Body shape perception in men and women without obesity during caloric restriction: a secondary analysis from the CALERIE study.

OBJECTIVE: To examine body shape perception in 218 adults without obesity or history of eating disorders during caloric restriction (CR). METHODS: Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) is a 2-year, randomized clinical trial using a 2:1 assignment (CR, 25% reduction in calories; Control, typical diet). For this secondary analysis, we examined perceived body shape using the Body Shape Questionnaire (BSQ). Analyses of BSQ scores are reported by group, over time, by sex, and by BMI. Data for body fat percentage, symptoms of depression, food cravings, maximal oxygen consumption, and stress were analyzed for their association with BSQ scores. RESULTS: Compared to control, CR reduced BSQ scores. Women tended to have greater concern with body shape than men across all measurement times. There was no difference in change in BSQ scores at 12 or 24 months between those with a BMI < 25 kg/m2 or ≥ 25 kg/m2. Change in body fat percentage was most correlated with change in BSQ score from 0 to 12 (r = 0.39) and 0-24 months (r = 0.38). For change in BSQ score, Akaike/ Bayesian information criterion (AIC/BIC) found that the model of best fit included the following three change predictors: change in body fat percentage, depression symptoms, and food cravings. For 0-12 months, AIC/BIC = 1482.0/1505.6 and for 0-24 months AIC/BIC = 1364.8/1386.5. CONCLUSIONS: CR is associated with reduced concern for body shape in men and women without obesity and with no history of eating disorders. Body shape perception among this sample was complex and influenced by multiple factors. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Liquid crystals of neat boron nitride nanotubes and their assembly into ordered macroscopic materials.

Boron nitride nanotubes (BNNTs) have attracted attention for their predicted extraordinary properties; yet, challenges in synthesis and processing have stifled progress on macroscopic materials. Recent advances have led to the production of highly pure BNNTs. Here we report that neat BNNTs dissolve in chlorosulfonic acid (CSA) and form birefringent liquid crystal domains at concentrations above 170 ppmw. These tactoidal domains merge into millimeter-sized regions upon light sonication in capillaries. Cryogenic electron microscopy directly shows nematic alignment of BNNTs in solution. BNNT liquid crystals can be processed into aligned films and extruded into neat BNNT fibers. This study of nematic liquid crystals of BNNTs demonstrates their ability to form macroscopic materials to be used in high-performance applications.

The Human Pangenome Project: a global resource to map genomic diversity.

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene-disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.

Prevalence of Shiga Toxin-Producing Escherichia coli and Salmonella in Native Pecan Orchards as Influenced by Waiting Periods between Grazing and Harvest.

ABSTRACT: Animals (grazing, working, or intrusion) in produce production areas may present a potential contamination source of foodborne pathogens on produce. Cattle grazing on native pecan production orchards, a common practice in the southern United States, provides an opportunity to study the impact of grazing practice and waiting periods on contamination rates of foodborne pathogens of tree nuts. Therefore, the objective of this study was to determine the prevalence of Salmonella and Shiga toxin-producing Escherichia coli (STEC) in native pecan production orchards as influenced by waiting periods between grazing cattle and pecan harvest. Soil (10 g), cattle feces (10 g), and in-shell pecans (25 g) were sampled from five cattle-grazed orchards in areas with cattle removed 2 or 4 months before harvest and not removed. Five nongrazing orchards were sampled at harvest for comparison. Detection and isolation of the pathogens were performed by enrichment, selective isolation, and multiplex PCR. Statistical analyses were performed using contingency tables with Pearson's chi-square test. The prevalence of STEC (36%) and Salmonella (29%) in cattle-grazed orchards was significantly higher than in nongrazed orchards (13 and 7%, respectively). STEC prevalence in cattle-grazed orchards was higher (38%) in areas with cattle at harvest than in fenced areas where cattle were removed 2 (29%) and 4 (27%) months before harvest. Salmonella prevalence was similar in areas without fencing (31%) and areas with cattle removed at 2 (22%) and 4 (30%) months before harvest. However, there were no significant differences (P > 0.05) in contamination rates between waiting periods for either pathogen, suggesting a limited impact of waiting periods on reducing the risk of contamination.

Skeletal Muscle Mitochondrial Function after a 100-km Ultramarathon: A Case Study in Monozygotic Twins.

PURPOSE: Very little research has investigated the effects of ultraendurance exercise on the bioenergetic status of muscle. The primary objective of this case study was to characterize the changes that occur in skeletal muscle mitochondria in response to a 100-km ultramarathon in monozygotic twins. A second objective was to determine whether mitochondrial function is altered by consuming a periodized low-carbohydrate, high-fat diet during training compared with a high-carbohydrate diet. METHODS: One pair of male monozygotic twins ran 100 km on treadmills after 4 wk of training on either a high-carbohydrate or periodized low-carbohydrate, high-fat diet. Muscle biopsies were collected 4 wk before the run, as well as 4 and 52 h postrun. Blood draws were also performed immediately before as well as 4 and 52 h after the run. RESULTS: Four hours postrun, respiratory capacity, citrate synthase activity, and mitochondrial complex protein content were decreased. Two days later, both twins showed signs of rapid recovery in several of these measures. Furthermore, blood levels of creatine phosphokinase, C-reactive protein, and aspartate transaminase were elevated 4 h after the run but partially recovered 2 d later. CONCLUSION: Although there were some differences between the twins, the primary finding is that there is significant mitochondrial impairment induced by running 100 km, which rapidly recovers within 2 d. These results provide ample rationale for future investigations of the effects of ultraendurance activity on mitochondrial function.

Application of Human Factors Methods to Understand Missed Follow-up of Abnormal Test Results.

OBJECTIVE: This study demonstrates application of human factors methods for understanding causes for lack of timely follow-up of abnormal test results ("missed results") in outpatient settings. METHODS: We identified 30 cases of missed test results by querying electronic health record data, developed a critical decision method (CDM)-based interview guide to understand decision-making processes, and interviewed physicians who ordered these tests. We analyzed transcribed responses using a contextual inquiry (CI)-based methodology to identify contextual factors contributing to missed results. We then developed a CI-based flow model and conducted a fault tree analysis (FTA) to identify hierarchical relationships between factors that delayed action. RESULTS: The flow model highlighted barriers in information flow and decision making, and the hierarchical model identified relationships between contributing factors for delayed action. Key findings including underdeveloped methods to track follow-up, as well as mismatches, in communication channels, timeframes, and expectations between patients and physicians. CONCLUSION: This case report illustrates how human factors-based approaches can enable analysis of contributing factors that lead to missed results, thus informing development of preventive strategies to address them.

Test results management and distributed cognition in electronic health record-enabled primary care.

Managing abnormal test results in primary care involves coordination across various settings. This study identifies how primary care teams manage test results in a large, computerized healthcare system in order to inform health information technology requirements for test results management and other distributed healthcare services. At five US Veterans Health Administration facilities, we interviewed 37 primary care team members, including 16 primary care providers, 12 registered nurses, and 9 licensed practical nurses. We performed content analysis using a distributed cognition approach, identifying patterns of information transmission across people and artifacts (e.g. electronic health records). Results illustrate challenges (e.g. information overload) as well as strategies used to overcome challenges. Various communication paths were used. Some team members served as intermediaries, processing information before relaying it. Artifacts were used as memory aids. Health information technology should address the risks of distributed work by supporting awareness of team and task status for reliable management of results.

Incorporating Guideline Adherence and Practice Implementation Issues into the Design of Decision Support for Beta-Blocker Titration for Heart Failure.

BACKGROUND: The recognition of and response to undertreatment of heart failure (HF) patients can be complicated. A clinical reminder can facilitate use of guideline-concordant ß-blocker titration for HF patients with depressed ejection fraction. However, the design must consider the cognitive demands on the providers and the context of the work. OBJECTIVE: This study's purpose is to develop requirements for a clinical decision support tool (a clinical reminder) by analyzing the cognitive demands of the task along with the factors in the Cabana framework of physician adherence to guidelines, the health information technology (HIT) sociotechnical framework, and the Promoting Action on Research Implementation in Health Services (PARIHS) framework of health services implementation. It utilizes a tool that extracts information from medical records (including ejection fraction in free text reports) to identify qualifying patients at risk of undertreatment. METHODS: We conducted interviews with 17 primary care providers, 5 PharmDs, and 5 Registered Nurses across three Veterans Health Administration outpatient clinics. The interviews were based on cognitive task analysis (CTA) methods and enhanced through the inclusion of the Cabana, HIT sociotechnical, and PARIHS frameworks. The analysis of the interview data led to the development of requirements and a prototype design for a clinical reminder. We conducted a small pilot usability assessment of the clinical reminder using realistic clinical scenarios. RESULTS: We identified organizational challenges (such as time pressures and underuse of pharmacists), knowledge issues regarding the guideline, and information needs regarding patient history and treatment status. We based the design of the clinical reminder on how to best address these challenges. The usability assessment indicated the tool could help the decision and titration processes. CONCLUSION: Through the use of CTA methods enhanced with adherence, sociotechnical, and implementation frameworks, we designed a decision support tool that considers important challenges in the decision and execution of ß-blocker titration for qualifying HF patients at risk of undertreatment.

Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk.

We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989-2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07-2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00-2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18-1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27-1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia.

A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development.

During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/ß-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders.

Severity of Scab and its Effects on Fruit Weight in Mechanically Hedge-Pruned and Topped Pecan Trees.

Scab is the most damaging disease of pecan in the southeastern United States. Pecan trees can attain 44 m in height, so managing disease in the upper canopy is a problem. Fungicide is ordinarily applied using ground-based air-blast sprayers. Although mechanical hedge-pruning and topping of pecan is done for several reasons, improved management of scab is an important reason in the humid, wet Southeast. Resulting shoot growth on cut limbs of susceptible cultivars could lead to more severe scab. In three experiments over three years, we explored the effect of hedge-pruning trees to ∼12 to 14 m compared with non-hedge-pruned trees. All trees received fungicide treatments (air-blast sprays and ≤3 aerial applications). Hedge-pruning either had no effect, or increased or decreased scab severity only slightly on leaflets, immature, or mature fruit (a -9.95 to +14.63% difference in scab severity compared with the control). However, height in the canopy invariably had a large and significant effect on scab severity, and amounted to a 0.05 to 73.77% difference in severity between the lowest and highest sample in the canopy. Fruit weight depended on sample height, with fruit most often weighing less when collected at greater sample heights. A robust relationship between fruit weight and scab severity was found at the highest sample heights where scab was also most often severe (R2 = 0.21 to 0.67, P < 0.0001). Hedge-pruning and topping pecan tree canopies to manage tree size will enable better fungicide coverage, reducing risk of a scab epidemic as more of the canopy is assured efficacious fungicide spray coverage.

Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).

BACKGROUND: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. RESULTS: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. CONCLUSIONS: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Loss of δ-catenin function in severe autism.

Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.

Graphical display of diagnostic test results in electronic health records: a comparison of 8 systems.

Accurate display and interpretation of clinical laboratory test results is essential for safe and effective diagnosis and treatment. In an attempt to ascertain how well current electronic health records (EHRs) facilitated these processes, we evaluated the graphical displays of laboratory test results in eight EHRs using objective criteria for optimal graphs based on literature and expert opinion. None of the EHRs met all 11 criteria; the magnitude of deficiency ranged from one EHR meeting 10 of 11 criteria to three EHRs meeting only 5 of 11 criteria. One criterion (i.e., the EHR has a graph with y-axis labels that display both the name of the measured variable and the units of measure) was absent from all EHRs. One EHR system graphed results in reverse chronological order. One EHR system plotted data collected at unequally-spaced points in time using equally-spaced data points, which had the effect of erroneously depicting the visual slope perception between data points. This deficiency could have a significant, negative impact on patient safety. Only two EHR systems allowed users to see, hover-over, or click on a data point to see the precise values of the x-y coordinates. Our study suggests that many current EHR-generated graphs do not meet evidence-based criteria aimed at improving laboratory data comprehension.

How context affects electronic health record-based test result follow-up: a mixed-methods evaluation.

OBJECTIVES: Electronic health record (EHR)-based alerts can facilitate transmission of test results to healthcare providers, helping ensure timely and appropriate follow-up. However, failure to follow-up on abnormal test results (missed test results) persists in EHR-enabled healthcare settings. We aimed to identify contextual factors associated with facility-level variation in missed test results within the Veterans Affairs (VA) health system. DESIGN, SETTING AND PARTICIPANTS: Based on a previous survey, we categorised VA facilities according to primary care providers' (PCPs') perceptions of low (n=20) versus high (n=20) risk of missed test results. We interviewed facility representatives to collect data on several contextual factors derived from a sociotechnical conceptual model of safe and effective EHR use. We compared these factors between facilities categorised as low and high perceived risk, adjusting for structural characteristics. RESULTS: Facilities with low perceived risk were significantly more likely to use specific strategies to prevent alerts from being lost to follow-up (p=0.0114). Qualitative analysis identified three high-risk scenarios for missed test results: alerts on tests ordered by trainees, alerts 'handed off' to another covering clinician (surrogate clinician), and alerts on patients not assigned in the EHR to a PCP. Test result management policies and procedures to address these high-risk situations varied considerably across facilities. CONCLUSIONS: Our study identified several scenarios that pose a higher risk for missed test results in EHR-based healthcare systems. In addition to implementing provider-level strategies to prevent missed test results, healthcare organisations should consider implementing monitoring systems to track missed test results.

An analysis of electronic health record-related patient safety concerns.

OBJECTIVE: A recent Institute of Medicine report called for attention to safety issues related to electronic health records (EHRs). We analyzed EHR-related safety concerns reported within a large, integrated healthcare system. METHODS: The Informatics Patient Safety Office of the Veterans Health Administration (VA) maintains a non-punitive, voluntary reporting system to collect and investigate EHR-related safety concerns (ie, adverse events, potential events, and near misses). We analyzed completed investigations using an eight-dimension sociotechnical conceptual model that accounted for both technical and non-technical dimensions of safety. Using the framework analysis approach to qualitative data, we identified emergent and recurring safety concerns common to multiple reports. RESULTS: We extracted 100 consecutive, unique, closed investigations between August 2009 and May 2013 from 344 reported incidents. Seventy-four involved unsafe technology and 25 involved unsafe use of technology. A majority (70%) involved two or more model dimensions. Most often, non-technical dimensions such as workflow, policies, and personnel interacted in a complex fashion with technical dimensions such as software/hardware, content, and user interface to produce safety concerns. Most (94%) safety concerns related to either unmet data-display needs in the EHR (ie, displayed information available to the end user failed to reduce uncertainty or led to increased potential for patient harm), software upgrades or modifications, data transmission between components of the EHR, or 'hidden dependencies' within the EHR. DISCUSSION: EHR-related safety concerns involving both unsafe technology and unsafe use of technology persist long after 'go-live' and despite the sophisticated EHR infrastructure represented in our data source. Currently, few healthcare institutions have reporting and analysis capabilities similar to the VA. CONCLUSIONS: Because EHR-related safety concerns have complex sociotechnical origins, institutions with long-standing as well as recent EHR implementations should build a robust infrastructure to monitor and learn from them.

"Generalized osteoarthritis": a systematic review.

OBJECTIVES: Given the conflicting definitions of "generalized osteoarthritis" (GOA) in the literature, we performed a systematic review of GOA definitions, risk factors, and outcomes. METHODS: We searched the MEDLINE literature with the terms osteoarthritis, generalized, polyarticular, multiple joint, and multi-joint to obtain articles related to GOA, following evidence-based guidelines. Titles and abstracts of 948 articles were reviewed, with full-text review of 108. Data were extracted based on pre-specified criteria for 74 articles plus 24 identified through bibliographic review (n = 98). RESULTS: Twenty-four large cohorts (n ~ 30,000) were represented along with numerous clinical series (n ~ 9000), across 22 countries and 60 years (1952-2012). No less than 15 definitions of GOA were given in 30 studies with a stated GOA definition; at least 6 groups used a summed score of joints or radiographic grades. Prevalence estimates based on these GOA definitions were 1-80%, although most were 5-25%. Increased risk and progression of GOA was associated with age, female sex, and genetic/familial factors. Associations with increased body mass index or bone mineral density were not consistent. A study estimated the heritability of GOA at 42%. Collagen biomarker levels increased with the number of involved joints. Increased OA burden was associated with increased mortality and disability, poorer health, and function. CONCLUSION: While there remains no standard definition of GOA, this term is commonly used. The impact on health may be greater when OA is in more than one joint. A descriptive term, such as multi-joint or polyarticular OA, designating OA of multiple joints or joint groups is recommended.

Resilient Practices in Maintaining Safety of Health Information Technologies.

Electronic health record systems (EHRs) can improve safety and reliability of health care, but they can also introduce new vulnerabilities by failing to accommodate changes within a dynamic EHR-enabled health care system. Continuous assessment and improvement is thus essential for achieving resilience in EHR-enabled health care systems. Given the rapid adoption of EHRs by many organizations that are still early in their experiences with EHR safety, it is important to understand practices for maintaining resilience used by organizations with a track record of success in EHR use. We conducted interviews about safety practices with 56 key informants (including information technology managers, chief medical information officers, physicians, and patient safety officers) at two large health care systems recognized as leaders in EHR use. We identified 156 references to resilience-related practices from 41 informants. Framework analysis generated five categories of resilient practices: (a) sensitivity to dynamics and interdependencies affecting risks, (b) basic monitoring and responding practices, (c) management of practices and resources for monitoring and responding, (d) sensitivity to risks beyond the horizon, and (e) reflecting on risks with the safety and quality control process itself. The categories reflect three functions that facilitate resilience: reflection, transcending boundaries, and involving sharp-end practitioners in safety management.

A genome-wide search for linkage of estimated glomerular filtration rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND).

OBJECTIVE: Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR. METHODS: Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula. RESULTS: The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4 × 10(-5)) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5 × 10(-4)) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5 × 10(-4)) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. CONCLUSION: The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.