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Refereed/Peer-reviewed Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

This report addresses the technical aspects of de-identification of medical images of human subjects and biospecimens, such that re-identification risk of ethical, moral, and legal concern is sufficiently reduced to allow unrestricted public sharing for any purpose, regardless of the jurisdiction of the source and distribution sites. All medical images, regardless of the mode of acquisition, are considered, though the primary emphasis is on those with accompanying data elements, especially those encoded in formats in which the data elements are embedded, particularly Digital Imaging and Communications in Medicine (DICOM). These images include image-like objects such as Segmentations, Parametric Maps, and Radiotherapy (RT) Dose objects. The scope also includes related non-image objects, such as RT Structure Sets, Plans and Dose Volume Histograms, Structured Reports, and Presentation States. Only de-identification of publicly released data is considered, and alternative approaches to privacy preservation, such as federated learning for artificial intelligence (AI) model development, are out of scope, as are issues of privacy leakage from AI model sharing. Only technical issues of public sharing are addressed., 131 pages

Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants inFBXO10which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Introduction The past two decades have seen a revolution in the management of labor and delivery; rates of cesarean delivery (CD), medical induction, and electronic fetal monitoring have increased dramatically. CD occurs in one third of deliveries and is the most common inpatient surgery. The increase in CD has occurred despite concerns about maternal complications (infection, blood loss, hysterectomy, uterine rupture) and racial disparities. Since 1993, black and white women have gone from comparable CD rates to rates 40% higher among black women compared to white women. Methods This project has assembled a cohort of over 800,000 deliveries from the Cerner Corporation’s Health Facts® database. Health Facts contains 63 million unique patients from over 600 U.S. healthcare facilities. Data include comprehensive clinical records from inpatient and outpatient encounters and includes data from pharmacy, laboratory, registration and billing data. Results CD was identified using a validated definition that incorporates International Classification of Disease (Version 9, Clinical Modification) codes for delivery outcome and relevant diagnosis-related groups and procedures. We examined 618,582 singleton deliveries to black and white women and identified 177,564 cesarean deliveries (28.7%). Conclusions The rate of cesarean was higher for black women overall and during the years 2000 – 2006 and 2011 – 2015 the CD rate for black women was significantly higher than for white women. Of note, during the period from 2007 – 2010 rates of cesarean were similar among black and white women. The rate of repeat cesarean was lower among black women, while the rate of induction of labor was higher., Introduction Ninety-five percent of all inmates are eventually released back into communities, with many being released without access to the most basic of necessities. Women in particular face complex health and social challenges – children, partners, strained employment opportunities, health problems – before incarceration that they must also face upon reentry. This poses a barrier to their successful reintegration back into society. Methods The present study analyzes data collected as part of the sexual health empowerment (SHE Project) health literacy intervention. Participants were recruited from three county jails in the greater Kansas City area. At baseline, participants completed a survey that assessed sociodemographic characteristics and social histories prior to incarceration. Women were followed annually after program completion to complete surveys to assess their long-term health and social circumstances. The present study is a secondary analysis of baseline and follow-up data. Anticipated Results We use Hobfoll’s Conservation of Resources (COR) Theory to conceptualize the stress that justice-involved women may experience as a result of perceived or actual loss of resources. We hypothesize that “loss spirals”, a term coined by Stevan Hobfoll, creates psychological stress that drives justice-involved women to assume risky sex and drug behaviors that will generate more resources and help to cope with the stress. Significance of Impact This study aims to define a succinct longitudinal timeline assessing biopsychosocial outcomes of women released from jail in order to improve prevention and intervention techniques for improvement in social and health circumstances of women leaving jail and their reduction in recidivism., Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a five-year survival rate ~7%. Thus, early detection could be key to reducing its mortality. Finding effective biomarkers is crucial to early detection. Pancreatic cancer biomarker studies typically consider more than two classes (i.e., recruited individuals that are either healthy, suffering from pancreatitis/cysts, or from aggressive PDAC). Conventional ROC curve analysis is the most popular tool to assess the discriminatory ability of biomarkers in distinguishing between two groups. For more than two groups, this approach is inadequate to determine decision cutoffs for decision-making purposes. Currently there is no accuracy-based statistical approach that is immune to the prevalence of the disease and is able to accommodate information from all three groups to optimally determine a decision rule for classification of patients. We propose a Euclidian distance-based approach as a method of estimating optimal cutoff values. We provide a full analysis framework when interest lies in decision-making and provide parametric and nonparametric approaches. Our approaches can easily be generalized into k-class problems when we are interested in distinguishing between four or more classes. We can extend our methods to consider the costs of incorrect decision making for each of the groups and weigh them accordingly. Additionally, combinations of biomarkers or relevant clinical information can also be accommodated straightforwardly to improve decision rules. We illustrate the usefulness of our approaches by analyzing a pancreatic cancer biomarker study conducted at the University of Texas MD Anderson Cancer Center., Introduction To study breast cancer progression, we developed the Mouse-Intraductal (MIND) model which involves intraductal injection of breast cancer cells into the mammary ducts of immunocompromised mice, where they display a course remarkably similar to the evolution of human breast cancer, with the formation of lesions in situ followed by invasion into the surrounding stroma. More recently, we are collecting peripheral blood from these same women and have been successful in humanizing mice with the patient’s own hematopoietic stem cells (HSC). Preliminary Data We have achieved successful engraftment of peripheral blood-derived and bone marrow-derived human CD34+ cells into NSG (immunodeficient NOD-SCID Il2rg−/−), MISTRG (immunodeficient Rag2−/−Il2rg−/− transgene SIRPa expressing GM-CSF, IL-3, M-CSF, TPO) and MISTRG6 mice (plus IL-6) and observed recruitment of their progenitors to breast cancer lesions. Our preliminary studies demonstrate preferential myeloid development when using peripheral blood derived CD34+ cells, while both myeloid and lymphoid development are achieved when using bone marrow derived CD34+ cells. Furthermore, MISTRG6 mice show improved development of both human myeloid and lymphoid hematopoietic cells compared to MISTRG and NSG mice. Impact and Future Aims The major advantage of our model is the ability to observe progression of patient breast cancer and their associated immune cells in vivo. Analyzing patient samples eliminates the ability to track the progression of lesions and their associated immune cells in vivo. By maximizing these unique advantages, we hope our results will help guide individualized immunotherapy in future patient care., Introduction Although causal linkage between hyperglycemia and decreased lung function in cystic fibrosis (CF) is unknown, it is thought to be related to excess inflammation and ion channel dysfunction. Methods We utilized complementary in vitro and in vivo approaches to assess the effects of hyperglycemia on the CF airway epithelium. In vitro: Primary CF bronchial epithelial (CFBE) cells at the air-liquid interface under hyperglycemic (HG; 255 mg/dL) or normoglycemic (NG; 100 mg/dL) conditions. Airway surface liquid (ASL) was measured by meniscus scanning and apical K+ (BK) ion channel current was measured in Ussing chambers. In vivo: In CF subjects with or without CF related diabetes (CFRD), glycemic control was measured using continuous glucose monitoring. Results Nasal epithelial cells were collected and analyzed by qPCR for the expression of RAGE, TGF-1, and LRRC26, the regulatory subunit of BK. Compared to normoglycemia, CFBE cells under hyperglycemia show significantly reduced ASL (68.4 ± 17.4 μL, NG vs. 51.5 ± 18.1 μL, HG; p, The University of Kansas Medical Center – Genomics Core leveraged the Frontiers: KU Clinical and Translational Science Institute infrastructure award to purchase an Eppendorf MasterCycler Pro thermal cycler and Countess II Automated Cell Counter to support the single cell initiative of the Genomics Core at KUMC. The MasterCycler Pro and Countess II are used to support the 10X Genomics Chromium Controller for performing the full suite of 10X Genomics single cell applications which include Single Cell 3′ Gene Expression, Single Cell 5′ Expression and V(D)J Enrichment and Single Cell ATAC – Chromatin Profiling. The Countess II Automated Cell Counter is used to ensure that adequate cell counts and high viability of submitted samples are present. The Countess also allows visualization of any cellular debris or cell clumping which will interfere with a successful 10X emulsification procedure required for a successful single cell library preparation. The MasterCycler Pro has been sequestered to exclusively support single cell library preparations. The MasterCycler performs the initial single strand synthesis which incorporates the 10X GEM barcode and Unique Molecular Identifier (UMI), second strand synthesis and Illumina adapter ligation to complete the 10X library preparation. These instruments have proven critical to the successful execution of 16 single cell projects in support of seven different investigators. Frontiers’ investment in the single cell initiative has had a positive impact on cutting edge single cell expression and epigenetic research performed at the University of Kansas Medical Center., Introduction Alzheimer’s disease (AD) is the most common form of irreversible, progressive dementia that affects memory loss, cognitive capabilities, and behavior. Although, significant progress has been made to understand genetic and clinical risk factors associated with AD, our understanding of AD remains incomplete resulting in ineffective prevention or cure. Methods Several studies have indicated that the polymorphisms in the mitochondrial DNA (mtDNA) play an important role in the mechanism of AD. Therefore, in order to understand the association of the mitochondrial genetic alteration with AD, we carried out cross-sectional association analysis using the clinical and mitochondrial single nucleotide polymorphism (SNP) data. We used the data collected at University of Kansas Alzheimer’s Disease Center (KU ADC) to carry out the analyses. We also used the data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) for the replication and validation analyses. Results The KU ADC data consists of 146 AD and 265 cognitively normal subjects, and ADNI data has 244 AD and 242 controls. For both datasets, the haplogroups information for each subject and APOE ɛ4 carrier status were also available. Conclusions We found that the rates of incidence of AD were statistically significantly different among the haplogroups, with differing strengths of association for different haplogroups. APOE ɛ4 was significantly associated with AD overall (p-value = 1.9×10–11) and the association varied by haplogroups (i.e., interaction). The results were consistent with the ADNI data. Our study has generated hypothesis and the data for further studies ahead to understand the etiology of AD., Introduction Age-related bone loss and associated fracture risk is an increasing concern worldwide. Oxidative stress causes mitochondrial damage and is associated with age-related degeneration in many cell systems, including bone cells. Methods To understand mitochondrial function in bone cells in situ, live-cell and intravital imaging of mitochondrial NADH and mitochondrial morphology was performed using transgenic mice expressing GFP in osteocytes as well as in MLO-Y4 osteocyte-like cells and OmGFP66 cells, which model osteoblast-to-osteocyte transition. NADH excitation and emission spectra in live osteocytes and osteoblasts matched well with pure NADH, with maximal multiphoton excitation at 740 – 760nm, resulting in blue NADH autofluorescence. With 760nm excitation, maximal NADH emission occurred at 460nm. Metabolic challenge was performed with carbonylcyanide-3-chlorophenylhydrazone and sodium cyanide, which convert NADH to its maximally oxidized or reduced states. Results This showed that osteoblasts had a lower resting redox state, with 40% of their NADH in a reduced state, compared to osteocytes with 75 – 80%. Live imaging using mitotracker Red-CMXRos showed that osteocytes have fewer mitochondria, lower mitochondrial area and % area, and increased solidity. Conclusions These data show that osteocytes in vivo under normoxic conditions have significant levels of mitochondrial NADH and show differences in mitochondrial number, morphology and function compared to osteoblasts. These live-cell imaging techniques can be used to determine changes in mitochondrial function during aging/cellular senescence and disease. These studies were supported by Frontiers equipment funding, including a Tokai-Hit CO2 incubation system, Leica 16× and 20× objectives and Imaris9.2 software which are available to other investigators through the UMKC Confocal Imaging Core., Introduction Pancreatic cancer (PDAC) is the fourth leading cause of cancer-related deaths in the U.S. Gemcitabine remains the drug of choice for metastatic disease, but only little improvement is seen in survival rates. Hence, there is a dire need for novel therapeutics for PDAC. We found that PRLR is overexpressed in PDAC tissues and cell lines and knockdown of the receptor resulted in reduced tumor formation in mice. Hence, PRLR is a novel target for therapeutic interventions in PDAC. Methods As there is no small molecular inhibitor available for targeting the receptor, we developed a homology model of the intracellular domain of PRLR that encodes the JAK2 binding site, and then performed a virtual screening of small molecules using IDOCK and I-TASSER servers. Using Fragment-based drug design, we derived commercially available compounds for virtual screening. We selected several compounds that came out of the virtual screening and performed in vitro proliferation assays in the PDAC cells. We identified antipsychotic drugs including penfluridol that can inhibit the proliferation of PDAC cell lines. Moreover, pretreatment of these antipsychotic drugs inhibited PRL-induced STAT3 and ERK phosphorylation in PDAC cell lines. Further, we used cellular thermal shift assay and drug affinity binding assay to confirm the binding of Penfluridol and PRLR. We also used cell-free systems such as surface plasmon resonance (SPR) and magnetic relaxometry to confirm the drug binding. Moreover, Penfluridol treatment significantly decreased pancreatic tumor burden in animal models. In conclusion, we identified penfluridol is a potential drug candidate for targeting PRLR in PDAC., Introduction Anorexia nervosa (AN) is a serious condition associated with numerous medical complications, psychiatric comorbidity, and the highest mortality rate of any psychiatric disorder. Relapse rates remain high and for many, AN becomes an enduring condition. The only reliable prognostic indicator for AN is “rapid response” (i.e., weight gain over the first four weeks of treatment). Yet, there are no reliable predictors of rapid response at baseline. There is a pressing need to identify novel neuro-markers that confer early risk for poor treatment outcome. Methods Study goals were to systematically identify potential neuro-markers related to short-term AN outcomes by assessing brain activation associated with delayed discounting (capacity to delay immediate gratification), sensitivity to food reward (responses to rewarding foods and decisions to choose palatable foods), and threat sensitivity (heightened reactivity to potential danger or harm). The purpose of this study was to identify neural predictors of short-term treatment response in adolescents with AN. Participants were adolescent females with AN who entered their first course of eating-disorder treatment within the past six months. Specific aims 1) Test neural activation during tasks measuring delayed discounting, food reinforcement, and threat and 2) Identify prospective associations of task-performance and task-based neural activation with eating-disorder symptoms at one-month follow-up. Conclusions Differentiating neurobiological processes that contribute to AN chronicity may lead to the development of prognostic indicators at initial treatment presentation. These neuromarkers may improve clinical decision-making and allow providers to identify patients requiring more intensive treatment interventions to prevent chronicity and mortality., Introduction Osteocytes are the primary mechanosensory cell in bone and activate β-catenin signaling in response to mechanical loading of bone. Methods In order to understand the mechanism by which osteocytes activate β-catenin signaling, we have developed a stably transfected osteocyte cell line that expresses luciferase when β-catenin signaling occurs in the nucleus. To quantitate luciferase activity, we purchased a VICTOR Nivo Multimode Plate Reader (Perkin-Elmer) with the support of Frontiers funding. This instrument quantitatively measures luciferase activity (fluorescence and absorbance) in several plate formats, thus permitting high throughput screening of compounds that activate β-catenin signaling. We stably transfected the MLO-Y4 osteocyte-like cell line with the TOPflash vector pGL4.9[luc2P/TCF_LEFRE/Hygro] (Promega). Clone A3–F9 gave a dose response to increasing concentrations of Wnt3a (1–100ng/ml) and activation with 10mM LiCl gave the equivalent of a submaximal dose of Wnt3a (10ng/ml). Results We demonstrated that C2C12 myotubes, but not myoblasts, produce a factor that activates β-catenin signaling two-fold using these TOPflash-MLO-Y4 cells, but in combination with Wnt3a (10 ng/ml; 10-fold activation) produces a 20–30-fold increase in activity measured in our luciferase assay. We demonstrated that production of this factor by C2C12 myotubes is partially regulated by mTOR signaling. We are currently seeking to identify this factor using our TOPflash-MLO-Y4 cells. Conclusions The acquisition of the VICTOR Nivo Multiplate reader provides us the means to conduct a high throughput screening approach to identify this factor(s). This instrument is part of a Core in the UMKC School of Dentistry Department of Oral and Craniofacial Sciences and available to other investigators for their studies., Introduction Initiation of JUUL use by young adults is one of the most significant issues of concern within the debate on vaping. Despite the proliferation of products and the surge in prevalence, no studies have investigated individual-level interventions or prevention strategies for pod-mod use. Methods Participants (N = 947) were young adults (< 30 years old) recruited from Amazon’s Mechanical Turk based on smoking (never, former, and current smokers) and JUUL use status (never and current users). In a pre-post design, participants completed baseline assessments, were presented with a brief JUUL-specific educational intervention and completed post-assessment measures. Primary outcomes were changes in JUUL knowledge, perceived harmfulness, intentions for future use, and motivation to change. Results Participants (Mean age = 26.1) were male (57%) and White (75%). Overall, the intervention increased JUUL-related knowledge, risk perceptions, commitment to quitting, and readiness to quit JUUL (all p ≤ 0.001). Similarly, participants showed decreased interest in future JUUL use, interest in purchasing JUUL, and interest in future regular JUUL use (all p ≤ 0.001). There were significant Time X Group interactions for JUUL-related knowledge (p < 0.001), with never JUUL/never smokers showing the greatest increase in product knowledge following the intervention. However, no other interaction effects were significant. Discussion The intervention was effective in increasing knowledge and risk perceptions while reducing intentions for future use. The intervention was most effective in increasing knowledge among non-users, suggesting that brief educational interventions may be useful tools for preventing pod-mod initiation while more intensive interventions may be necessary to alter attitudes and use behaviors among current users., Introduction American Indians (AI) have the highest rates of smoking and smokeless tobacco (SLT) use among all major racial/ethnic groups. There is limited information about the use of alternative tobacco (AT) products such as electronic cigarettes. The objective of this pilot study is to understand the knowledge, attitudes, beliefs, and behaviors (KABB) surrounding AT product use among AI college students. Methods We conducted 19 focus groups with AI college students age 18 and older. Participants were stratified by AT use, cigarette use, and never users of tobacco products. Focus groups were audio-recorded and transcribed verbatim in preparation for coding and standard text analysis. Participants completed a short survey that collected information on demographics and KABB about tobacco products. Surveys were analyzed with frequencies and measures of central tendencies. Results Participants included 105 AI college students. Participant’s mean age was 21 years and 50% were female. Focus groups ranged in size from two to nine. Related to e-cigarette use, participants cited flavors, discreteness, stress, and social aspects as factors for use. Survey results indicate that 35% of participants were current e-cigarette users, 30% were current smokers, and 9% were current SLT users. Conclusion This pilot study confirms that AI college students are following a similar trend to other racial/ethnic groups in terms of AT use. It is important that we obtain estimates of AT use and include AI in prevention and cessation efforts. This study will help develop appropriate prevention and cessation messaging for this population., Introduction A proof of concept trial (NCT02914977) was designed to measure the ability of low dose DNR to inhibit pS552-β-catenin in LSCs of adult relapsed/refractory AML patients. A protocol amendment added a second cohort of patients with newly diagnosed AML undergoing standard chemotherapy with DNR and cytarabine (7+3 induction). Methods Treatment in each cohort consisted of DNR given at a dose of 6.75mg/m2/day × five days. Patients with relapsed/refractory AML had bone marrow aspiration pre-treatment prior to day 1, followed by DNR on days 1–5, and a post-treatment bone marrow aspiration on day 8. Patients with newly diagnosed AML were treated with conventional 7+3 chemotherapy. Results A sample from the day 14 bone marrow was collected. DNR was given on days 15 – 19. Bone marrow aspiration was performed with blood count recovery and samples sent for LSC marker assessment. Discussion In this study, we will determine the safety, pharmacokinetics, and pharmacodynamic effects of low dose DNR. The LSC population and phosphorylation status of β-catenin will be measured pre-and post-treatment. Two or more prior induction attempts are required for study entry for refractory patients; relapsed patients require only one prior induction. The trial completed its accrual goal of 18 patients. Low-dose DNR treatment was well-tolerated with no unexpected adverse events. In this pilot proof of concept trial, we will demonstrate the feasibility of serial bone marrow aspiration to measure biomarkers of LSC response., Introduction American Indians (AI) are disproportionately and significantly impacted by disease morbidity, mortality and poor behavioral health outcomes. Based on data from the National Vital Statistics Reports, the leading cause of death among AI is cancer (19%), followed by heart disease (18%). Regionally, health disparities among AIs reflect national statistics. Health communication targeted to address these health disparities exist; however, few evidence-based strategies integrate holistic approaches. The impact of health communication research and practice is evolving and continues to emerge as a core part of health promotion. Strategies that appeal and increase persuasiveness of health messages are more likely to penetrate existing cultural beliefs and positively influence health behavior outcomes. The objective of this study was to explore how tribal and elder leaders throughout the Plains viewed themselves as health communicators within their communities. Methods Members of the Center for American Indian Community Health conducted 39 in-depth interviews from December 2017 to December 2018 with members of federally recognized tribes living in reservation communities, as well as urban tribal communities across the region. Results Results from this sample show that these individuals do not see themselves as the “authority” health communicator within their tribe and community. The term health promoter was viewed as problematic in Native communities for cultural reasons. Conclusion Overarching themes included seeing themselves as communicators of holistic health, specific health prevention programs, access, targeted communication and health promoters as a collective unit. Collective social and cultural authority in tailored messages is perceived to bolster health communication and positively impact health outcome., Introduction Minority and underserved populations carry the largest cancer burden for the United States (ACS, 2016). Genetic counseling, testing and technologies show promise to help reduce cancer through personalized medicine opportunities however disproportions of genetic services, uptake and research about genetic testing among these populations exist (Ricker, et al., 2018). Inequitable cancer-related genetic and genomic testing (CGT) communication among minority and underserved populations and other barriers (e.g., genetic counselor bias) may contribute to CGT disparities. Exploring existing attitudes, perceptions and beliefs toward CGT among minority and underserved patient populations may bolster strategies to address communication inequities. The study aims were to explore an under-researched area of precision medicine, i.e., the communication of genetic risk factors among minority and underserved patient populations with high to moderate risk and disseminate and share findings with the community. Methods A Community Advisory Board comprised of researchers, cancer survivors and family members of cancer patients met from December 2018 – March 2019 to discuss research design and data collection. Six stratified focus group discussions (N = 53) were held March – May 2019 where a pre-focus group survey was administered. Results Survey results show most had not talked to their doctor/health care provider about genetic testing (87%). African Americans (AA) and Latinos expressed a lack of awareness and knowledge about CGT and the importance of cultural tailoring. Conclusion Separate themes that emerged among Latinos included immigration status and language as barriers to CGT. Among AA, participants were highly distrustful of medical personnel and expressed outrage about the lack of recommendation for CGT., Introduction Engaging in healthy behaviors is not always rewarding (e.g., carrot vs. cake). Neural models of healthy behaviors focus on the balance between reward and regulation brain regions. This pilot study examines the engagement of reward and regulation regions during the evaluation of food and nonfood cues before and after a guided imagery exercise targeting positive associations with food and regulation. Our long-term goal is to understand the interaction between positive associations with healthy foods and thinking about future rewards may influence healthy decision-making. The objective of the current study is to empirically test the combined effects of positive affect and positive episodic future thinking on brain activation. Methods The project examined the effect of positive affect and episodic future thinking guided imagery on brain activation in regulation and reward regions. Participants included individuals with a body mass index greater than 25 (n = 20). Results Functional neuroimaging showed reduced activation in regulation-related brain regions (i.e., dorsomedial prefrontal cortex) to healthy and unhealthy food following guided imagery. Conclusions These results suggest more efficient regulation-related brain activation after positive episodic future thinking guided imagery., Introduction The Establishing Meaningful Patient-centered Outcomes With Relevance for patients with Polycystic Kidney Disease (EMPOWER PKD) initiative aims to engage PKD stakeholders and patients to learn about health priorities, insurance issues, and patient engagement. Methods We utilized semi-structured focus groups. We developed and pre-piloted a guide that allowed for both conversational flow and consistency in questions among groups. We audio-recorded each group and transcribed the conversations verbatim. We performed an inductive thematic analysis. Two investigators completed all data coding independently and in duplicate. We compare the results of an ethnically diverse focus group to the other seven that mainly included Caucasian participants. Results 14 individuals participated in this part of the study. Of these, (64.2%) reported having PKD, and (14.2%) being caregivers. The mean age of participants was 48.8 (range 29 – 75) years. The group included 85.75% African American and 7.1% reported more than one race. Conclusions It was challenging to recruit this group and it required establishing a relation with community nephrologists and faith-based organizations leads. Multiple participants stated that they would not have participated if the group was not exclusively ethnically diverse as they fear that their opinion may be outnumbered by a Caucasian majority. Some discussed believing that PKD was a “white” disease. Many discussed hiding their diagnosis which affected their activation and engagement and came with unanticipated psychological impacts. Participants unanimously described lack of trust-worthy, easy to understand educational resources for minorities as a main barrier to engagement., Introduction The highest rates of obesity in the U.S. are among black women with a prevalence of 54.8%. Psychosocial factors, such as stress from racism, have been proposed as contributors to this disparity, but the mechanisms are unclear. The objective of this study is to understand the relationship between race-related stress and food choice among black women. Methods Forty-five participants were asked to come in fasted for two appointments, randomized to the order of stress exposure in a within subject design. Forty images for each condition were collected from two validated picture sets (International Affective Picture set and Socio Moral Image Database). The images were shown in random order and contained either racially charged scenes (e.g., Ku Klux Klan) or non-racially charged scenes (e.g., aggressive dog) matched on valence (pleasant vs. unpleasant) and arousal (physiologically stimulating). Food choice and food demand tasks were completed pre and post stress exposure. Participants were surveyed on their stress levels, past experiences of racism, and trauma. Anticipated Results It is expected that preferences for unhealthy foods will be greater after race related stress exposure compared to the other stress condition. We anticipate that those who have higher BMI’s are more likely to be affected in their changes in eating behaviors in both stress exposure states, with a larger impact from the race related stress induction. Data collection is ongoing., Introdution To examine the impact of residential distance and socioeconomic status on survival outcomes for patients receiving treatment for ovarian cancer at an NCI-CC. Methods Patients who were treated for ovarian cancer at a single institution from 2010 – 2015 were identified. Age at diagnosis, insurance status, and distance from the patient’s home to the institution were abstracted. Clinical data including stage at diagnosis, surgical status, chemotherapy cycles, dates of diagnosis, recurrence, and death were obtained. Patients treated at other institutions and those with non-epithelial pathology were excluded. Patients were stratified into three groups based on distance from the institution. Overall survival (OS) and progression free survival (PFS) were generated by Kaplan Meier survival curves and Cox proportional hazard models using SAS v9.4. Results Two hundred and three patients were identified. Survival analysis based on distance demonstrated that patients who lived less than 10 miles from the institution have worse survival (p = 0.0412). Lower median income (< 56,179) regardless of distance to institution was also associated with worse survival, p = 0.0283. After adjusting for stage of disease, age at diagnosis, surgery status, chemotherapy resistance, income quartile and presence of comorbid conditions, distance < 10 miles from the institution was still a significant predictor of worse overall survival, HR 2.62 95% CI (1.333 – 5.142), p = 0.0052. Conclusion Among patients who received guideline-adherent care for ovarian cancer, lower median income and residential distance less than 10 miles to an NCI-CC was associated with worse overall survival., Introduction The shooting of unarmed citizens by police officers is a topic at the forefront of public awareness. The disproportionate rate at which unarmed Black citizens are shot is believed to reflect widespread racial bias on behalf of officers, which erodes public trust and reduces policing effectiveness. Methods We have developed an Attention-integrated Model-based Shooting Simulator (AiMSS) to gain a deeper understanding of the mechanisms underlying the decision to shoot. The AiMSS combines computational models of decision making, visual psychophysics and eye-tracking methods, and an immersive decision simulator to map the processes police officers use to decide to shoot. Results Results with the AiMSS reveal that policing scenario and suspect behavior accounted for the most variation in decisions. Process level measures show little evidence of an initial bias to shoot Black suspects. Instead, results reveal a diminished ability to distinguish objects held by Black suspects. Conclusions This work emphasizes the importance of contextual factors in the decision to shoot and highlights how past experimental studies on racial bias have neglected critical inputs into officer deadly force decisions., The Emerging Imaging Technologies and Applications Laboratory (EITAL) is a shared resource serving as a proof-of-concept hub for performing innovative and rigorous fundamental cancer biology research at subcellular to cellular length-scales in conjunction with the development and translation of advanced imaging technologies and applications. The scientific staff of EITAL are experts in developing and improving reagents, methods, and optical and electron microscopic imaging technologies, antibody development, screening, and characterization, immunohistochemistry, immunocytochemistry, correlative optical and electron microscopy, immunoelectron microscopy, workflow development, and experimental design and data analysis of imaging studies. EITAL promotes synergies between its imaging technology developers and University of Kansas Cancer Center (KUCC) cancer biology researchers. EITAL also provides research training and career development programs to ensure a talented and diverse workforce engaged in cellular tumor cancer biology imaging research. The collaboration between EITAL and the University of Kansas (KU) Microscopy and Analytical Imaging Research Resource Core Laboratory (MAI) imaging scientists, enables imaging research at the level of the whole animal, individual cells, as well as molecules inside the cells, and provides instrumentation and expertise for optical and electron microscopies, resulting in multi-scale/multi-dimensional correlative imaging research of living and fixed cells and tissues. The KUCC Support Grant (P30 CA168524) supports EITAL., Introduction Sensorimotor integration deficits are common in Autism Spectrum Disorders (ASD). Evidence exists for an over-reliance on both visual and proprioceptive feedback during motor control in ASD, suggesting deficits in the modulation of sensory feedback processing and inability to use the most reliable input. This study aims to test this hypothesis. Methods Forty persons with ASD (10 – 33 yrs) and 25 age-, sex- and nonverbal IQ-matched controls completed precision gripping tasks. They squeezed a force sensor with their index finger and thumb and tried to match their force output to a target force. Visual feedback was presented on a computer screen across low, medium, and high gain levels; the force output bar moved a greater distance per change in force at higher gains. A stationary bar represented the target force. 80Hz tendon vibration was applied at the wrist to create a proprioceptive illusion of muscle contraction. Force regularity (approximate entropy; ApEn) was examined. Results Preliminary results from 18 participants with ASD and 13 controls indicate a Group × Tendon Vibration × Visual Gain interaction for ApEn (F = 1.559, p = 0.023). Controls showed increased ApEn during 80Hz tendon vibration at low visual gain but decreased ApEn with vibration at high visual gain. Individuals with ASD show slight increases in ApEn with 80Hz vibration across visual conditions. Conclusions Early findings indicate that controls shift to a secondary source of sensory feedback (e.g., proprioception) when the primary source (e.g., vision) is degraded. Persons with ASD fail to dynamically recalibrate feedback processes across sensory systems when feedback conditions change., Introduction African American women experience higher incidence and mortality rates of cervical and breast cancer. The purpose of this study is to develop and implement a breast and cervical cancer screening intervention to increase awareness, uptake of screening, and follow-up among an African American female church-population in Sedgwick County, Kansas. Methods Academic researchers recruited local pastors (N = 11) to develop a faith taskforce. Using intervention mapping, we conducted three focus groups with the taskforce to assess barriers and facilitators to seeking breast and cervical screenings and multi-component strategies to improve education and awareness of breast and cervical cancer screening recommendations, screening rates, and follow-up among African American women. Preliminary Results Of the 11 faith taskforce pastors, three were females. The key identified themes focused on barriers and facilitators to implementation of church-based cervical/breast cancer interventions, such as time constraints, limited expertise in conducting faith-based interventions, and lack of awareness on burden of cancer in the community, awareness of screening recommendations, and support/accountability in cancer screening and follow-up. Participants also indicated that a mobile phone app to track screenings, follow-up appointments, and promote education about risk factors and a church health navigator to assist with app utilization and track screenings and follow-up appointments would need to be primary intervention components. Conclusions Findings from the taskforce focus groups highlight the need for multi-component church-based interventions that include a mHealth app and church health navigators to improve awareness and adherence to breast/cervical cancer screening recommendations and follow-up among African American female church populations., Introduction Rituximab (RTX) is an effective maintenance therapy in forms of ANCA-associated vasculitis (AAV), specifically granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) (MAINRITSAN trial). Sixteen percent of patients will relapse despite RTX. Infliximab, an anti-chimeric antibody like RTX, is associated with a high rate of anti-drug antibody formation which effects its efficacy. The aims of this study are to a) evaluate the incidence of immunogenicity toward rituximab in AVV; and b) evaluate the relationship between anti-RTX antibodies and drug response. Herein we present the baseline data. Methods Inclusion criteria: a) meet either 1990 ACR and/or 2012 revised CHCC criteria for GPA or MPA; b) remission at entry; c) received Rituximab in last 12 months; d) plan to continue Rituximab; and e) no contraindications for receiving further RTX infusions. Results 30 participants (25 GPA and 5 MPA) were enrolled. ANCA by EIA was MPO positive in 14 (47%), PR3 positive in 13 (43%) and negative in 3 (10%). Mean age at enrollment was 62.5 years (IQR 46.5 – 67.5). 70% were female. The average immunoglobulin G (IgG) at baseline was 663 mg/dl (95% CI 566 – 760). 67% of participants had undetectable B-cells at baseline. Average time between the last Rituximab infusion and the first study Rituximab infusion was 34 weeks (95% CI 28 – 40 weeks). Conclusions At study baseline most of the participants were found to be B-cell depleted and mildly hypogammaglobulinemic. The average duration since the last Rituximab infusion at entry (8.5 months) was slightly longer than in the MAINRITSAN trial (six months)., Objective To determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement. Background Ranolazine, an FDA-approved drug for angina which inhibits the late Na+ current and intracellular Ca2+ accumulation, may be neuroprotective in ALS and reduce cramp frequency by reducing neuronal hyperexcitability. Design/Methods Open-label dose-ascending study of ranolazine with 12 participants in two sequential cohorts: 500 mg and 1,000 mg orally twice daily. Each has a two-week run-in period, four-week drug administration and six-week safety follow up. Primary outcome is the frequency of dose limiting toxicities and adverse events. Exploratory measures include cramp frequency and severity, fasciculation frequency (on ultrasound), cramp potential duration, ALS Functional Rating Scale-revised (ALSFRS-r), and forced vital capacity (FVC) compared from baseline to week six. Results The 10 currently enrolled patients (Cohort 1, n = 6; Cohort 2, n = 4) are mostly male (80%), and middle aged (median 53 years). There were no serious adverse events. One subject in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (38%). Cramp frequency reduced by 44% (p = 0.01) and severity decreased by 36% (p = 0.002), with decreased awakening due to cramps and cramps interfering with daily activities or causing activity avoidance. Fasciculations, cramp potential duration, ALSFRS-r and FVC did not change. Conclusion Ranolazine was well tolerated in ALS up to 2,000 mg daily with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity without significant effect on fasciculations, ALSFRS-r or FVC., Dietary intake of fruits and vegetables is consistently related to chronic disease risk. Unfortunately, measurement of fruit and vegetable intake is most often by self-report and thus, there are concerns about the validity of the data. The Veggie Meter (VM) uses Resonance Raman light scattering spectroscopy (RRS) to non-invasively measure skin carotenoid content. Skin carotenoids have recently been reported as a reproducible and valid biomarker for dietary intake of fruits and vegetables. In August of 2017, we purchased a VM and began using it in several studies. Due to demand, we were unable to accommodate all studies. Thus, in July 2018 Frontiers provided funds to purchase another VM. To date, we have used VM in seven completed pilot studies (six interventions and one observational study) and are using it in three ongoing studies. Specifically, the Frontiers-purchased machine is being used in two NIH-funded clinical trials. It is also used in community outreach events. The average age of individuals screened using this VM is 74.9 years and the VM score is 281.9 ± 70.1, indicating poor intake similar to the national average. Within 54 healthy older adults, VM scores correlated with intake of vegetables (r2 = 0.2, p = 0.001), fruits and vegetables (r2 = 0.15, p < 0.01), and four individual carotenoids (r2 > 0.18 & p < 0.01 for all) derived from self-reported 3-day food records. The VM is quick, non-invasive, and easy to use. It provides an objective measure of fruit and vegetable intake and will continue to be incorporated into our nutrition clinical trials and observational studies., Objective Greater cognitive function (CF) is associated with adherence to prescription medications, better program adherence and weight loss (WL) following bariatric surgery. The purpose of this study was to evaluate the association between baseline CF, intervention dropout, adherence and three-month WL. Methods One hundred and seven (Mean age = 40.9 yrs.), overweight/obese (BMI = 35.6 kg/m2) men (N = 17) and women (N = 90) completed a three-month WL intervention. Participants were asked to attend weekly behavioral sessions, comply with a reduced calorie diet and complete 100 min of moderate intensity physical activity (PA)/wk. CF tasks including Flanker (attention), Stroop (Executive control) and working memory, body weight and cardiovascular fitness (covariate) were assessed at baseline and three-months. Session attendance, adherence to PA and diet prescriptions and number of off-diet episodes were recorded weekly. Results Results indicated that attention was positively correlated with session attendance (p = 0.016), adherence to the diet (p < 0.01) and PA (p = 0.023). Executive control was positively correlated with WL (p = 0.042). Working memory (two tasks) was also positively correlated with WL (p = 0.017 and p = 0.025). Analysis of variance (ANOVA) indicated that baseline attention (p = 0.012) was positively related to WL and negatively associated with drop out (p < 0.05). Hierarchical linear regression showed executive control (p = 0.036, R2 = 0.054) and working memory (p = 0.013, R2 = 0.073 and p = 0.017, R2 = 0.068) were associated with WL when controlling for fitness. Significance These results suggest that stronger baseline attention is associated with completion of a three-month WL intervention. Executive control and working memory are associated with amount of WL achieved. Additional, larger and longer trials to assess the role of baseline CF on WL and evaluating the impact of interventions designed to improve CF on WL are indicated., Introduction Adolescent mothers are less likely to initiate and sustain exclusive or partial breastfeeding. About 70% of mothers under age 20 initiate breastfeeding, compared to 80% of 20 – 29-year-old mothers. Duration of breastfeeding to six months and one year by young mothers is 28% and 18%, compared to 48% and 28% in 20 – 29-year olds. Early breastfeeding experiences can adversely influence duration of breastfeeding. This study describes the early postpartum breastfeeding experiences among mothers 16 – 19 years of age. Methods This is a descriptive study within a larger pilot clinical trial. Four to eight weeks after giving birth, participants completed the Breastfeeding Experience Scale (BES), a 30-item measure which documents breastfeeding experiences, feeding patterns, and weaning. Severity of 18 early experiences are rated on a Likert type scale of 1 – 5 (1 = “not at all” to 5 = “unbearable”). Cronbach’s alpha for the 18-item summated scale of the BES was 0.80. Descriptive statistics characterized experiences for this in-progress study. Results Thirty breastfeeding participants, ages 16 – 19 (X = 17.97, SD = 0.96) completed the BES. Twenty-one (70%) were breastfeeding at time of survey and 57% were doing so exclusively. The most frequently reported breastfeeding problems were engorgement and leaking which were rated mild to moderate in severity (X = 2.97, SD = 1.03). Nine mothers (30%) weaned between 14 and 30 days after birth; engorgement, latching difficulty, and drop in milk supply were most common reasons. Conclusions Most teenage mothers in this sample maintained breastfeeding past one month after birth and reported few problems., Introduction Obesity affects ~14 million children/adolescents in the U.S. (8.9% of 2 – 5-year-olds; 17.5% of 6 – 11-year-olds) and increases the risk of developing type 2 diabetes (T2DM). Early metformin intervention may delay or halt progression to T2DM. However, clinical response to metformin in children with insulin resistance or T2DM is unpredictable. Additionally, no dosing recommendations exist for children < 10 years. Preliminary data show that clinical response to metformin may depend on the amount of metformin present in the body over time (systemic exposure), with maximum response observed at exposures = 30 mg/L*h. Modelling and simulations can help determine individualized doses to achieve this exposure, ideally achieving favorable response for every patient. This study aims to prospectively validate simulations of the metformin dose-exposure relationship in young children. Methods A 24-hour pharmacokinetic study (measuring systemic exposure) of 500 mg metformin in children (6 – 12 years) with IR. Pharmacokinetic simulations including individual parameters (e.g., sex, age, weight) were conducted for each subject using Simcyp, a physiologically-based pharmacokinetic simulator. Results Two out of 12 subjects have completed the research study: Subject 1: Female, 12 years, 158.6 cm, 70.2 kg, BMI: 97.44 percentile, HbA1C: 6.7%; simulation-recommended dose: 1750 mg. Subject 2: Male, 8 years, 134.9 cm, 36.5 kg. BMI 95.58 percentile, HbA1C: 6.5%; simulation-recommended dose: 1100 mg. Clinical pharmacokinetic data is not yet available. Conclusion Individualized doses of metformin may benefit young children with IR. Smaller/younger patients may require smaller doses of metformin than larger/older children; clinical pharmacokinetic data is needed to support simulation-guided individualized dosing., Introduction Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has one of the worst one-year survival rates of any cancers. Understanding molecular mechanisms leading to HCC and developing novel strategies for effective prevention and treatment are urgent medical needs. HCC arises exclusively on the background of chronic liver injury and inflammation. Thus, an attractive therapeutic approach is to target key genes that regulate both inflammation and oncogenic pathways in HCC. RNA-binding protein Hu Antigen R (HuR) is one such candidate that controls the translation of multiple genes involved in inflammation and oncogenic process. The objective of this study is to characterize HuR targets in human HCC and test HuR-targeted intervention for HCC treatment. Methods HuR knockout (HuR-KO) in HCC cell line MHCC97H cells was accomplished by CRISPR/Cas9 gene editing system. The transcriptome comparison identified 1,516 differentially-expressed genes between HuR-KO cells and wild type controls. The top pathways altered by HuR knockout were cell proliferation, hippo signaling, beta integrin, pluripotent stem cells, EGFR, WNT, and FAK-PI3K-Akt-mTOR. To test HuR-targeted intervention for HCC treatment in vivo, MHCC97H cells were subcutaneously injected into athymic nude mice to establish HCC xenografts. Mice were then treated with a novel synthetic HuR inhibitor KH-3 for four weeks. Results and Conclusions Strikingly, KH-3 treatment significantly inhibited the growth of HCC xenografts. Taken together, our study provides a foundation for understanding the role of HuR in HCC. The mechanistic insights elucidated from our study may pave the way for developing therapeutic strategies to specifically target HuR for HCC treatment.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.

The conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and ∼50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development. These are features of the human syndrome pre-eclampsia. In a genome-wide association study of 7,219 pre-eclampsia cases, we found a 7% greater relative risk associated with the maternal HLA-B allele that does not favor NKG2A education. These results show that the maternal HLA-B→HLA-E→NKG2A pathway contributes to healthy pregnancy and may have repercussions on offspring health, thus establishing the physiological relevance for NK cell education. VIDEO ABSTRACT.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10-36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI., Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12–70 years, Australia: 16–73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a ‘rolling weights’ model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41–70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role later in life. Supplementary Information The online version contains supplementary material available at 10.1007/s10519-021-10076-6.

Additional file 1. Additional figures and tables.

Cosmic ray muons, that reach the earth's surface, provide a natural source of radiation that is used for radiography. In this paper, we show that radiography using cosmic radiation background provides a method that can be used to monitor bulk aspects of human anatomy. We describe a method that can be used to measure changes in patients as a function of time by radiographing them using cosmic-ray muons. This could provide hourly readouts of parameters such as lung density with sufficient sensitivity to detect time changes in inflammation of the lungs in, e.g., Covid patients.

This dissertation examines the significance of America’s interactions with stateless actors. It argues that it was groups such as the Muslim Brotherhood, Palestine’s refugees, and ethnic minorities, not the U.S. and Soviet governments, nor the state governments of the region, which dictated how the Cold War unfolded in the Middle East. These groups transformed the policy decisions, strategies, and alliances of both native regimes and the superpowers. Traditionally, historians have looked at the global politics of the Cold War through the lens of state-to-state relations. How have state governments interacted with each other and how did this influence the strategies and alliances of the superpowers? However, this work challenges state-centric models and points to new factors in the history of the United States and the world. Furthermore, much of the literature on groups such as Palestinian refugees and ethnic minorities has characterized them as victims, or actors without agency. Far from victims, this study contends that the Muslim Brotherhood, Palestine’s refugees, and minority groups such as the Armenians and Kurds defined the history of the period and, in key ways, were the primary agents of change. Not only does such research demonstrate the significance of non-state actors with regards to the Cold War, it also highlights the limits of postcolonialism. The non-state groups of this study did not fit into the nation-state system that developed in the Middle East after World War II. While these actors fit within imperial modes of power, the transition from Empire to nation-state left them stateless. As a result, they contested the nation-state system that came into being in the Middle East in the late 1940s and 1950s., © 2021 John Perry

Supplementary Notes, Tables and Figures for journal article. Full article published in The Journal of Clinical Endocrinology & Metabolism https://doi.org/10.1210/clinem/dgab215. The polygenic risk score is available on the PGS Catalog https://www.pgscatalog.org/score/PGS000758/.Important note (Aug 2021): SNPs included in this polygenic risk score may be imputed. For imputed SNPs, probability-based dosages (continuous values ranging from 0 to 2) should be used to calculate the score rather than hard-coded dosages (0/1/2). Extra caution must be taken if using programs by default rounding dosages to integers such as plink(2). Important note (Mar 2022): We spotted a mistake in the previously submitted version of the score file, as some of the predictor SNPs had effect / alternative alleles mistakenly flipped. We have included a corrected version in this repository and are contacting the PGS Catalog to correct deposited file as well. TL sincerely apologizes for this mistake.

Contains fulltext : 195595.pdf (Publisher’s version ) (Open Access) Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Background Early in the COVID-19 pandemic, there was serious concern that the United States (US) would encounter a short fall of mechanical ventilators. In response, the US government, utilizing the Defense Production Act ordered the development of 200,000 ventilators from 11 different manufacturers. These ventilators have different capabilities and it is not evident whether all are able to support COVID-19 patients. Research Question Evaluate ventilator requirements for affected COVID-19 patients, assess the clinical performance of current SNS ventilators employed during the pandemic, and finally compare ordered ventilators functionality based on COVID-19 patient needs. Study Design and Methods Current published literature, publicly available documents, and lay press articles were reviewed by a diverse team of disaster experts. Data was assembled into tabular format which formed the basis for analysis and future recommendations. Results COVID-19 patients often develop severe hypoxemic acute respiratory failure and ARDS requiring high levels of ventilator support. Current SNS ventilators were unable to fully support all COVID-19 patients, and only about half of newly ordered ventilators have the capacity to support the most severely affected patients; ventilators with less capacity for providing high level support are still of significant value in caring for many patients. Interpretation Current SNS ventilators and those on order are capable of supporting most but not all COVID-19 patients. Technologic, logistic, and educational challenges encountered from current SNS ventilators are summarized, with potential next generation SNS ventilator updates offered. Clinical Trial Registration N/A

The timing of reproductive behaviour – age at first sexual intercourse (AFS) and age at first birth (AFB) – has implications for reproductive health, adolescent development and evolutionary fitness. In the largest genome-wide association study to date (AFS, N=387,338; AFB, N=542,901), we identify 370 independent signals, 11 which are sex-specific, with a 5-6% polygenic score prediction. Heritability shifted from 10% for those born in 1940 to 23% for the 1965 birth cohort. Using Genomic SEM, we show that signals are largely driven by the genetics of reproductive biology and externalizing behaviour. This is supported by extensive biological follow-up that isolates key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility (endometriosis, spontaneous abortion) and spermatid differentiation, morphogenesis and binding (KLF17, ZPBP). Later AFB is protective against later-life disease (type 2 diabetes, cardiovascular) and associated with longevity. Those from higher childhood socioeconomic circumstances and polygenic scores in the highest deciles (90%+) experience markedly later reproductive onset. Results are relevant for interventions in teenage sexual, reproductive and mental health, deepen our understanding of the drivers of later-life health and longevity, and fuel infertility and functional follow-up experiments.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of this participation bias is challenging as it requires the genotypes of unseen individuals. However, we demonstrate that it is possible to estimate comparative biases by performing GWAS contrasting one subgroup versus another. For example, we show that sex exhibits autosomal heritability in the presence of sex-differential participation bias. By performing a GWAS of sex in ~3.3 million males and females, we identify over 158 autosomal loci significantly associated with sex and highlight complex traits underpinning differences in study participation between sexes. For example, the body mass index (BMI) increasing allele at the FTO locus was observed at higher frequency in males compared to females (OR 1.02 [1.02-1.03], P=4.4×10−36). Finally, we demonstrate how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Supplemental material, sj-pdf-1-pia-10.1177_0957650920930166 for Development and evaluation of a composite supercapacitor-based 12 V transient start–stop power system for vehicles: Modelling, design and fabrication scaling up by Chunhong Lei, Richard Fields, Peter Wilson, Constantina Lekakou, Negar Amini, Stephen Tennison, John Perry, Michele Gosso and Brunetto Martorana in Proceedings of the Institution of Mechanical Engineers, Part A: Journal of Power and Energy

Supplemental material, Sage_Open_Supplementary for Different Version, Similar Result? A Critical Analysis of the Multiplicity of Shortened Versions of the Zimbardo Time Perspective Inventory by John L. Perry, Elizabeth C. Temple, Frank C. Worrell, Urška Zivkovic, Zena R. Mello, Bojan Musil, Jon C. Cole and Michael T. McKay in SAGE Open

Supplemental material, sj-pdf-1-pia-10.1177_0957650920930166 for Development and evaluation of a composite supercapacitor-based 12 V transient start–stop power system for vehicles: Modelling, design and fabrication scaling up by Chunhong Lei, Richard Fields, Peter Wilson, Constantina Lekakou, Negar Amini, Stephen Tennison, John Perry, Michele Gosso and Brunetto Martorana in Proceedings of the Institution of Mechanical Engineers, Part A: Journal of Power and Energy

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.

Despite food choices being one of the most important factors influencing health, efforts to identify individual food groups and dietary patterns that cause disease have been challenging, with traditional nutritional epidemiological approaches plagued by biases and confounding. After identifying 302 (289 novel) individual genetic determinants of dietary intake in 445,779 individuals in the UK Biobank study, we develop a statistical genetics framework that enables us, for the first time, to directly assess the impact of food choices on health outcomes. We show that the biases which affect observational studies extend also to GWAS, genetic correlations and causal inference through genetics, which can be corrected by applying our methods. Finally, by applying Mendelian Randomization approaches to the corrected results we identify some of the first robust causal associations between eating patterns and risks of cancer, heart disease and obesity, distinguishing between the effects of specific foods or dietary patterns.

The global threat of antimicrobial resistance (AMR) requires coordinated actions by and across different sectors. Increasing attention at the global and national levels has led to different strategies to tackle the challenge. The diversity of possible actions to address AMR is currently not well understood from a One Health perspective. AMR-Intervene, an interdisciplinary social-ecological framework, describes interventions to tackle AMR in terms of six components: (i) core information about the publication; (ii) social system; (iii) bio-ecological system; (iv) triggers and goals; (v) implementation and governance; and (vi) assessment. AMR-Intervene provides a broadly applicable framework, which can inform the design, implementation, assessment and reporting of interventions to tackle AMR and, in turn, enable faster uptake of successful interventions to build societal resilience to AMR.

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as describedw previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

IMPORTANCE: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. OBJECTIVES: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). MAIN OUTCOME AND MEASURES: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. RESULTS: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. CONCLUSIONS AND RELEVANCE: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.

Progress identifying the genetic determinants of personality has historically been slow, with candidate gene studies and small-scale genome-wide association studies yielding few reproducible results. In the UK Biobank study, genetic variants in CADM2 and MSRA were recently shown to influence risk taking behavior and irritability respectively, representing some of the first genomic loci to be associated with aspects of personality. We extend this observation by performing a personality "phenome-scan" across 16 traits in up to 140,487 participants from 23andMe for these two genes. Genome-wide heritability estimates for these traits ranged from 5-19%, with both CADM2 and MSRA demonstrating significant effects on multiple personality types. These associations covered all aspects of the big five personality domains, including specific facet traits such as compliance, altruism, anxiety and activity/energy. This study both confirms and extends the original observations, highlighting the role of genetics in aspects of mental health and behavior.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Since its publication in 1921, The Teaching of English in England, otherwise known as the Newbolt Report, has informed both the shape of English as a school subject and the discourse about the teaching of English in England. The 1960s saw the report as promoting a cultural heritage rooted in outdated social values; the 1970s explored how it encouraged a version of personal growth through a love of literature. The 1980s returned to issues around social class, which were further developed in the 1990s. More recently there has been a limited reappraisal of the Newbolt Report, crediting it with introducing the modern discourse around English teaching. This paper argues that a deeper understanding of the Newbolt Report would allow teachers to become more engaged with the discourse about English teaching and re-connect this with their values.

Several occurrences of the word ‘schizophrenia’ have been re-worded as ‘liability to schizophrenia’ or ‘schizophrenia risk’, including in the title, which should have been “GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability,” as well as in Supplementary Figures 1–10 and Supplementary Tables 7–10, to more accurately reflect the findings of the work.

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Using a newly developed approach, we estimate that 20% of the UK Biobank male population (N=205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. Genetic susceptibility to LOY is associated with non-haematological health outcomes in both men and women, supporting the hypothesis that clonal haematopoiesis is a biomarker of genome instability in other tissues. Single-cell RNA sequencing identifies dysregulated autosomal gene expression in leukocytes with LOY, providing insights into how LOY may confer cellular growth advantage. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases.

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites., We are grateful to all families and participants who took part in these studies. We also acknowledge and appreciate the unique efforts of the research teams and practitioners contributing to the collection of this wealth of data. C. M. M. is supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 721567. J. F. F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). R. M. F. and R. N. B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). D. L. C. is funded by the American Diabetes Association Grant 1-17-PDF-077. D. O. M-K. was supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). N. M. W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). T. S. A. was partially funded by the Gene-Diet Interactions in Obesity (GENDINOB) project on behalf of GOYA male cohort data management and analyses and acknowledges the same. S. D. was supported by National Institute of Health Research. T. M. F. is supported by the European Research Council grant: 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).H.H.is funded by The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. A. T. H. is supported by the Wellcome Trust Senior Investigator Awards (WT098395), National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219). J. Hebebrand received grants from German Research Society, German Ministry of Education and Research. M-F. H. is currently supported by an American Diabetes Association (ADA) Pathway Program Accelerator Early Investigator Award (1-15-ACE-26). S. J. is supported by Helse Vest no. 23929, Bergen Forskningsstiftelse and KG Jebsen Foundation and University of Bergen. J. K. has been supported by the Academy of Finland Research Professor program (grants 265240 & 263278). J. P. K. is funded by a University of Queensland Development Fellowship (UQFEL1718945). H. L. has served as a speaker for Eli-Lilly and Shire and has received research grants from Shire; all outside the submitted work. C. M. L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). S. E. M. was funded by an NHMRC Senior Reseach Fellowship (APP1103623). K. Panoutsopoulou is funded by a career development fellowship (grant 20308) and by the Wellcome Trust (WT098051). C. P. at UCL Institute of Child Health, with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. I. P. was funded in part by the Wellcome Trust (WT205915), and the European Union's Horizon 2020 research, the European Union FP7-IDEAS-ERC Advanced Grant (GEPIDIAB, ERC-AG -ERC-294785), and innovation programme (DYNAhealth, H2020-PHC-2014-633595). R. C. R. is supported by CRUK (grant number C18281/A19169). J. G. S. is supported by an NHMRC Practitioner Fellowship Grant (APP1105807). J. T.; r is funded by the European Regional Development Fund (ERDF), the European Social Fund (ESF), Convergence Programme for Cornwall and the Isles of Scilly and the Diabetes Research and Wellness Foundation Non-Clinical Fellowship. N. V-T. is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B 00636), Generalitat de Catalunya. T. G. M. V was supported by ZonMW (TOP 40-00812-98-11010. J. F. W. is supported by the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease. H. Y. is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NL (CP2013-50). E. Z. is supported by the Wellcome Trust (098051). B. F. is supported by Novo Nordisk Foundation (12955) and an Oak Foundation Fellowship. S. S. and M-R. J. have received funding from the European Union's Horizon 2020 research and innovation programme [under grant agreement No 633595] for the DynaHEALTH action. P. R. N. was supported by the European Research Council (ERC), University of Bergen, KG Jebsen and Helse Vest. G. D. S. works within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1). D. A. L was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (Grant number 669545; DevelopObese), US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MC_UU_00011/6), Wellcome Trust GWAS grant (WT088806), an NIHR Senior Investigator Award (NF-SI-0611-10196) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L. Paternoster was supported by the UK Medical Research Council Unit grants MC_UU_12013_5. N. J. T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). D. M. E. is funded by the UK Medical Research Council Unit grant MC_UU_12013_4, Australian Research Council Future Fellowship (FT130101709) and a NHMRC Senior Research Fellowship (GNT1137714). S. F. A. G. is funded by the Daniel B. Burke Endowed Chair for Diabetes Research and R01 HD056465. D. I. B. is supported by Spinozapremie (NWO-56-464-14192) and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. M. I. M. is a Wellcome Senior Investgator and NIHR Senior Investigator supported by the Wellcome (090532, 098381, 203141), NIHR (NF-SI-0617-10090) and the US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MCiabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NLNIHR Biomedical Research Centre, Oxford. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Funding for this research was provided by the John Templeton Foundation, grant number 59023 Recent critiques of methodological naturalism (MN) claim that it fails by conflicting with Christian belief and being insufficiently humble. We defend MN by tracing the real history of the debate, contending that the story as it is usually told is mythic. We show how MN works in practice, including among real scientists. The debate is a red herring. It only appears problematic because of confusion among its opponents about how scientists respond to experimental anomalies. We conclude by introducing our preferred approach, Science‐Engaged Theology. Postprint

Recent critiques of methodological naturalism (MN) claim that it fails by conflicting with Christian belief and being insufficiently humble. We defend MN by tracing the real history of the debate, contending that the story as it’s usually told is mythic. We show how MN works in practice, including among real scientists. The debate is a red herring. It only appears problematic because of confusion among its opponents about how scientists respond to experimental anomalies. We conclude by introducing our preferred approach, Science-Engaged Theology.