A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.

Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China.

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted. METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis. RESULTS: Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10-8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34). CONCLUSIONS: While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

A prospective study of smoking-related white blood cell DNA methylation markers and risk of bladder cancer.

Bladder cancer, a common neoplasm, is primarily caused by tobacco smoking. Epigenetic alterations including DNA methylation have the potential to be used as prospective markers of increased risk, particularly in at-risk populations such as smokers. We aimed to investigate the potential of smoking-related white blood cell (WBC) methylation markers to contribute to an increase in bladder cancer risk prediction over classical questionnaire-based smoking metrics (i.e., duration, intensity, packyears) in a nested case-control study within the prospective prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial and the alpha-tocopherol, beta-carotene cancer (ATBC) Prevention Study (789 cases; 849 controls). We identified 200 differentially methylated sites associated with smoking status and 28 significantly associated (after correction for multiple testing) with bladder cancer risk among 2670 previously reported smoking-related cytosine-phosphate-guanines sites (CpGs). Similar patterns were observed across cohorts. Receiver operating characteristic (ROC) analyses indicated that cg05575921 (AHHR), the strongest smoking-related association we identified for bladder cancer risk, alone yielded similar predictive performance (AUC: 0.60) than classical smoking metrics (AUC: 0.59-0.62). Best prediction was achieved by including the first principal component (PC1) from the 200 smoking-related CpGs alongside smoking metrics (AUC: 0.63-0.65). Further, PC1 remained significantly associated with elevated bladder cancer risk after adjusting for smoking metrics. These findings suggest DNA methylation profiles reflect aspects of tobacco smoke exposure in addition to those captured by smoking duration, intensity and packyears, and/or individual susceptibility relevant to bladder cancer etiology, warranting further investigation.

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.

A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

A Multicenter Retrospective Cohort Study to Characterize Patients Hospitalized With Multisystem Inflammatory Syndrome in Adults and Coronavirus Disease 2019 in the United States, 2020-2021.

BACKGROUND: The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute coronavirus disease 2019 (COVID-19) and may affect clinical management. METHODS: In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at 6 academic medical centers from 1 March 2020 to 31 December 2021. Patients MIS-A were matched by age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographic characteristics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts. RESULTS: Through medical record review of 10 223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched patients with COVID-19, those with MIS-A were more likely to be non-Hispanic black and less likely to be non-Hispanic white. They more likely had laboratory-confirmed COVID-19 ≥14 days before hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, patients with MIS-A had higher neutrophil-to-lymphocyte ratio and higher levels of C-reactive protein, ferritin, procalcitonin, and D-dimer than patients with COVID-19. They also had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. The mortality rate was 6% in both cohorts. CONCLUSIONS: Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management.

Age-specific survival rates, causes of death, and allowable take of golden eagles in the western United States.

In the United States, the Bald and Golden Eagle Protection Act prohibits take of golden eagles (Aquila chrysaetos) unless authorized by permit, and stipulates that all permitted take must be sustainable. Golden eagles are unintentionally killed in conjunction with many lawful activities (e.g., electrocution on power poles, collision with wind turbines). Managers who issue permits for incidental take of golden eagles must determine allowable take levels and manage permitted take accordingly. To aid managers in making these decisions in the western United States, we used an integrated population model to obtain estimates of golden eagle vital rates and population size, and then used those estimates in a prescribed take level (PTL) model to estimate the allowable take level. Estimated mean annual survival rates for golden eagles ranged from 0.70 (95% credible interval = 0.66-0.74) for first-year birds to 0.90 (0.88-0.91) for adults. Models suggested a high proportion of adult female golden eagles attempted to breed and breeding pairs fledged a mean of 0.53 (0.39-0.72) young annually. Population size in the coterminous western United States has averaged ~31,800 individuals for several decades, with λ = 1.0 (0.96-1.05). The PTL model estimated a median allowable take limit of ~2227 (708-4182) individuals annually given a management objective of maintaining a stable population. We estimate that take averaged 2572 out of 4373 (59%) deaths annually, based on a representative sample of transmitter-tagged golden eagles. For the subset of golden eagles that were recovered and a cause of death determined, anthropogenic mortality accounted for an average of 74% of deaths after their first year; leading forms of take over all age classes were shooting (~670 per year), collisions (~611), electrocutions (~506), and poisoning (~427). Although observed take overlapped the credible interval of our allowable take estimate and the population overall has been stable, our findings indicate that additional take, unless mitigated for, may not be sustainable. Our analysis demonstrates the utility of the joint application of integrated population and prescribed take level models to management of incidental take of a protected species.

Reducing Emergency Department Visits Among Patients With Diabetes by Embedding Clinical Pharmacists in the Primary Care Teams.

BACKGROUND: Pharmacists are effective at improving control of cardiovascular risk factors, but it less clear whether these improvements translate into less emergency department (ED) use and fewer hospitalizations. The UCMyRx program embed pharmacists in primary care. OBJECTIVE: The objective of this study was to examine if the integration of pharmacists into primary care was associated with lower ED and hospital use for patients with diabetes. DESIGN: This was a quasi-experimental study with a comparator group. SUBJECTS: The analytic sample included patients with diabetes with uncontrolled cardiovascular risk factors (A1C >9%, blood pressure >140/90 mm Hg, low-density lipoprotein-cholesterol >130 mg/dL) who had 1 or more visits in either a UCMyRx (648 patients, 14 practices) or usual care practice (1944 patients, 14 practices). MEASURES: Our outcomes were ED and hospitalization rates as measured before and after the consultations between UCMyRx and usual care. Our predictor variable was the pharmacist consultation. Poisson generalized estimating equations model was used to estimate the adjusted predicted change in utilization before and after the pharmacist consultation. The Average Treatment Effect on the Treated was estimated. RESULTS: In models adjusted, the adjusted mean predicted number of emergency department visits/month during the year before the consultation was 0.09 among UCMyRx patients. During the year after initiating the care with the pharmacists, this rate decreased to an adjusted mean monthly rate of 0.07, with an Average Treatment Effect on the Treated=0.021 (P=0.035), a predicted reduction of 21% in emergency department visits associated with the clinical pharmacist consults. There was a nonsignificant predicted 3.2% reduction in hospitalizations over time for patients in the UCMyRx program. CONCLUSION: Clinical pharmacists are an important addition to clinical care teams in primary care practices and significantly decreased utilization of the ED among patients with poorly controlled diabetes.

Does taxonomic and numerical resolution affect the assessment of invertebrate community structure in New World freshwater wetlands?

The efficiency of biodiversity assessments and biomonitoring studies is commonly challenged by limitations in taxonomic identification and quantification approaches. In this study, we assessed the effects of different taxonomic and numerical resolutions on a range of community structure metrics in invertebrate compositional data sets from six regions distributed across North and South America. We specifically assessed the degree of similarity in the metrics (richness, equitability, beta diversity, heterogeneity in community composition and congruence) for data sets identified to a coarse resolution (usually family level) and the finest taxonomic resolution practical (usually genus level, sometimes species or morphospecies) and by presence-absence and relative abundance numerical resolutions. Spearman correlations showed highly significant and positive associations between univariate metrics (richness and equitability) calculated for coarse- and finest-resolution datasets. Procrustes analysis detected significant congruence between composition datasets. Higher correlation coefficients were found for datasets with the same numerical resolutions regardless of the taxonomic level (about 90%), while the correlations for comparisons across numerical resolutions were consistently lower. Our findings indicate that family-level resolution can be used as a surrogate of finer taxonomic resolutions to calculate a range of biodiversity metrics commonly used to describe invertebrate community structure patterns in New World freshwater wetlands without significant loss of information. However, conclusions on biodiversity patterns derived from datasets with different numerical resolutions should be critically considered in studies on wetland invertebrates.

Malignant Hyperthermia-Associated Rhabdomyolysis After Succinylcholine: A Case Report.

Malignant hyperthermia-associated rhabdomyolysis is a condition that lies on the spectrum of malignant hyperthermia (MH). Unlike MH, malignant-hyperthermia-associated rhabdomyolysis is a condition which most commonly is recognized in the postoperative period by the development of discolored brown urine with notably absent rigidity, tachypnea, tachycardia, and hyperthermia. The presented case describes the subtle onset of malignant hyperthermia-associated rhabdomyolysis, along with a review of relevant literature.

An Effectiveness Evaluation of a Primary Care-Embedded Clinical Pharmacist-Led Intervention Among Blacks with Diabetes.

BACKGROUND: Black individuals with type 2 diabetes suffer disproportionate morbidity and mortality relative to whites with type 2 diabetes, irrespective of health insurance coverage. OBJECTIVE: Examine the impact of a primary care-embedded clinical pharmacist-led intervention (UCMyRx) on cardiovascular risk factor control among blacks with type 2 diabetes in a large healthcare system. DESIGN: We used data extracted from the electronic health records (EHR) system and a difference-in-differences study design with a propensity-matched comparison group to evaluate the impact of UCMyRx on HbA1c and systolic blood pressure (SBP) among black patients with type 2 diabetes, relative to usual care. PARTICIPANTS: Individuals with type 2 diabetes identified as either black or African American in the EHR that were ≥ 18 years of age that had the following observations during the study window (03/02/2013-12/31/18: (1) HbA1C ≥ 8%, at least once, anywhere between 365 days before and 14 days after the UCMyRx visit and a follow-up HbA1c measure within 120 to 365 days after the visit and/or (2) SBP ≥ 140 mmHg at least once between 365 days before and 14 days after the UCMyRx visit that had a follow-up SBP measure within 120 to 450 days after the visit. INTERVENTION: UCMyRx pharmacists review labs and vital signs, perform medication reconciliation, use a standardized survey to assess barriers to medication adherence, and develop tailored interventions to improve medication adherence. MAIN MEASURES: Change in HbA1c and change in SBP from before to after the first UCMyRx visit. KEY RESULTS: Having at least one visit with a UCMyRx clinical pharmacist was associated with a significant reduction in HbA1c (- 0.4%, p value = .01); however, there was no significant impact on SBP (- .051 mmHg, p value = 0.74). CONCLUSIONS: The UCMyRx intervention is a useful strategy for improving HbA1c control among blacks with type 2 diabetes.

Adherence to the SEP-1 Sepsis Bundle in Hospital-Onset v. Community-Onset Sepsis: a Multicenter Retrospective Cohort Study.

BACKGROUND: Sepsis is the leading cause of in-hospital death. The SEP-1 sepsis bundle is a protocol for early sepsis care that requires providers to diagnose and treat sepsis quickly. Limited evidence suggests that adherence to the sepsis bundle is lower in cases of hospital-onset sepsis. OBJECTIVE: To compare sepsis bundle adherence in hospital-onset vs. community-onset sepsis. DESIGN: Retrospective cohort study using multivariable analysis of clinical data. PARTICIPANTS: A total of 4658 inpatients age 18 or older were identified by diagnosis codes consistent with sepsis or disseminated infection. SETTING: Four university hospitals in California between 2014 and 2016. MAIN OUTCOMES AND MEASURES: The primary outcome was adherence to key components of the sepsis bundle defined by the Centers for Medicare and Medicaid Services in their core measure, SEP-1. Covariates included clinical characteristics related to the patient, infection, and pathogen. KEY RESULTS: Compared with community-onset, cases of hospital-onset sepsis were less likely to receive SEP-1 adherent care (relative risk 0.33, 95% confidence interval 0.29-0.38, p < 0.001). With the exception of vasopressors (RR 1.11, p = 0.002), each component of SEP-1 evaluated-blood cultures (RR 0.76, p < 0.001), serum lactate (RR 0.51, p < 0001), broad-spectrum antibiotics (RR 0.62, p < 0.001), intravenous fluids (0.47, p < 0.001), and follow-up lactate (RR 0.71, p < 0.001)-was less likely to be performed within the recommended time frame in hospital-onset sepsis. Within the hospital, cases of hospital-onset sepsis arising on the ward were less likely to receive SEP-1-adherent care than were cases arising in the intensive care unit (RR 0.68, p = 0.004). CONCLUSIONS: Inpatients with hospital-onset sepsis receive different management than individuals with community-onset sepsis. It remains to be determined whether system-level factors, provider-level factors, or factors related to measurement explain the observed variation in care or whether variation in care affects outcomes.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Crohn's disease IRGM risk alleles are associated with altered gene expression in human tissues.

Crohn's disease (CD) is a chronic inflammatory gastrointestinal disorder. Genetic association studies have implicated dysregulated autophagy in CD. Among risk loci identified are a promoter single nucleotide polymorphism (SNP)( rs13361189 ) and two intragenic SNPs ( rs9637876 , rs10065172 ) in immunity-related GTPase family M ( IRGM) a gene that encodes a protein of the autophagy initiation complex. All three SNPs have been proposed to modify IRGM expression, but reports have been divergent and largely derived from cell lines. Here, analyzing RNA-Sequencing data of human tissues from the Genotype-Tissue Expression Project, we found that rs13361189 minor allele carriers had reduced IRGM expression in whole blood and terminal ileum, and upregulation in ileum of ZNF300P1, a locus adjacent to IRGM on chromosome 5q33.1 that encodes a long noncoding RNA. Whole blood and ileum from minor allele carriers had altered expression of multiple additional genes that have previously been linked to colitis and/or autophagy. Notable among these was an increase in ileum of LTF (lactoferrin), an established fecal inflammatory biomarker of CD, and in whole blood of TNF, a key cytokine in CD pathogenesis. Last, we confirmed that risk alleles at all three loci associated with increased risk for CD but not ulcerative colitis in a case-control study. Taken together, our findings suggest that genetically encoded IRGM deficiency may predispose to CD through dysregulation of inflammatory gene networks. Gene expression profiling of disease target tissues in genetically susceptible populations is a promising strategy for revealing new leads for the study of molecular pathogenesis and, potentially, for precision medicine. NEW & NOTEWORTHY Single nucleotide polymorphisms in immunity-related GTPase family M ( IRGM), a gene that encodes an autophagy initiation protein, have been linked epidemiologically to increased risk for Crohn's disease (CD). Here, we show for the first time that subjects with risk alleles at two such loci, rs13361189 and rs10065172 , have reduced IRGM expression in whole blood and terminal ileum, as well as dysregulated expression of a wide array of additional genes that regulate inflammation and autophagy.

Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice.

Nrf2 is essential to antioxidant response element (ARE)-mediated host defense. Sulforaphane (SFN) is a phytochemical antioxidant known to affect multiple cellular targets including Nrf2-ARE pathway in chemoprevention. However, the role of SFN in non-malignant airway disorders remain unclear. To test if pre-activation of Nrf2-ARE signaling protects lungs from oxidant-induced acute injury, wild-type (Nrf2+/+) and Nrf2-deficient (Nrf2-/-) mice were given SFN orally or as standardized broccoli sprout extract diet (SBE) before hyperoxia or air exposure. Hyperoxia-induced pulmonary injury and oxidation indices were significantly reduced by SFN or SBE in Nrf2+/+ mice but not in Nrf2-/- mice. SFN upregulated a large cluster of basal lung genes that are involved in mitochondrial oxidative phosphorylation, energy metabolism, and cardiovascular protection only in Nrf2+/+ mice. Bioinformatic analysis elucidated ARE-like motifs on these genes. Transcript abundance of the mitochondrial machinery genes remained significantly higher after hyperoxia exposure in SFN-treated Nrf2+/+ mice than in SFN-treated Nrf2-/- mice. Nuclear factor-κB was suggested to be a central molecule in transcriptome networks affected by SFN. Minor improvement of hyperoxia-caused lung histopathology and neutrophilia by SFN in Nrf2-/- mice implies Nrf2-independent or alternate effector mechanisms. In conclusion, SFN is suggested to be as a preventive intervention in a preclinical model of acute lung injury by linking mitochondria and Nrf2. Administration of SFN alleviated acute lung injury-like pathogenesis in a Nrf2-dependent manner. Potential AREs in the SFN-inducible transcriptome for mitochondria bioenergetics provided a new insight into the downstream mechanisms of Nrf2-mediated pulmonary protection.

Elevated Heterozygosity in Adults Relative to Juveniles Provides Evidence of Viability Selection on Eagles and Falcons.

Viability selection yields adult populations that are more genetically variable than those of juveniles, producing a positive correlation between heterozygosity and survival. Viability selection could be the result of decreased heterozygosity across many loci in inbred individuals and a subsequent decrease in survivorship resulting from the expression of the deleterious alleles. Alternatively, locus-specific differences in genetic variability between adults and juveniles may be driven by forms of balancing selection, including heterozygote advantage, frequency-dependent selection, or selection across temporal and spatial scales. We use a pooled-sequencing approach to compare genome-wide and locus-specific genetic variability between 74 golden eagle (Aquila chrysaetos), 62 imperial eagle (Aquila heliaca), and 69 prairie falcon (Falco mexicanus) juveniles and adults. Although genome-wide genetic variability is comparable between juvenile and adult golden eagles and prairie falcons, imperial eagle adults are significantly more heterozygous than juveniles. This evidence of viability selection may stem from a relatively smaller imperial eagle effective population size and potentially greater genetic load. We additionally identify ~2000 single-nucleotide polymorphisms across the 3 species with extreme differences in heterozygosity between juveniles and adults. Many of these markers are associated with genes implicated in immune function or olfaction. These loci represent potential targets for studies of how heterozygote advantage, frequency-dependent selection, and selection over spatial and temporal scales influence survivorship in avian species. Overall, our genome-wide data extend previous studies that used allozyme or microsatellite markers and indicate that viability selection may be a more common evolutionary phenomenon than often appreciated.

Rationale and design of a multicenter Chronic Kidney Disease (CKD) and at-risk for CKD electronic health records-based registry: CURE-CKD.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem, exhibiting sharp increases in incidence, prevalence, and attributable morbidity and mortality. There is a critical need to better understand the demographics, clinical characteristics, and key risk factors for CKD; and to develop platforms for testing novel interventions to improve modifiable risk factors, particularly for the CKD patients with a rapid decline in kidney function. METHODS: We describe a novel collaboration between two large healthcare systems (Providence St. Joseph Health and University of California, Los Angeles Health) supported by leadership from both institutions, which was created to develop harmonized cohorts of patients with CKD or those at increased risk for CKD (hypertension/HTN, diabetes/DM, pre-diabetes) from electronic health record data. RESULTS: The combined repository of candidate records included more than 3.3 million patients with at least a single qualifying measure for CKD and/or at-risk for CKD. The CURE-CKD registry includes over 2.6 million patients with and/or at-risk for CKD identified by stricter guide-line based criteria using a combination of administrative encounter codes, physical examinations, laboratory values and medication use. Notably, data based on race/ethnicity and geography in part, will enable robust analyses to study traditionally disadvantaged or marginalized patients not typically included in clinical trials. DISCUSSION: CURE-CKD project is a unique multidisciplinary collaboration between nephrologists, endocrinologists, primary care physicians with health services research skills, health economists, and those with expertise in statistics, bio-informatics and machine learning. The CURE-CKD registry uses curated observations from real-world settings across two large healthcare systems and has great potential to provide important contributions for healthcare and for improving clinical outcomes in patients with and at-risk for CKD.

The discovery BPD (D-BPD) program: study protocol of a prospective translational multicenter collaborative study to investigate determinants of chronic lung disease in very low birth weight infants.

BACKGROUND: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease. METHODS: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies. DISCUSSION: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants. TRIAL REGISTRATION: Does not apply for this study.

Recommendations From a National Panel on Quality Improvement in Obstetrics.

This paper describes the recommendations of a national panel on quality improvement in obstetrics to identify priorities for action among five areas of greatest medico-legal risk. Using previously conducted medico-legal data analyses and a systematic literature review, the panel reviewed existing data and developed recommendations for areas of focus in quality improvement in five obstetrical high-risk areas. The panel recommended clarification of definitions in some areas, identified needs for data collection and standardization of practices in others. The most promising interventions to improve care in the five areas were grouped into: standardized processes (such as protocols and communication tools), checklists, audit and feedback, mentoring and coaching, inter-professional communication, simulation and training, and shared decision making guides. This national panel of experts created 18 action-oriented recommendations focused on quality improvement to reduce medico-legal risk and improve the safety of care for Canadian mothers and babies.

New insights into the phylogenetics and population structure of the prairie falcon (Falco mexicanus).

BACKGROUND: Management requires a robust understanding of between- and within-species genetic variability, however such data are still lacking in many species. For example, although multiple population genetics studies of the peregrine falcon (Falco peregrinus) have been conducted, no similar studies have been done of the closely-related prairie falcon (F. mexicanus) and it is unclear how much genetic variation and population structure exists across the species' range. Furthermore, the phylogenetic relationship of F. mexicanus relative to other falcon species is contested. We utilized a genomics approach (i.e., genome sequencing and assembly followed by single nucleotide polymorphism genotyping) to rapidly address these gaps in knowledge. RESULTS: We sequenced the genome of a single female prairie falcon and generated a 1.17 Gb (gigabases) draft genome assembly. We generated maximum likelihood phylogenetic trees using complete mitochondrial genomes as well as nuclear protein-coding genes. This process provided evidence that F. mexicanus is an outgroup to the clade that includes the peregrine falcon and members of the subgenus Hierofalco. We annotated > 16,000 genes and almost 600,000 high-quality single nucleotide polymorphisms (SNPs) in the nuclear genome, providing the raw material for a SNP assay design featuring > 140 gene-associated markers and a molecular-sexing marker. We subsequently genotyped ~ 100 individuals from California (including the San Francisco East Bay Area, Pinnacles National Park and the Mojave Desert) and Idaho (Snake River Birds of Prey National Conservation Area). We tested for population structure and found evidence that individuals sampled in California and Idaho represent a single panmictic population. CONCLUSIONS: Our study illustrates how genomic resources can rapidly shed light on genetic variability in understudied species and resolve phylogenetic relationships. Furthermore, we found evidence of a single, randomly mating population of prairie falcons across our sampling locations. Prairie falcons are highly mobile and relatively rare long-distance dispersal events may promote gene flow throughout the range. As such, California's prairie falcons might be managed as a single population, indicating that management actions undertaken to benefit the species at the local level have the potential to influence the species as a whole.