Information exchange among providers and patient-centeredness in transitional care: A five-year retrospective analysis.

BACKGROUND: Responding to the shift toward value-based care, hospitals engaged in widespread experimentation of implementing transitional care (TC) strategies to improve patient experience and reduce unnecessary readmissions. However, which groups of these strategies are most strongly associated with better outcomes remains unknown. METHODS: Using a retrospective longitudinal design, we collected hospitals' TC strategy implementation data for 370 U S. hospitals and obtained claims data for 2.4 million Medicare fee-for-service beneficiaries hospitalized at them from 2009 to 2014. We applied estimated mixed-effects regression models controlling for patient, hospital, and community covariates to assess relationships between TC strategy groups and trends in hospitals' 30-day hospital readmissions, with observation stay and mortality rates as secondary outcomes. RESULTS: Hospitals' adoption of TC groups was associated with higher readmission rates at baseline and larger readmission rate reductions compared to not adopting any of 5 TC groups. The TC group including timely information exchange across care settings, engaging patients and caregivers in education, and/or identifying and addressing patients' transition needs was associated with the largest reductions. Hospitals not implementing any of the 5 TC groups had higher mortality rates and lower observation stay rates throughout the study period. CONCLUSIONS: Our findings suggest that timely information sharing among providers across the care continuum and engaging patients in discharge planning and education may correspond with reduced readmissions. IMPLICATIONS: Our research suggests that hospitals responded to shifts in policy by implementing a diversity of TC strategy combinations; it also provides guidance regarding which combinations of TC strategies corresponded with larger readmission reductions.

Mobility Levels With Physical Rehabilitation Delivered During and After Extracorporeal Membrane Oxygenation: A Marker of Illness Severity or an Indication of Recovery?

OBJECTIVE: The aims of this study were to determine whether physical rehabilitation intervention for individuals who required extracorporeal membrane oxygenation (ECMO) is associated with clinical outcomes and to assess whether the patient mobility response over initial rehabilitation sessions early in the intensive care unit (ICU) course predicts or is associated with survival, lengths of stay, discharge disposition, and 30-day readmissions. METHODS: This study was a 10-year retrospective practice analysis of adults who were critically ill and required ECMO for >72 hours in the cardiothoracic ICU at an academic medical center. Physical rehabilitation implemented during or following the initiation of ECMO was quantified on the basis of timing, frequency, and change in mobility level in response to the intervention over the first 4 consecutive sessions. The primary dependent outcome was in-hospital mortality. Secondary outcomes included 30-day readmission and discharge disposition ranked on an ordinal scale. RESULTS: Three hundred fifteen individuals (mean age = 50 years [SD = 15 years]; 63% men; mean Sequential Organ Failure Assessment score = 11.6 [SD = 3.3]) met the inclusion criteria. Two hundred eighteen individuals (69%) received at least 1 physical rehabilitation session while requiring ECMO, 70 (22%) received rehabilitation after ECMO was discontinued, and 27 (9%) never received rehabilitation. Individuals discharged alive achieved higher mobility levels and had a steeper, more positive rate of change in mobility over the first 4 sessions than individuals who died in the hospital (2.8 vs 0.38; degrees of freedom = 199, t = 8.24). Those who received rehabilitation and achieved the milestones of sitting on the edge of the bed and walking for >45 m were more likely to survive (47% vs 13%; χ2 = 156) than those who did not (26% vs 3.5%; χ2 = 80). CONCLUSION: A positive rate of change in mobility and the ability to achieve mobility milestones with rehabilitation were associated with improved clinical outcomes. IMPACT: An individual's mobility response to physical rehabilitation early in the ICU course is an important indicator of illness and should be used with clinical presentation to guide clinical decision-making and predict outcomes.

Effects of Different Transitional Care Strategies on Outcomes after Hospital Discharge-Trust Matters, Too.

BACKGROUND: As health systems shift toward value-based care, strategies to reduce readmissions and improve patient outcomes become increasingly important. Despite extensive research, the combinations of transitional care (TC) strategies associated with best patient-centered outcomes remain uncertain. METHODS: Using an observational, prospective cohort study design, Project ACHIEVE sought to determine the association of different combinations of TC strategies with patient-reported and postdischarge health care utilization outcomes. Using purposive sampling, the research team recruited a diverse sample of short-term acute care and critical access hospitals in the United States (N = 42) and analyzed data on eligible Medicare beneficiaries (N = 7,939) discharged from their medical/surgical units. Using both hospital- and patient-reported TC strategy exposure data, the project compared patients "exposed" to each of five overlapping groups of TC strategies to their "control" counterparts. Primary outcomes included 30-day hospital readmissions, 7-day postdischarge emergency department (ED) visits and patient-reported physical and mental health, pain, and participation in daily activities. RESULTS: Participants averaged 72.3 years old (standard deviation =10.1), 53.4% were female, and most were White (78.9%). Patients exposed to one TC group (Hospital-Based Trust, Plain Language, and Coordination) were less likely to have 30-day readmissions (risk ratio [RR], 0.72; 95% confidence interval [CI] = 0.57-0.92, p < 0.001) or 7-day ED visits (RR, 0.72; 95% CI, 0.55-0.93, p < 0.001) and more likely to report excellent physical and mental health, greater participation in daily activities, and less pain (RR ranged from 1.11 to 1.15, p < 0.01). CONCLUSION: In concert with care coordination activities that bridge the transition from hospital to home, hospitals' clear communication and fostering of trust with patients were associated with better patient-reported outcomes and reduced health care utilization.

Developing and Demonstrating the Viability and Availability of the Multilevel Implementation Strategy for Syncope Optimal Care Through Engagement (MISSION) Syncope App: Evidence-Based Clinical Decision Support Tool.

BACKGROUND: Syncope evaluation and management is associated with testing overuse and unnecessary hospitalizations. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Syncope Guideline aims to standardize clinical practice and reduce unnecessary services. The use of clinical decision support (CDS) tools offers the potential to successfully implement evidence-based clinical guidelines. However, CDS tools that provide an evidence-based differential diagnosis (DDx) of syncope at the point of care are currently lacking. OBJECTIVE: With input from diverse health systems, we developed and demonstrated the viability of a mobile app, the Multilevel Implementation Strategy for Syncope optImal care thrOugh eNgagement (MISSION) Syncope, as a CDS tool for syncope diagnosis and prognosis. METHODS: Development of the app had three main goals: (1) reliable generation of an accurate DDx, (2) incorporation of an evidence-based clinical risk tool for prognosis, and (3) user-based design and technical development. To generate a DDx that incorporated assessment recommendations, we reviewed guidelines and the literature to determine clinical assessment questions (variables) and likelihood ratios (LHRs) for each variable in predicting etiology. The creation and validation of the app diagnosis occurred through an iterative clinician review and application to actual clinical cases. The review of available risk score calculators focused on identifying an easily applied and valid evidence-based clinical risk stratification tool. The review and decision-making factors included characteristics of the original study, clinical variables, and validation studies. App design and development relied on user-centered design principles. We used observations of the emergency department workflow, storyboard demonstration, multiple mock review sessions, and beta-testing to optimize functionality and usability. RESULTS: The MISSION Syncope app is consistent with guideline recommendations on evidence-based practice (EBP), and its user interface (UI) reflects steps in a real-world patient evaluation: assessment, DDx, risk stratification, and recommendations. The app provides flexible clinical decision making, while emphasizing a care continuum; it generates recommendations for diagnosis and prognosis based on user input. The DDx in the app is deemed a pragmatic model that more closely aligns with real-world clinical practice and was validated using actual clinical cases. The beta-testing of the app demonstrated well-accepted functionality and usability of this syncope CDS tool. CONCLUSIONS: The MISSION Syncope app development integrated the current literature and clinical expertise to provide an evidence-based DDx, a prognosis using a validated scoring system, and recommendations based on clinical guidelines. This app demonstrates the importance of using research literature in the development of a CDS tool and applying clinical experience to fill the gaps in available research. It is essential for a successful app to be deliberate in pursuing a practical clinical model instead of striving for a perfect mathematical model, given available published evidence. This hybrid methodology can be applied to similar CDS tool development.

Understanding the groups of care transition strategies used by U.S. hospitals: an application of factor analytic and latent class methods.

BACKGROUND: After activation of the Hospital Readmission Reduction Program (HRRP) in 2012, hospitals nationwide experimented broadly with the implementation of Transitional Care (TC) strategies to reduce hospital readmissions. Although numerous evidence-based TC models exist, they are often adapted to local contexts, rendering large-scale evaluation difficult. Little systematic evidence exists about prevailing implementation patterns of TC strategies among hospitals, nor which strategies in which combinations are most effective at improving patient outcomes. We aimed to identify and define combinations of TC strategies, or groups of transitional care activities, implemented among a large and diverse cohort of U.S. hospitals, with the ultimate goal of evaluating their comparative effectiveness. METHODS: We collected implementation data for 13 TC strategies through a nationwide, web-based survey of representatives from short-term acute-care and critical access hospitals (N = 370) and obtained Medicare claims data for patients discharged from participating hospitals. TC strategies were grouped separately through factor analysis and latent class analysis. RESULTS: We observed 348 variations in how hospitals implemented 13 TC strategies, highlighting the diversity of hospitals' TC strategy implementation. Factor analysis resulted in five overlapping groups of TC strategies, including those characterized by 1) medication reconciliation, 2) shared decision making, 3) identifying high risk patients, 4) care plan, and 5) cross-setting information exchange. We determined that the groups suggested by factor analysis results provided a more logical grouping. Further, groups of TC strategies based on factor analysis performed better than the ones based on latent class analysis in detecting differences in 30-day readmission trends. CONCLUSIONS: U.S. hospitals uniquely combine TC strategies in ways that require further evaluation. Factor analysis provides a logical method for grouping such strategies for comparative effectiveness analysis when the groups are dependent. Our findings provide hospitals and health systems 1) information about what groups of TC strategies are commonly being implemented by hospitals, 2) strengths associated with the factor analysis approach for classifying these groups, and ultimately, 3) information upon which comparative effectiveness trials can be designed. Our results further reveal promising targets for comparative effectiveness analyses, including groups incorporating cross-setting information exchange.

Improving evidence-based grouping of transitional care strategies in hospital implementation using statistical tools and expert review.

BACKGROUND: As health systems transition to value-based care, improving transitional care (TC) remains a priority. Hospitals implementing evidence-based TC models often adapt them to local contexts. However, limited research has evaluated which groups of TC strategies, or transitional care activities, commonly implemented by hospitals correspond with improved patient outcomes. In order to identify TC strategy groups for evaluation, we applied a data-driven approach informed by literature review and expert opinion. METHODS: Based on a review of evidence-based TC models and the literature, focus groups with patients and family caregivers identifying what matters most to them during care transitions, and expert review, the Project ACHIEVE team identified 22 TC strategies to evaluate. Patient exposure to TC strategies was measured through a hospital survey (N = 42) and prospective survey of patients discharged from those hospitals (N = 8080). To define groups of TC strategies for evaluation, we performed a multistep process including: using ACHIEVE'S prior retrospective analysis; performing exploratory factor analysis, latent class analysis, and finite mixture model analysis on hospital and patient survey data; and confirming results through expert review. Machine learning (e.g., random forest) was performed using patient claims data to explore the predictive influence of individual strategies, strategy groups, and key covariates on 30-day hospital readmissions. RESULTS: The methodological approach identified five groups of TC strategies that were commonly delivered as a bundle by hospitals: 1) Patient Communication and Care Management, 2) Hospital-Based Trust, Plain Language, and Coordination, 3) Home-Based Trust, Plain language, and Coordination, 4) Patient/Family Caregiver Assessment and Information Exchange Among Providers, and 5) Assessment and Teach Back. Each TC strategy group comprises three to six, non-mutually exclusive TC strategies (i.e., some strategies are in multiple TC strategy groups). Results from random forest analyses revealed that TC strategies patients reported receiving were more important in predicting readmissions than TC strategies that hospitals reported delivering, and that other key co-variates, such as patient comorbidities, were the most important variables. CONCLUSION: Sophisticated statistical tools can help identify underlying patterns of hospitals' TC efforts. Using such tools, this study identified five groups of TC strategies that have potential to improve patient outcomes.

Value-based syncope evaluation and management: Perspectives of health care professionals on readiness, barriers and enablers.

BACKGROUND: Syncope is a common condition seen in the emergency department. Given the multitude of etiologies, research exists on the evaluation and management of syncope. Yet, physicians' approach to patients with syncope is variable and often not value based. The 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients with Syncope includes a focus on unnecessary medical testing. However, little research assesses implementation of the guidelines. METHODS: Mixed methods approach was applied. The targeted provider specialties include emergency medicine, hospital medicine and cardiology. The Evidence-based Practice Attitude Scale-36 and the Organizational Readiness to Change Assessment surveys were distributed to four different hospital sites. We then conducted focus groups and key informant interviews to obtain more information about clinicians' perceptions to guideline-based practice and barriers/facilitators to implementation. Descriptive statistics and bivariate analyses were used for survey analysis. Two-stage coding was used to identify themes with NVivo. RESULTS: Analysis of surveys revealed that overall attitude toward evidence-based practices was moderate and implementation of new guidelines were seen as a burden, potentially decreasing compliance. There were differences across hospital settings. Five common themes emerged from interviews: uncertainty of a syncope diagnosis, rise of consumerism in health care, communication challenge with patient, provider differences in standardized care, and organizational processes to change. CONCLUSIONS: Despite recommendations for the use of syncope guidelines, adherence is suboptimal. Overcoming barriers to use will require a paradigm shift. A multifaceted approach and collaborative relationships are needed to adhere to the Guidelines to improve patient care and operational efficiency.

Incidence and Cost of Acute Kidney Injury in Hospitalized Patients with Infective Endocarditis.

Acute kidney injury (AKI) is a frequent complication of hospitalized patients with infective endocarditis (IE). Further, AKI in the setting of IE is associated with high morbidity and mortality. We aimed to examine the incidence, clinical parameters, and hospital costs associated with AKI in hospitalized patients with IE in an endemic area with an increasing prevalence of opioid use. This retrospective cohort study included 269 patients admitted to a major referral center in Kentucky with a primary diagnosis of IE from January 2013 to December 2015. Of these, 178 (66.2%) patients had AKI by Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria: 74 (41.6%) had AKI stage 1 and 104 (58.4%) had AKI stage ≥2. In multivariable analysis, higher comorbidity scores and the need for diuretics were independently associated with AKI, while the involvement of the tricuspid valve and the need for vasopressor/inotrope support were independently associated with severe AKI (stage ≥2). The median total direct cost of hospitalization was progressively higher according to each stage of AKI ($17,069 for no AKI; $37,111 for AKI stage 1; and $61,357 for AKI stage ≥2; p < 0.001). In conclusion, two-thirds of patients admitted to the hospital due to IE had incident AKI. The occurrence of AKI significantly increased healthcare costs. The higher level of comorbidity, the affection of the tricuspid valve, and the need for diuretics and/or vasoactive drugs were associated with severe AKI in this susceptible population.

Development of a novel mouth model as an alternative tool to test the effectiveness of an in vivo EPR dosimetry system.

In a large-scale radiation event, thousands may be exposed to unknown amounts of radiation, some of which may be life-threatening without immediate attention. In such situations, a method to quickly and reliably estimate dose would help medical responders triage victims to receive life-saving care. We developed such a method using electron paramagnetic resonance (EPR) to make in vivo measurements of the maxillary incisors. This report provides evidence that the use of in vitro studies can provide data that are fully representative of the measurements made in vivo. This is necessary because, in order to systematically test and improve the reliability and accuracy of the dose estimates made with our EPR dosimetry system, it is important to conduct controlled studies in vitro using irradiated human teeth. Therefore, it is imperative to validate whether our in vitro models adequately simulate the measurements made in vivo, which are intended to help guide decisions on triage after a radiation event. Using a healthy volunteer with a dentition gap that allows using a partial denture, human teeth were serially irradiated in vitro and then, using a partial denture, placed in the volunteer's mouth for measurements. We compared dose estimates made using in vivo measurements made in the volunteer's mouth to measurements made on the same teeth in our complex mouth model that simulates electromagnetic and anatomic properties of the mouth. Our results demonstrate that this mouth model can be used in in vitro studies to develop the system because these measurements appropriately model in vivo conditions.

Temporal variation in the response of tumors to hyperoxia with breathing carbogen and oxygen.

The effect of hyperoxygenation with carbogen (95% O2 + 5% CO2) and 100% oxygen inhalation on partial pressure of oxygen (pO2) of radiation-induced fibrosarcoma (RIF-1) tumor was investigated. RIF-1 tumors were innoculated in C3H mice, and aggregates of oximetry probe, lithium phthalocyanine (LiPc), was implanted in each tumor. A baseline tumor pO2 was measured by electron paramagnetic resonance (EPR) oximetry for 20 minutes in anesthetized mice breathing 30% O2 and then the gas was switched to carbogen or 100 % oxygen for 60 minutes. These experiments were repeated for 10 days. RIF-1 tumors were hypoxic with a baseline tissue pO2 of 6.2-8.3 mmHg in mice breathing 30% O2. Carbogen and 100% oxygen significantly increased tumor pO2 on days 1 to 5, with a maximal increase at approximately 32-45 minutes on each day. However, the extent of increase in pO2 from the baseline declined significantly on day 5 and day 10. The results provide quantitative information on the effect of hyperoxic gas inhalation on tumor pO2 over the course of 10 days. EPR oximetry can be effectively used to repeatedly monitor tumor pO2 and test hyperoxic methods for potential clinical applications.

Evolution and Optimization of Tooth Models for Testing In Vivo EPR Tooth Dosimetry.

Testing and verification are an integral part of any cycle to design, manufacture and improve a novel device intended for use in humans. In the case of testing Dartmouth's electron paramagnetic resonance (EPR) in vivo tooth dosimetry device, in vitro studies are needed throughout its development to test its performance, i.e. to verify its current capability for assessing dose in individuals potentially exposed to ionizing radiation. Since the EPR device uses the enamel of human teeth to assess dose, models that include human teeth have been an integral mechanism to carry out in vitro studies during development and testing its ability to meet performance standards for its ultimate intended in vivo use. As the instrument improves over time, new demands for in vitro studies change as well. This paper describes the tooth models used to perform in vitro studies and their evolution to meet the changing demands for testing in vivo EPR tooth dosimetry.

Advances in in vivo EPR Tooth BIOdosimetry: Meeting the targets for initial triage following a large-scale radiation event.

Several important recent advances in the development and evolution of in vivo Tooth Biodosimetry using Electron Paramagnetic Resonance (EPR) allow its performance to meet or exceed the U.S. targeted requirements for accuracy and ease of operation and throughput in a large-scale radiation event. Ergonomically based changes to the magnet, coupled with the development of rotation of the magnet and advanced software to automate collection of data, have made it easier and faster to make a measurement. From start to finish, measurements require a total elapsed time of 5 min, with data acquisition taking place in less than 3 min. At the same time, the accuracy of the data for triage of large populations has improved, as indicated using the metrics of sensitivity, specificity and area under the ROC curve. Applying these standards to the intended population, EPR in vivo Tooth Biodosimetry has approximately the same diagnostic accuracy as the purported 'gold standard' (dicentric chromosome assay). Other improvements include miniaturisation of the spectrometer, leading to the creation of a significantly lighter and more compact prototype that is suitable for transporting for Point of Care (POC) operation and that can be operated off a single standard power outlet. Additional advancements in the resonator, including use of a disposable sensing loop attached to the incisor tooth, have resulted in a biodosimetry method where measurements can be made quickly with a simple 5-step workflow and by people needing only a few minutes of training (which can be built into the instrument as a training video). In sum, recent advancements allow this prototype to meet or exceed the US Federal Government's recommended targets for POC biodosimetry in large-scale events.

Evaluating the Special Needs of The Military for Radiation Biodosimetry for Tactical Warfare Against Deployed Troops: Comparing Military to Civilian Needs for Biodosimetry Methods.

The aim of this paper is to delineate characteristics of biodosimetry most suitable for assessing individuals who have potentially been exposed to significant radiation from a nuclear device explosion when the primary population targeted by the explosion and needing rapid assessment for triage is civilians vs. deployed military personnel. The authors first carry out a systematic analysis of the requirements for biodosimetry to meet the military's needs to assess deployed troops in a warfare situation, which include accomplishing the military mission. Then the military's special capabilities to respond and carry out biodosimetry for deployed troops in warfare are compared and contrasted systematically, in contrast to those available to respond and conduct biodosimetry for civilians who have been targeted by terrorists, for example. Then the effectiveness of different biodosimetry methods to address military vs. civilian needs and capabilities in these scenarios was compared and, using five representative types of biodosimetry with sufficient published data to be useful for the simulations, the number of individuals are estimated who could be assessed by military vs. civilian responders within the timeframe needed for triage decisions. Analyses based on these scenarios indicate that, in comparison to responses for a civilian population, a wartime military response for deployed troops has both more complex requirements for and greater capabilities to use different types of biodosimetry to evaluate radiation exposure in a very short timeframe after the exposure occurs. Greater complexity for the deployed military is based on factors such as a greater likelihood of partial or whole body exposure, conditions that include exposure to neutrons, and a greater likelihood of combined injury. These simulations showed, for both the military and civilian response, that a very fast rate of initiating the processing (24,000 d) is needed to have at least some methods capable of completing the assessment of 50,000 people within a 2- or 6-d timeframe following exposure. This in turn suggests a very high capacity (i.e., laboratories, devices, supplies and expertise) would be necessary to achieve these rates. These simulations also demonstrated the practical importance of the military's superior capacity to minimize time to transport samples to offsite facilities and use the results to carry out triage quickly. Assuming sufficient resources and the fastest daily rate to initiate processing victims, the military scenario revealed that two biodosimetry methods could achieve the necessary throughput to triage 50,000 victims in 2 d (i.e., the timeframe needed for injured victims), and all five achieved the targeted throughput within 6 d. In contrast, simulations based on the civilian scenario revealed that no method could process 50,000 people in 2 d and only two could succeed within 6 d.

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry.

Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognosis of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2 ) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were ∼56-69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation.

Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma.

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.

In vivo EPR tooth dosimetry for triage after a radiation event involving large populations.

The management of radiation injuries following a catastrophic event where large numbers of people may have been exposed to life-threatening doses of ionizing radiation will rely critically on the availability and use of suitable biodosimetry methods. In vivo electron paramagnetic resonance (EPR) tooth dosimetry has a number of valuable and unique characteristics and capabilities that may help enable effective triage. We have produced a prototype of a deployable EPR tooth dosimeter and tested it in several in vitro and in vivo studies to characterize the performance and utility at the state of the art. This report focuses on recent advances in the technology, which strengthen the evidence that in vivo EPR tooth dosimetry can provide practical, accurate, and rapid measurements in the context of its intended use to help triage victims in the event of an improvised nuclear device. These advances provide evidence that the signal is stable, accurate to within 0.5 Gy, and can be successfully carried out in vivo. The stability over time of the radiation-induced EPR signal from whole teeth was measured to confirm its long-term stability and better characterize signal behavior in the hours following irradiation. Dosimetry measurements were taken for five pairs of natural human upper central incisors mounted within a simple anatomic mouth model that demonstrates the ability to achieve 0.5 Gy standard error of inverse dose prediction. An assessment of the use of intact upper incisors for dose estimation and screening was performed with volunteer subjects who have not been exposed to significant levels of ionizing radiation and patients who have undergone total body irradiation as part of bone marrow transplant procedures. Based on these and previous evaluations of the performance and use of the in vivo tooth dosimetry system, it is concluded that this system could be a very valuable resource to aid in the management of a massive radiological event.

Advances in a framework to compare bio-dosimetry methods for triage in large-scale radiation events.

Planning and preparation for a large-scale nuclear event would be advanced by assessing the applicability of potentially available bio-dosimetry methods. Using an updated comparative framework the performance of six bio-dosimetry methods was compared for five different population sizes (100-1,000,000) and two rates for initiating processing of the marker (15 or 15,000 people per hour) with four additional time windows. These updated factors are extrinsic to the bio-dosimetry methods themselves but have direct effects on each method's ability to begin processing individuals and the size of the population that can be accommodated. The results indicate that increased population size, along with severely compromised infrastructure, increases the time needed to triage, which decreases the usefulness of many time intensive dosimetry methods. This framework and model for evaluating bio-dosimetry provides important information for policy-makers and response planners to facilitate evaluation of each method and should advance coordination of these methods into effective triage plans.

Genome-wide association study of lung function phenotypes in a founder population.

BACKGROUND: Lung function is a long-term predictor of mortality and morbidity. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. METHODS: We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. RESULTS: Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10(-8) to 3.4 × 10(-9)). Nine SNPs at or near 4 additional loci had P < 10(-5) with FEV1/FVC. Only 2 SNPs were found with P < 10(-5) for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of ß-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B. CONCLUSION: This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.

Rhinovirus wheezing illness and genetic risk of childhood-onset asthma.

BACKGROUND: Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. METHODS: We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). RESULTS: The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific. CONCLUSIONS: Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).