Exposure considerations in human safety assessment: Report from an EPAA Partners' Forum.

Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a Partners' Forum (PF) to explore exposure considerations in human safety assessment of industrial products to agree key conclusions for the regulatory acceptance of exposure assessment approaches and priority areas for further research investment. The PF recognised the widescale use of exposure information across industrial sectors with the possibilities of creating synergies between different sectors. Further, the PF acknowledged that the EPAA could make a significant contribution to promote the use of exposure data in human safety assessment, with an aim to address specific regulatory needs. To achieve this, research needs, as well as synergies and areas for potential collaboration across sectors, were identified.

Prevalence and Characteristics of Diagnostic Error in Pediatric Critical Care: A Multicenter Study.

OBJECTIVES: Effective interventions to prevent diagnostic error among critically ill children should be informed by diagnostic error prevalence and etiologies. We aimed to determine the prevalence and characteristics of diagnostic errors and identify factors associated with error in patients admitted to the PICU. DESIGN: Multicenter retrospective cohort study using structured medical record review by trained clinicians using the Revised Safer Dx instrument to identify diagnostic error (defined as missed opportunities in diagnosis). Cases with potential errors were further reviewed by four pediatric intensivists who made final consensus determinations of diagnostic error occurrence. Demographic, clinical, clinician, and encounter data were also collected. SETTING: Four academic tertiary-referral PICUs. PATIENTS: Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 882 patient admissions, 13 (1.5%) had a diagnostic error up to 7 days after PICU admission. Infections (46%) and respiratory conditions (23%) were the most common missed diagnoses. One diagnostic error caused harm with a prolonged hospital stay. Common missed diagnostic opportunities included failure to consider the diagnosis despite a suggestive history (69%) and failure to broaden diagnostic testing (69%). Unadjusted analysis identified more diagnostic errors in patients with atypical presentations (23.1% vs 3.6%, p = 0.011), neurologic chief complaints (46.2% vs 18.8%, p = 0.024), admitting intensivists greater than or equal to 45 years old (92.3% vs 65.1%, p = 0.042), admitting intensivists with more service weeks/year (mean 12.8 vs 10.9 wk, p = 0.031), and diagnostic uncertainty on admission (77% vs 25.1%, p < 0.001). Generalized linear mixed models determined that atypical presentation (odds ratio [OR] 4.58; 95% CI, 0.94-17.1) and diagnostic uncertainty on admission (OR 9.67; 95% CI, 2.86-44.0) were significantly associated with diagnostic error. CONCLUSIONS: Among critically ill children, 1.5% had a diagnostic error up to 7 days after PICU admission. Diagnostic errors were associated with atypical presentations and diagnostic uncertainty on admission, suggesting possible targets for intervention.

Impact of subspecialty consultations on diagnosis in the pediatric intensive care unit.

OBJECTIVES: Intensivists and subspecialists often collaborate in diagnosing patients in the pediatric intensive care unit (PICU). Our objectives were to characterize critically ill children for whom subspecialty consultations were requested, describe consultation characteristics, and determine consultations' impact on PICU diagnosis. METHODS: We performed a retrospective study using chart review in a single tertiary referral PICU including children admitted for acute illness. We collected data on patients with and without subspecialty consultations within the first three days of PICU admission and determined changes in PICU clinicians' diagnostic evaluation or treatment after consultations. RESULTS: PICU clinicians requested 152 subspecialty consultations for 87 of 101 (86%) patients. Consultations were requested equally for assistance in diagnosis (65%) and treatment (66%). Eighteen of 87 (21%) patients with consultations had a change in diagnosis from PICU admission to discharge, 11 (61%) attributed to subspecialty input. Thirty-nine (45%) patients with consultations had additional imaging and/or laboratory testing and 48 (55%) had medication changes and/or a procedure performed immediately after consultation. CONCLUSIONS: Subspecialty consultations were requested during a majority of PICU admissions. Consultations can influence the diagnosis and treatment of critically ill children. Future research should investigate PICU interdisciplinary collaborations, which are essential for teamwork in diagnosis.

Incorporating human exposure information in a weight of evidence approach to inform design of repeated dose animal studies.

Human health risks from chronic exposures to environmental chemicals are typically estimated from potential human exposure estimates and dose-response data obtained from repeated-dose animal toxicity studies. Various criteria are available for selecting the top (highest) dose used in these animal studies. For example, toxicokinetic (TK) and toxicological data provided by shorter-term or dose range finding studies can be evaluated in a weight of evidence approach to provide insight into the dose range that would provide dose-response data that are relevant to human exposures. However, there are concerns that a top dose resulting from the consideration of TK data may be too low compared to other criteria, such as the limit dose or the maximum tolerated dose. In this paper, we address several concerns related to human exposures by discussing 1) the resources and methods available to predict human exposure levels and the associated uncertainty and variability, and 2) the margin between predicted human exposure levels and the dose levels used in repeated-dose animal studies. A series of case studies, ranging from data-rich to data-poor chemicals, are presented to demonstrate that expected human exposures to environmental chemicals are typically orders of magnitude lower than no-observed-adverse-effect levels/lowest-observed-adverse-effect levels (NOAELs/LOAELs) when available (used as conservative surrogates for top doses). The results of these case studies support that a top dose based, in part, on TK data is typically orders of magnitude higher than expected human exposure levels.

Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.

Comparative effectiveness of five fecal immunochemical tests using colonoscopy as the gold standard: study protocol.

BACKGROUND: There are nearly 50,000 colorectal cancer (CRC) deaths in the United States each year. CRC is curable if detected in its early stages. Fecal immunochemical tests (FITs) can detect precursor lesions and many can be analyzed at the point-of-care (POC) in physician offices. However, there are few data to guide test selection. Broader use of FITs could make CRC screening more accessible, especially in resource-poor settings. METHODS: A total of 3600 racially and ethnically diverse individuals aged 50 to 85 years having either a screening or surveillance colonoscopy will be recruited. Each participant will complete five FITs on a single stool sample. Test characteristics for each FIT for advanced colorectal neoplasia (ACN) will be calculated using colonoscopy as the gold standard. RESULTS: We have complete data from a total of 2990 individuals. Thirty percent are Latino and 5.3% are black/African American. We will present full results once the study is completed. CONCLUSIONS: Our focus in this study is how well FITs detect ACN, using colonoscopy as the gold standard. Four of the five FITs being used are POC tests. Although FITs have been shown to have acceptable performance, there is little data to guide which ones have the best test characteristics and colonoscopy is the main CRC screening test used in the United States. Use of FITs will allow broader segments of the population to access CRC screening because these tests require no preparation, are inexpensive, and can be collected in the privacy of one's home. Increasing CRC screening uptake will reduce the burden of advanced adenomas and colorectal cancer.

Gas Exchange, Water Use Efficiency, and Biomass Partitioning among Geographic Sources of Acer saccharum Subsp. saccharum and Subsp. nigrum Seedlings in Response to Water Stress.

Responses to water stress were measured for sugar maple (Acer saccharum subsp. saccharum Marshall) sources from Oklahoma (Caddo sugar maple), Missouri, Tennessee, Ontario, and a black maple (Acer saccharum subsp. nigrum F. Michx.) source from Iowa. Seedling sources were selected for differences in temperature and precipitation of their geographic origins. Seedlings were preconditioned through moist (watered daily) or dry (watered every 4-7 days) cycles and then exposed to prolonged water stress. As water stress increased, dry preconditioned 17-week-old sugar maple seedlings from Oklahoma, Missouri, and Tennessee, sources from warmer, and/or drier climates with greater restrained photosynthesis, stomatal conductance, and water use efficiency than those from cooler and moister climates. Under imposed water stress, the Ontario and Iowa sourced seedlings increased their root to shoot ratios and decreased their specific leaf area, mechanisms for drought avoidance. However, no corresponding changes in these values occurred for Oklahoma, Missouri, and Tennessee sources and for the variable of leaf wilting across all sources. Results from this study suggest greater tolerance of water stress in the Oklahoma, Missouri, and Tennessee ecotypes from the western and southern range of sugar maple resulted primarily with water use efficiency (WUE) rather than other water stress coping mechanisms. Findings from this study provide evidence to support selection of sugar maples sources for forestation.

DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan.

OBJECTIVE: Myotonic dystrophy is a multisystem disorder caused by a trinucleotide repeat expansion on the myotonic dystrophy protein kinase (DMPK) gene. To determine whether wildtype DMPK expression patterns vary as a function of age, we analyzed DMPK expression in the brain from 99 donors ranging from 5 postconceptional weeks to 80 years old. METHODS: We used the BrainSpan messenger RNA sequencing and the Yale Microarray data sets, which included brain tissue samples from 42 and 57 donors, respectively. Collectively, donors ranged in age from 5 postconceptional weeks to 80 years old. DMPK expression was normalized for each donor across regions available in both data sets. Restricted cubic spline linear regression models were used to analyze the effects of log-transformed age and sex on normalized DMPK expression data. RESULTS: Age was a statistically significant predictor of normalized DMPK expression pattern in the human brain in the BrainSpan (p < 0.005) and Yale data sets (p < 0.005). Sex was not a significant predictor. Across both data sets, normalized wildtype DMPK expression steadily increases during fetal development, peaks around birth, and then declines to reach a nadir around age 10. CONCLUSIONS: Peak expression of DMPK coincides with a time of dynamic brain development. Abnormal brain DMPK expression due to myotonic dystrophy may have implications for early brain development.

Dissemination of a telehealth cardiovascular risk service: The CVRS live protocol.

BACKGROUND: Medical clinics are increasingly hiring clinical pharmacists to improve management of cardiovascular disease (CVD). However, the limited number of clinical pharmacists employed in a clinic may not impact the large number of complex patients needing the services. We have developed a remote telehealth service provided by clinical pharmacists to complement CVD services provided by on-site clinical pharmacists and aid sites without a clinical pharmacist. This cardiovascular risk service (CVRS) has been studied in two NIH-funded trials, however, we identified barriers to optimal intervention implementation. The purpose of this study is to examine how to implement the CVRS into medical offices and see if the intervention will be sustained. METHODS: This is a 5-year, pragmatic, cluster-randomized clinical trial in 13 primary care clinics across the US. We randomized clinics to receive CVRS or usual care and will enroll 325 patient subjects and 288 key stakeholder subjects. We have obtained access to the electronic medical records (EMRs) of all study clinics to recruit subjects and provide the pharmacist intervention. The intervention is staggered so that after 12 months, the usual care sites will receive the intervention for 12 months. Follow-up will be accomplished though medical record abstraction at baseline, 12 months, 24 months, and 36 months. CONCLUSIONS: This study will enroll subjects through 2021 and results will be available in 2024. This study will provide unique information on how the CVRS provided by remote clinical pharmacists can be effectively implemented in medical offices, many of which already employ on-site clinical pharmacists. CLINICAL TRIAL REGISTRATION INFORMATION: NCT03660631: http://clinicaltrials.gov/ct2/show/NCT03660631.

Visual and Cognitive Impairments Differentially Affect Speed Limit Compliance in Older Drivers.

OBJECTIVES: We test the hypothesis that clinical measures of age-related cognitive, visual, and mobility impairments negatively impact older driver speed limit compliance to advance method developments that improve older patient care and screen, identify, and advise at-risk older drivers. DESIGN: Real-world driver behaviors of older adults who had a range of cognitive, visual, and mobility abilities (measured with standardized, clinical tests) were assessed in environmental context (e.g., speed limit, traffic density, roadway type). Older driver speed limit compliance was measured in constant speed limit zones and at transition zones, where speed limits changed. SETTING: A naturalistic driving study of older adults living around Omaha, Nebraska. PARTICIPANTS: Seventy-seven, legally licensed, active, and typically aging older drivers (65-90 years) who had a range of cognitive and visual abilities. MEASUREMENTS: Drivers typical, daily driving was continuously monitored for 3 months using sensor instrumentation installed in their own vehicles. At study start, each participant completed a comprehensive, standardized, clinical assessment of cognitive, visual, and mobility abilities relevant to aging and driving. RESULTS: Older drivers with greater cognitive impairment (P = .10) drove slower than drivers with less cognitive impairment, linking cognitive impairment to speed control. Drivers with greater visual impairment overall complied less with speed limit changes at transition zones (P = .01) and were more likely to comply with speed limit transitions when they occurred concurrently with changes in roadway features (P < .01). CONCLUSION: Results link clinical measures of age-related cognitive and visual impairment to impaired driver safety in real-world contexts. Real-world sensor data coupled with detailed, personalized older driver profiles can inform patients, caregivers, interventions, policy, and the design of supportive in-vehicle technology for at-risk older drivers.

Factors Associated With Diagnostic Error on Admission to a PICU: A Pilot Study.

OBJECTIVES: Diagnostic errors can harm critically ill children. However, we know little about their prevalence in PICUs and factors associated with error. The objective of this pilot study was to determine feasibility of record review to identify patient, provider, and work system factors associated with diagnostic errors during the first 12 hours after PICU admission. DESIGN: Pilot retrospective cohort study with structured record review using a structured tool (Safer Dx instrument) to identify diagnostic error. SETTING: Academic tertiary referral PICU. PATIENTS: Patients 0-17 years old admitted nonelectively to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four of 50 patients (8%) had diagnostic errors in the first 12 hours after admission. The Safer Dx instrument helped identify delayed diagnoses of chronic ear infection, increased intracranial pressure (two cases), and Bartonella encephalitis. We calculated that 610 PICU admissions are needed to achieve 80% power (α = 0.05) to detect significant associations with error. CONCLUSIONS: Our pilot study found four patients with diagnostic error out of 50 children admitted nonelectively to a PICU. Retrospective record review using a structured tool to identify diagnostic errors is feasible in this population. Pilot data are being used to inform a larger and more definitive multicenter study.

Fourth Ventricle Enlargement in Chiari Malformation Type I.

OBJECTIVE: How Chiari malformation type I (CM-I) affects posterior fossa brain structures and produces various symptoms remains unclear. The fourth ventricle is surrounded by critical structures required for normal function. The foramen of Magendie can be obstructed in CM-I; therefore, fourth ventricle changes may occur. To test this hypothesis, we assessed fourth ventricle volume in CM-I compared with healthy controls. METHODS: Using our database from 2007-2016, we studied 72 patients with CM-I and 30 age-matched healthy control subjects. Fourth and lateral ventricle volumes and posterior fossa volumes (PFV) were assessed and correlated with clinical signs and symptoms. Statistical analysis was performed. RESULTS: Patients with CM-I had larger fourth ventricle volumes compared with control subjects (1.31 vs. 0.95 mL; P = 0.012). There were no differences in lateral ventricle volume or PFV. CM-I fourth ventricle volume was associated with tonsillar descent (P = 0.030). CM-I fourth ventricle volume variance was larger than healthy controls (F71,29 = 8.33; P < 0.0001). Patients with CM-I with severe signs and symptoms had a significantly larger fourth ventricle than patients with CM-I with mild signs and symptoms (1.565 vs. 1.015 mL; P = 0.0002). CONCLUSIONS: The fourth ventricle can be enlarged in CM-I independent of lateral ventricle size and is associated with greater tonsillar descent. Most importantly, fourth ventricle enlargement was associated with a worse clinical and radiographic presentation independent of PFV. Fourth ventricle enlargement can affect critical structures and may be a mechanism contributing to symptoms unexplained by tonsil descent. Fourth ventricle enlargement is a useful adjunct in assessing CM-I.

Real-world risk exposure in older drivers with cognitive and visual dysfunction.

Objective: This study addresses the need to measure and monitor objective, real-world driver safety behavior in at-risk drivers with age-related dysfunction. Older drivers are at risk for age-related cognitive and visual dysfunction, which may reduce mobility and increase errors that lead to crashes. Understanding patterns of real-world behavior, exposure, and cognitive-perceptual processes underlying risk in environmental context and in older drivers requires new approaches.Methods: We assessed patterns of objective, real-world driver risk exposure and vehicle control related to steering, braking, and accelerating in older adults with a range of cognitive and visual functional abilities. Real-world driver behavior was collected from passive-monitoring systems installed in 77 drivers' vehicles and analyzed across 242,153 km (150,467 miles) driven. Driver behavior was assessed cross-sectionally in relationship to driver functional abilities and safety-critical environmental contexts (roadway type and visibility condition).Results: Results suggest that cognitive dysfunction impairs vehicle control across wide-ranging environments. Drivers with greater cognitive dysfunction showed more erratic braking and accelerating during daytime commercial and interstate driving. Drivers with less cognitive dysfunction showed more erratic braking and accelerating on residential roadways regardless of visibility condition. Greater cognitive dysfunction predicted more erratic steering on commercial and interstate roadways and less erratic steering on residential roadways. Greater visual dysfunction impaired braking and accelerating during nighttime and interstate driving, but not on residential or commercial roadways. Steering behavior was unaffected by visual abilities. Drivers with greater cognitive dysfunction did not appear to reduce driving frequency in higher-risk environments. Visually impaired drivers drove more on residential roadways and less on commercial roadways, but did not reduce driving on interstates, where they showed the greatest risk per mile driven.Conclusions: Results successfully mapped driver cognitive and visual profiles onto contemporaneous, real-world behavior and risk loci. Results link age-related dysfunction to real-world vehicle control and show that drivers may not sufficiently reduce exposure to higher-risk driving environments. Employing naturalistic observation to monitor and measure patterns of driver behavior can inform methods for early detection of age-related risk, fitness-to-drive assessments, and interventions to preserve safety, mobility, and quality of life in aging or other at-risk populations.

Reducing the need for animal testing while increasing efficiency in a pesticide regulatory setting: Lessons from the EPA Office of Pesticide Programs' Hazard and Science Policy Council.

As part of EPA's commitment to reducing animal testing, the Office of Pesticide Programs (OPP) created the Hazard and Science Policy Council (HASPOC). This group considers requests for waiving animal study requirements for human health risk assessments and makes recommendations based on a weight-of-the-evidence approach. Since its inception in 2012, the HASPOC has evaluated over one thousand requests to waive animal studies required by default for pesticide evaluation. Here, the number of studies waived, and the types of studies represented were analyzed to determine the impact of the HASPOC decisions in terms of animal and monetary savings. Overall, the waiving of studies by HASPOC resulted in over 200 thousand animals saved. There were also savings of over $300 million in study costs and over $6 million in study review costs as well as less time spent in study processing and review by EPA staff. Thus, the HASPOC has built significant efficiencies into the risk assessment process while continuing to protect human health.

Brain structure in juvenile-onset Huntington disease.

OBJECTIVE: To assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype. METHODS: Despite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models. RESULTS: Participants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results. CONCLUSIONS: The primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.

Practical and statistical challenges in driving research.

Driving is an integral aspect of many modern societies, and motor vehicle safety is an important public health issue. With advances in sensor technology, more and more driving data are being collected by researchers, insurers, and automobile companies, which has increased the need and opportunities for statisticians to be involved in driving research. This report discusses several practical and statistical challenges in driver-level studies, including the process of defining meaningful driving metrics, issues related to "Big Data" aspects of driving research, and the principle of reproducible research.

Using Topic Modeling to Develop Multi-level Descriptions of Naturalistic Driving Data from Drivers with and without Sleep Apnea.

One challenge in using naturalistic driving data is producing a holistic analysis of these highly variable datasets. Typical analyses focus on isolated events, such as large g-force accelerations indicating a possible near-crash. Examining isolated events is ill-suited for identifying patterns in continuous activities such as maintaining vehicle control. We present an alternative approach that converts driving data into a text representation and uses topic modeling to identify patterns across the dataset. This approach enables the discovery of non-linear patterns, reduces the dimensionality of the data, and captures subtle variations in driver behavior. In this study topic models are used to concisely described patterns in trips from drivers with and without untreated obstructive sleep apnea (OSA). The analysis included 5000 trips (50 trips from 100 drivers; 66 drivers with OSA; 34 comparison drivers). Trips were treated as documents, and speed and acceleration data from the trips were converted to "driving words." The identified patterns, called topics, were determined based on regularities in the co-occurrence of the driving words within the trips. This representation was used in random forest models to predict the driver condition (i.e., OSA or comparison) for each trip. Models with 10, 15 and 20 topics had better accuracy in predicting the driver condition, with a maximum AUC of 0.73 for a model with 20 topics. Trips from drivers with OSA were more likely to be defined by topics for smaller lateral accelerations at low speeds. The results demonstrate topic modeling as a useful tool for extracting meaningful information from naturalistic driving datasets.

Black Clouds vs Random Variation in Hospital Admissions.

BACKGROUND AND OBJECTIVES: Physicians often accuse their peers of being "black clouds" if they repeatedly have more than the average number of hospital admissions while on call. Our purpose was to determine whether the black-cloud phenomenon is real or explainable by random variation. METHODS: We analyzed hospital admissions to the University of Iowa family medicine service from July 1, 2010 to June 30, 2015. Analyses were stratified by peer group (eg, night shift attending physicians, day shift senior residents). We analyzed admission numbers to find evidence of black-cloud physicians (those with significantly more admissions than their peers) and white-cloud physicians (those with significantly fewer admissions). The statistical significance of whether there were actual differences across physicians was tested with mixed-effects negative binomial regression. RESULTS: The 5-year study included 96 physicians and 6,194 admissions. The number of daytime admissions ranged from 0 to 10 (mean 2.17, SD 1.63). Night admissions ranged from 0 to 11 (mean 1.23, SD 1.22). Admissions increased from 1,016 in the first year to 1,523 in the fifth year. We found 18 white-cloud and 16 black-cloud physicians in simple regression models that did not control for this upward trend. After including study year and other potential confounding variables in the regression models, there were no significant associations between physicians and admission numbers and therefore no true black or white clouds. CONCLUSIONS: In this study, apparent black-cloud and white-cloud physicians could be explained by random variation in hospital admissions. However, this randomness incorporated a wide range in workload among physicians, with potential impact on resident education at the low end and patient safety at the high end.

Cluster-Randomized Trial to Evaluate a Centralized Clinical Pharmacy Service in Private Family Medicine Offices.

BACKGROUND: The use of clinical pharmacists in primary care has improved the control of several chronic cardiovascular conditions. However, many private physician practices lack the resources to implement team-based care with pharmacists. The purpose of this study was to evaluate whether a centralized, remote, clinical pharmacy service could improve guideline adherence and secondary measures of cardiovascular risk in primary care offices in rural and small communities. METHODS AND RESULTS: This study was a prospective trial in 12 family medicine offices cluster randomized to either the intervention or usual care. The intervention was delivered for 12 months, and subjects had research visits at baseline and 12 months. The primary outcome was adherence to guidelines, and secondary outcomes included changes in key cardiovascular risk factors and preventative health measures. We enrolled 302 subjects. There was no improvement in the Guideline Advantage score from baseline to 12 months in the control group (64.7% versus 63.1%, respectively; P=0.21). There was a statistically significant improvement in the intervention group from 63.3% at baseline to 67.8% at 12 months (P=0.02). The estimated benefit of the intervention was 5.0%±2.4% (95% confidence interval=-0.5% to 10.4%; P=0.07). Several criteria were significantly better for intervention subjects, including appropriate statin therapy (P<0.001), body mass index, screening (P<0.001), and alcohol screening (P<0.001). Only 13.7% of subjects with diabetes mellitus had hemoglobin A1c at goal at baseline, and this increased to 30.8% and 21.0% in the intervention and control group, respectively, at 12 months (P=0.10). CONCLUSIONS: The centralized, remote pharmacist intervention was successfully implemented. The improvements in outcomes were modest, in part because of higher than expected baseline guideline adherence. Future studies of this model should focus on patients with uncontrolled conditions at high risk for cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT 01983813.

Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence.

BACKGROUND: Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58. METHODS: We evaluated brain function in children ages 6-18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function. FINDINGS: The number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40-41 repeats. After this peak, increasing repeat length was associated with declining GAI scores. INTERPRETATION: HTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease.