Among lean subjects (72%), the tertile representing the greatest proportion of EUADM was associated with higher SI (P<.001) and serum glucose (P<.05) and lower insulin (P<.05), AIRg (P<.001), high-density lipoprotein cholesterol (P=.05), and blood pressure (P<.05). However, among obese subjects, EUADM was associated only with SI (P<.05). CONCLUSIONS: Our results suggest that population differences in IRS likely have a genetic component, but that the influence of genetic background may be masked by obesity.

Phenotypic variability among café-au-lait macules in neurofibromatosis type 1.

BACKGROUND: Café-au-lait macules (CALMs) in neurofibromatosis type 1 (NF1) are an early and accessible phenotype in NF1, but have not been extensively studied. OBJECTIVE: We sought to more fully characterize the phenotype of CALMs in patients with NF1. METHODS: In all, 24 patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the genetics department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin based on its absorption of visible light. The major response was defined as the difference between the mean melanin from the CALM and the mean melanin from the surrounding skin. The major response for each spot was compared with spots within an individual and across individuals in the study population. RESULTS: There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, P < .0001) and secondly to interpersonal variability (33.0%, P < .0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. LIMITATIONS: The study was performed on a small population of patients and the method has not yet been used extensively for this purpose. CONCLUSIONS: CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1.

Race-based and sex-based differences in bioactive lipid mediators after myocardial infarction.

AIMS: Leucocyte-directed specialized pro-resolving mediators (SPMs) are essential for cardiac repair, and their biosynthesis coincides with the expression of pro-inflammatory mediators; however, the precise quantitation during an acute myocardial infarction (MI) event is poorly understood in race-specific and sex-specific manner. Coronary heart disease is the leading cause of death and disability in the USA. Although the prevalence of coronary heart disease is similar between Black and White patients, cardiovascular events (including MI), rehospitalization, and mortality are disproportionately higher in Black patients. Therefore, understanding differences in inflammation and resolution can enable the development of predictive, personalized, and precise treatment and attenuate sex/racial disparities. Thus, herein, we assess differences in bioactive lipids and SPMs, between Black and White patients experiencing an acute MI. METHODS AND RESULTS: From the PRiME-GGAT cohort, we collected plasma after MI within 24-48 h from 22 Black (15 male and 7 female) and 31 White (23 male and 8 female) subjects for a comparative race-based and sex-based analyses. MI was confirmed using a biochemical measurement of plasma troponin and ST elevation. Plasma levels of three essential polyunsaturated fatty acids [arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)] and a set of 40 bioactive lipid mediators with major emphasis on SPMs were quantified by liquid chromatography-mass spectrometry. AA and DHA were higher in White male and female patients, and EPA was noted higher only in White male patients compared with White female and Black male and female patients. Lipoxygenase-mediated AA-derived 12-hydroxyeicosatetraenoic acid (29-63%) and 15-hydroxyeicosatetraenoic acid (3-9%) and DHA-derived 17-hydroxydocosahexaenoic acid (3-22%) and 14-hydroxydocosahexaenoic acid (7-10%) were major bioactive lipid mediators in plasma. The SPM signature resolvin E1 was significantly lower in Black patients compared with White male and female patients, whereas protectin D1 was lower in White male patients compared with White female and Black male and female patients. CONCLUSION: Our comparative analyses of fatty acids and respective cyclooxygenase-derived and lipoxygenase-derived SPM signatures capture the heterogeneity of disease pathology and elucidate potential mechanisms underlying sex-based and race-based differences following MI.

Risk of Major Adverse Cardiovascular Events and Major Hemorrhage Among White and Black Patients Undergoing Percutaneous Coronary Intervention.

Background Data on racial disparities in major adverse cardiovascular events (MACE) and major hemorrhage (HEM) after percutaneous coronary intervention are limited. Factors contributing to these disparities are unknown. Methods and Results PRiME-GGAT (Pharmacogenomic Resource to Improve Medication Effectiveness-Genotype-Guided Antiplatelet Therapy) is a prospective cohort. Patients aged ≥18 years undergoing percutaneous coronary intervention were enrolled and followed for up to 1 year. Racial disparities in risk of MACE and HEM were assessed using an incident rate ratio. Sequential cumulative adjustment analyses were performed to identify factors contributing to these disparities. Data from 919 patients were included in the analysis. Compared with white patients, black patients (n=203; 22.1% of the cohort) were younger and were more likely to be female, to be a smoker, and to have higher body mass index, lower socioeconomic status, higher prevalence of diabetes mellitus and moderate to severe chronic kidney disease, and presentation with acute coronary syndrome and to undergo urgent percutaneous coronary intervention. The incident rates of MACE (34.1% versus 18.2% per 100 person-years, P<0.001) and HEM (17.7% versus 10.3% per 100 person-years, P=0.02) were higher in black patients. The incident rate ratio was 1.9 (95% CI, 1.3-2.6; P<0.001) for MACE and 1.7 (95% CI, 1.1-2. 7; P=0.02) for HEM. After adjustment for nonclinical and clinical factors, black race was not significantly associated with outcomes. Rather, differences in socioeconomic status, comorbidities, and coronary heart disease severity were attributed to racial disparities in outcomes. Conclusions Despite receiving similar treatment, racial disparities in MACE and HEM still exist. Opportunities exist to narrow these disparities by mitigating the identified contributors.

An empirical Bayes method for updating inferences in analysis of quantitative trait loci using information from related genome scans.

Individual genome scans for quantitative trait loci (QTL) mapping often suffer from low statistical power and imprecise estimates of QTL location and effect. This lack of precision yields large confidence intervals for QTL location, which are problematic for subsequent fine mapping and positional cloning. In prioritizing areas for follow-up after an initial genome scan and in evaluating the credibility of apparent linkage signals, investigators typically examine the results of other genome scans of the same phenotype and informally update their beliefs about which linkage signals in their scan most merit confidence and follow-up via a subjective-intuitive integration approach. A method that acknowledges the wisdom of this general paradigm but formally borrows information from other scans to increase confidence in objectivity would be a benefit. We developed an empirical Bayes analytic method to integrate information from multiple genome scans. The linkage statistic obtained from a single genome scan study is updated by incorporating statistics from other genome scans as prior information. This technique does not require that all studies have an identical marker map or a common estimated QTL effect. The updated linkage statistic can then be used for the estimation of QTL location and effect. We evaluate the performance of our method by using extensive simulations based on actual marker spacing and allele frequencies from available data. Results indicate that the empirical Bayes method can account for between-study heterogeneity, estimate the QTL location and effect more precisely, and provide narrower confidence intervals than results from any single individual study. We also compared the empirical Bayes method with a method originally developed for meta-analysis (a closely related but distinct purpose). In the face of marked heterogeneity among studies, the empirical Bayes method outperforms the comparator.

Comparison of low-abundance biomarker levels in capillary-collected nonstimulated tears and washout tears of aqueous-deficient and normal patients.

PURPOSE: Low tear volume limits the use of nonstimulated (NS) microcapillary tear collection in aqueous-deficient (AD) patients. Adding a small amount of "washout" fluid to the eye prior to tear collection is a potentially viable alternative method for abundant proteins, but is relatively untested for low-abundance biomarkers. This study determined the feasibility of the washout (WO) method as an NS alternative for low-abundance biomarkers. NS and WO biomarker profiles were compared between AD patients and non-AD controls to determine if the two methods identify the same intergroup differences. METHODS: Matching NS and WO tears were collected from 48 patients by micropipette, the WO sample after instillation of 10 µL saline. Tear cytokine levels were measured by 27-Plex Bio-Rad assay. Bland-Altman analyses for each biomarker determined the agreement between tear sample types. Patients were grouped as AD or non-AD based on Schirmer score to determine if NS profile between-group differences were preserved in WO tears. RESULTS: Bland-Altman plots showed good biomarker level agreement between NS and WO tears for most cytokines. Five biomarkers, among those most often cited as differing in AD dry eye, differed significantly between non-AD and AD groups in both tear types. Additional biomarker differences were seen in NS tears only. CONCLUSIONS: The WO tear collection method is a viable alternative to NS tears for many low-abundance biomarkers and is able to replicate major NS tear differences between dry eye groups. More subtle intergroup differences are lost in WO samples because of reduced statistical power.

Hyperammonemia following intravenous valproate loading.

BACKGROUND: Valproic acid (VPA) has been associated with hyperammonemia with and without encephalopathy. We report the frequent but transient nature of hyperammonemia following intravenous (IV) administration of loading doses of VPA. METHODS: Forty participants received a VPA loading dose (20 or 30 mg/kg) at 6 or 10mg/kg/min. All participants were monitored for signs of systemic and local intolerance. Serum VPA level, ammonia, complete blood count, bilirubin, transaminases, pancreatic enzymes, and level of consciousness were obtained at baseline, 1 and 24h after administration. Changes in ammonia levels were assessed using repeated-measures ANOVA. RESULTS: Asymptomatic hyperammonemia occurred in 30 of 40 participants at 1h post-VPA infusion. Majority of the participants (66%) demonstrated decreasing ammonia concentrations at 24h post-infusion. Multivariable repeated-measures analysis indicates the lack of influence of VPA dose (p=0.8), VPA levels (p>0.24, all time points), infusion rate (p=0.41) and gender (0.68) on ammonia levels across time. Age (p=0.015), time since dosing (p=0.017) and co-therapy with enzyme-inducing antiepileptic drugs (p=0.035) were significant predictors of changes in ammonia levels. CONCLUSIONS: Hyperammonemia is a frequent but transient finding following intravenous administration of loading doses of VPA. Hyperammonemia was not associated with alteration in consciousness or hepatic transaminases.

An adaptive alpha spending algorithm improves the power of statistical inference in microarray data analysis.

The adaptive alpha-spending algorithm incorporates additional contextual evidence (including correlations among genes) about differential expression to adjust the initial p-values to yield the alpha-spending adjusted p-values. The alpha-spending algorithm is named so because of its similarity with the alpha-spending algorithm in interim analysis of clinical trials in which stage-specific significance levels are assigned to each stage of the clinical trial. We show that the Bonferroni correction applied to the alpha-spending adjusted p-values approximately controls the Family Wise Error Rate under the complete null hypothesis. Using simulations we also show that the use of the alpha spending algorithm yields increased power over the unadjusted p-values while controlling FDR. We found the greater benefits of the alpha spending algorithm with increasing sample sizes and correlation among genes. The use of the alpha spending algorithm will result in microarray experiments that make more efficient use of their data and may help conserve resources.

Influences of calorie restriction and age on energy expenditure in the rhesus monkey.

Caloric restriction (CR) is known to retard the aging process, and a marker of aging is decreased energy expenditure (EE). To assess longitudinal effects of CR on EE in rhesus monkeys (Macaca mulatta), data from 41 males (M) and 26 females (F) subjected to 9 or 15 yr of CR were studied. EE and body composition of monkeys 11-28 yr of age were measured using indirect calorimetry and dual X-ray absorptiometry. Total EE (24-h EE) was divided into daytime (day EE), nighttime (night EE), and daytime minus nighttime (D - N EE). M calorie-restricted monkeys showed a lower 24-h EE (means +/- SD = 568 +/- 96 kcal/day, P < 0.0001) than controls (C; 630 +/- 129 kcal/day). Calorie-restricted M had a lower night EE (difference = 36 kcal P < 0.0001) compared with C M, but after adjusting for FFM and FM, night EE was not different between calorie-restricted and C males (P = 0.72). The 24-h EE decreased with age (13 kcal decrease/yr, P < 0.0001), but there was no difference between CR and C. Adjusted for FFM and FM, D - N EE decreased with age (9 kcal/yr, P < 0.0001), with no interaction with age (P = 0.72). The F were compared with age-matched M selected from the male cohort. F had a lower 24-h EE (496 +/- 84 kcal/day) than M (636 +/- 139 kcal/day) (P < 0.0001). Adjusting for FFM and FM, night EE was lower in F compared with M (difference = 18 kcal, P = 0.077). Night EE did not differ between calorie-restricted and C younger monkeys after adjusting for FFM and FM. In conclusion, CR did not alter the age-related decrease in EE with CR.