Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Primary weight loss failure after Roux-en-Y gastric bypass is characterized by impaired gut-hormone mediated regulation of food intake.

BACKGROUND/OBJECTIVES: After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure. SUBJECTS/METHODS: Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting. RESULTS: On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]). CONCLUSIONS: Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

Sequencing and de novo assembly of 150 genomes from Denmark as a population reference.

Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.

Postpartum pelvic floor muscle training, levator ani avulsion and levator hiatus area: a randomized trial.

INTRODUCTION AND HYPOTHESIS: Vaginal delivery may lead to tearing of the levator ani (LA) muscle from its bony insertions (complete LA avulsion) and increased levator hiatus (LH) area, both risk factors for pelvic floor dysfunctions. Early active rehabilitation is standard treatment after musculo-skeletal injury. We hypothesized that pelvic floor muscle training (PFMT) early postpartum would reduce the presence of LA avulsions and reduce LH area. METHODS: We carried out a planned secondary analysis from a randomized controlled study. Primiparous women (n=175) giving birth vaginally were included 6 weeks postpartum, stratified on complete LA avulsion, and thereafter randomized to PFMT or control. The training participants (n=87) attended a supervised PFMT class once a week and performed home-based PFMT daily for 16 weeks. The control participants (n=88) received no intervention. Presence of complete LA avulsion, LH area at rest, maximal contraction, and maximal Valsalva maneuver were assessed by transperineal ultrasound. Between-group comparisons were analyzed by analysis of covariance for continuous data, and relative risk (RR) for categorical data. RESULTS: Six months postpartum, the number of women who had complete LA avulsion was reduced from 27 to 14 within the PFMT group (44% reduction) and from 28 to 17 within the control group (39% reduction). The between-group difference was not significant, RR 0.85 (95% CI 0.53 to 1.37). Further, no significant between-group differences were found for LH area at rest, during contraction, or Valsalva. CONCLUSIONS: Supervised PFMT class combined with home exercise early postpartum did not reduce the presence of complete LA avulsion or LH area more than natural remission.

Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB.

BACKGROUND: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. OBJECTIVE: We sought to identify genetic interaction associated with the development of childhood asthma. METHODS: We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. RESULTS: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. CONCLUSIONS: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Pelvic floor symptoms from first pregnancy up to 8 years after the first delivery: a longitudinal study.

BACKGROUND: Despite the strong association between vaginal childbirth and pelvic floor dysfunction, genetic factors, pregnancy, advancing age, and lifestyle also play a role. The pelvic floor undergoes substantial changes during pregnancy, which may contribute to pelvic floor dysfunction. Conversely, these changes may be favorable for vaginal delivery. However, there is a lack of studies assessing pelvic floor symptoms over time according to delivery mode and including predelivery assessment. OBJECTIVE: This study aimed to describe urinary incontinence, vaginal symptoms, and bowel control symptoms from 21 weeks of gestation in the first pregnancy up to 8 years after the first delivery, stratified by delivery mode. STUDY DESIGN: This was a longitudinal observational cohort study. A total of 300 nulliparous women were recruited during their first pregnancy. Pelvic floor symptoms were assessed at 21 and 37 weeks of gestation, and at 6 weeks, 6 months, 12 months, and 8 years after first delivery using the International Consultation on Incontinence Questionnaire modules: the urinary incontinence sum score, the weighted vaginal symptom sum score, the vaginal-associated quality of life score, the bowel control sum score, and the bowel-associated quality of life sum score. Delivery mode at first delivery defined delivery groups as: normal vaginal, operative vaginal, and cesarean delivery. A linear mixed-model analysis was used to assess symptom scores over time and differences in symptom scores between the delivery groups. RESULTS: Of the 300 women included in the study, 193 attended the 8-year follow-up. Pelvic floor symptoms differed between women who had vaginal delivery and those who had cesarean delivery. The symptom scores showed a nonlinear statistically significant trend. In women who delivered vaginally, there was an increase of urinary incontinence and vaginal symptom scores already during pregnancy. In women who later delivered by cesarean, there was a decrease of symptom scores during pregnancy, and overall lower symptom scores relative to women who had vaginal delivery at 12 months after the first delivery. Pelvic floor symptom scores increased from 12 months to 8 years after the first delivery and exceeded pregnancy levels in all delivery groups; however, overall symptom scores were low. Differences between delivery groups were not statistically significant. CONCLUSION: Pelvic floor symptoms differed between women who had vaginal delivery and those who had cesarean delivery from the first pregnancy up to 8 years after the first delivery. These differences were already recognizable before the first delivery.

Recovery of pelvic floor muscle strength and endurance 6 and 12 months postpartum in primiparous women-a prospective cohort study.

INTRODUCTION AND HYPOTHESIS: To date there has been scant knowledge on the natural recovery of the pelvic floor muscles (PFMs) after childbirth. The aims of the present study were to investigate whether PFM variables at 6 and 12 months postpartum had returned to mid-pregnancy levels and assess risk factors for reduced recovery at 12 months postpartum. METHODS: This was a prospective cohort study following 235 nulliparous pregnant women from mid-pregnancy to 12 months postpartum. Vaginal resting pressure (VRP), PFM strength and endurance were assessed by manometry at 22 weeks, 6 and 12 months postpartum. Multiple linear regression was used to address factors influencing PFM variables beyond birth mode. RESULTS: Cesarean section was protective for change in PFM variables. From mid-pregnancy to 12 months postpartum there was a 20% reduction in VRP (p<0.001) and a 7.5 % reduction in PFM strength (p=0.007), and an increase of 9% in PFM endurance (p=0.002) in the normal vaginal birth. The instrumental vaginal group had a decline in VRP of 21% (p<0.001) and PFM strength of 15% (p=0.011), but no significant change in PFM endurance. Higher BMI at 12 months postpartum, longer second stage of labor, and major tears of the levator ani muscle had a negative influence on the PFM recovery beyond delivery mode. CONCLUSIONS: At 12 months postpartum following vaginal delivery, the PFMs are not fully recovered compared with mid-pregnancy values. More follow-up physical therapy may be warranted in the postpartum period, especially for women with complicated vaginal births and higher BMI.

Sociodemographic characterisation of antibiotic heavy users in the Danish elderly population.

AIMS: The development of effective interventions to reduce inappropriate use of antibiotics in the elderly population requires knowledge on who can benefit from such interventions. Thus, we aimed to identify and characterise antibiotic heavy users among elderly patients in general practice with respect to sociodemographic variables. METHODS: We conducted a retrospective nationwide register-based study on all Danish elderly citizens (⩾65 years) who redeemed an antibiotic prescription in 2017. Heavy users were defined as the 10% with the highest excess use, that is, their recorded use minus the average use for their sex, age group and comorbidity level as estimated from a linear regression model. Comparative analyses of sociodemographic characteristics (civil status, employment status, urbanity, educational level and country of origin) of heavy users and non-heavy users were performed using logistic regression models. RESULTS: The study population consisted of 251,733 elderly individuals, who in total redeemed 573,265 prescriptions of antibiotics. Heavy users accounted for 68% of all excess use of antibiotics. In multivariable analyses, individuals with an educational level above basic schooling, non-retired, residing in an urban municipality and being born in a country outside Scandinavia all had lower odds of being a heavy user. Widowed, divorced or single individuals had higher odds of being a heavy user compared with married individuals. Relative importance analyses showed that civil status and educational level contributed considerably to the explained variance. CONCLUSIONS: This study found an association between sociodemographic characteristics and risk of being a heavy user, indicating that sociodemographic variation exists with regard to antibiotic prescribing.

A Framework for Standardizing Emergency Nursing Education and Training Across a Regional Health Care System: Programming, Planning, and Development via International Collaboration.

INTRODUCTION: The challenges related to providing continuing education and competence management for emergency nurses are not unique to any one organization, health system, or geographic location. These shared challenges, along with a desire to ensure high-quality practice of emergency nursing, were the catalyst for an international collaboration between emergency nurse leaders in Region Zealand, Denmark, and nurse leaders and educators from a large academic medical center in Boston, Massachusetts. The goal of the collaboration was to design a competency-based education framework to support high-quality emergency nursing care in Region Zealand. The core objectives of the collaboration included the following: (1) elevation of nursing practice, (2) development of a sustainable continuing education framework, and (3) standardization of training and nursing practice across the 4 emergency departments in Region Zealand. METHODS: To accomplish the core objectives, a multi-phased strategic approach was implemented. The initial phase, the needs assessment, included semi-structured interviews, a self-evaluation of skills of all regional emergency nurses, and a survey regarding nursing competency completed by emergency nurse leadership. Two hundred ninety emergency nurses completed the self-evaluation. The survey results were utilized to inform the strategic planning and design of a regional competency-based education framework. RESULTS: In 18 months, and through an international collaboration, emergency nursing education, training, and evaluation tools were developed and integrated into the 4 regional emergency departments. Initial feedback indicates that the education has had a positive impact. The annual competency day program has continued through 2021 and is now fully institutionalized within the regional emergency nursing continuing education program. Furthermore, use of this innovative education framework has expanded beyond the emergency department to other regional nursing specialties. DISCUSSION AND CONCLUSION: Through this unique collaboration with regional and international participants, a sustainable, regional emergency nursing education program was developed that has elevated and standardized the practice of emergency nurses in Region Zealand, Denmark. This program development can serve as a model for region-wide or health care system-wide collaborations in other countries.

Scleroderma en Coup de Sabre, Parry-Romberg Hemifacial Atrophy and Associated Manifestations of the Eye, the Oral Cavity and the Teeth: A Danish Follow-Up Study of 35 Patients Diagnosed between 1975 and 2015.

BACKGROUND: Scleroderma en coup de sabre (ECDS) and Parry-Romberg idiopathic hemifacial atrophy (IHA) may affect the eyes, oral cavity, teeth and possibly the brain. OBJECTIVE: Systematic follow-up study of ECDS/IHA-associated manifestations including ophthalmic and dental status. METHODS: Medical records of ECDS and IHA patients diagnosed in a 40-year period (1975-2015) were reviewed, and patients were re-examined. RESULTS: Thirty-five patients were included. Twenty-two patients (63%) had ECDS and 4 patients (11%) IHA. In 9 cases (26%), ECDS and IHA were found in the same patient. The ipsilateral eye was affected in 9 patients (26%). Ipsilateral abnormalities of the teeth and the tongue were found in 13 (46%) out of 28 examined. Eleven (31%) had extrafacial scleroderma on the trunk or the extremities. Neurological findings were not verified as ECDS/IHA related. CONCLUSION: ECDS and IHA are related and often overlap with concomitant affections of the connective tissues of the face on the ipsilateral side. Ocular and dental abnormalities are common and follow the distribution of the primary affection, for example, a paramedian line in the front and segmental affection of the maxilla and the mandible. The affections point to predisposing dysmorphogenetic events in embryonal life affecting the face, with abnormality of crest cells at the stage when they migrate from behind over the scalp or laterally to the face to mix up with mesenchymal tissues of the frontonasal, maxillary and mandibular processes. The study emphasizes that routine evaluation of ECDS and IHA should include ophthalmological and dental specialist examinations.

Antibiotic prescribing in Danish general practice in the elderly population from 2010 to 2017.

OBJECTIVE: This study aimed to describe prescription of antibiotics to the elderly population in general practice in Denmark from 2010-2017. DESIGN: This is a national register-based observational study. SETTING: General practice, Denmark. MAIN OUTCOME MEASURE: The main outcome measure was prescriptions/1,000 inhabitants/day (PrID) in relation to year, age and sex, indication, and antibiotic agent. SUBJECTS: In this study, we included inhabitants of Denmark, ≥65 years of age between 01st July 2010-30th June 2017. RESULTS: A total of 5,168,878 prescriptions were included in the study. Antibiotic prescriptions decreased from 2.2 PrID to 1.7 (-26.9%, CI95% [-31.1;-22.4]) PrID during the study. The decrease in PrID was most noticeable among 65-74-year-olds (-25%). The ≥85-year-olds were exposed to twice as many PrID than the 65-74-year-olds, but only accounted for 20% of the total use. Urinary tract infection (UTI) was the most common indication for antibiotic prescription and increased with advancing age. The most commonly prescribed antibiotics were pivmecillinam and phenoxymethylpenicillin. Prescribing with no informative indication was present in one third of all cases. CONCLUSION: The prescription of antibiotics in the elderly population in general practice decreased from 2010 to 2017. The oldest age group was exposed twice as frequently to antibiotic prescriptions as the 65-74-year-olds. The smallest reduction was observed for the ≥85-year-olds, suggesting targeting interventions at this group.Key PointsHigh antibiotic use among elderly is well known and studies indicate mis- and overuse within this population. Our study shows.The prescription rate is decreasing within all age groups of the elderly population.The ≥85-year-olds receive twice as many prescriptions/1000/day as the 65-74-years-olds.

Change in prevalence of major levator ani muscle defects from 6 weeks to 1 year postpartum, and maternal and obstetric risk factors: A longitudinal ultrasound study.

INTRODUCTION: The present study aimed first to investigate the change in prevalence of major levator ani muscle (LAM) defects, also called avulsions, from 6 weeks to 1 year postpartum, and second to assess maternal and obstetric risk factors for having persistent major LAM defects/avulsions at 1 year postpartum. MATERIAL AND METHODS: This is a secondary analysis of data from a prospective cohort study including 300 nulliparous women at 17-19 weeks of gestation. Major LAM defects were diagnosed at 6 weeks and 1 year postpartum using transperineal ultrasonography. We defined persistent major LAM defects as a defect diagnosed both at 6 weeks and 1 year postpartum. Maternal and obstetric data were obtained from the hospital's electronic birth records. Pelvic floor muscle function was measured vaginally by manometer at 21 weeks of gestation. The main outcome measurement was change in prevalence of major LAM defects. Maternal and obstetric risk factors for having persistent major LAM defect were also assessed. RESULTS: Prevalence of major LAM defects was 19.4% at 6 weeks and 10.4% at 1 year postpartum. No new major LAM defects were diagnosed at 1 year postpartum. Persisting major LAM defects were associated with longer second stage of labor (median 74.5 minutes vs median 48.0 minutes, P = .012) and higher neonatal birthweight (mean difference of 232.3 g, 95% confidence interval [CI] 21.5-443.1). Vacuum delivery was independently associated with persistent major LAM defects, adjusted OR 3.0 (95% CI 1.0-9.0). CONCLUSIONS: There was a 50% reduction of sonographically diagnosed major LAM defects from 6 weeks to 1 year postpartum. This finding suggests that assessment of the major LAM 6 weeks postpartum may be too early to diagnose defects/avulsions. Long second stage of labor, high neonatal birthweight and vacuum delivery were associated with persistent major LAM defects/avulsions.

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.

AIMS/HYPOTHESIS: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. METHODS: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, ß = 0.27, p = 1.3 × 10-11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10-4, ß with diabetes = 0.69, ß without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10-6). CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Risk factors for anatomic pelvic organ prolapse at 6 weeks postpartum: a prospective observational study.

INTRODUCTION AND HYPOTHESIS: The objective was to identify risk factors for postpartum anatomic pelvic organ prolapse (aPOP) by comparing women with and without aPOP at 6 weeks postpartum with regard to pelvic floor measurements antepartum and obstetrical characteristics. METHODS: We carried out a prospective observational cohort study including nulliparous pregnant women in a Norwegian university hospital. Participants underwent clinical examinations, including pelvic organ prolapse quantification system (POP-Q) and transperineal ultrasound at gestational week 21 and at 6 weeks postpartum. Background and obstetrical information was obtained from an electronic questionnaire and from the patient's electronic medical file respectively. Associations were estimated using logistic regression analyses. The dependent variable was aPOP, defined as POP-Q stage ≥2 at 6 weeks postpartum. Independent variables were mid-pregnancy measurements of selected POP-Q variables and levator hiatus area (LHarea), delivery route, and the presence of major levator ani muscle (LAM) injuries at 6 weeks postpartum. RESULTS: A larger LHarea, a more distensible LAM, a longer distance from the meatus urethra to the anus (Gh + Pb) and a more caudal position of the anterior vaginal wall (Ba) at mid-pregnancy were risk factors for aPOP at 6 weeks postpartum, whereas delivery route and the presence of major LAM injuries were not. CONCLUSION: Prelabor differences in the pelvic floor rather than obstetrical events were risk factors for aPOP at 6 weeks postpartum.

Comparison of antibiotic prescribing and antimicrobial resistance in urinary tract infections at the municipal level among women in two Nordic regions.

Objectives: To describe and compare the prescribing of antibiotics used for urinary tract infections and its correlation with resistance in Escherichia coli in urinary samples across two adjacent regions-the Capital Region and the Skaane Region-and their municipalities in Denmark and Sweden. Methods: The Capital Region consists of 29 municipalities and 725 960 female inhabitants aged ≥18 years and the Skaane Region consists of 33 municipalities and 515 668 female inhabitants aged ≥18 years. Aggregated data from outpatient care on the prescribing of pivmecillinam, trimethoprim and nitrofurantoin from both regions were analysed. The Department of Clinical Microbiology in both regions provided data on E. coli resistance in urinary samples from women aged ≥18 years. Data were measured as the number of prescriptions/1000 women/year, number of DDDs/1000 women/year and DDDs/prescription. Correlation analyses between antibiotic prescribing and antibiotic resistance rates were performed. Results: Antibiotic prescribing and resistance rates were significantly higher in the Capital Region compared with the Skaane Region. Large variations in prescription and resistance rates were found at the municipal level, but there were no correlations between the antibiotic prescription and resistance rates when each region was analysed separately. Conclusions: Although closely related, there are large differences in antibiotic prescribing and antibiotic resistance. It is suggested that the regional guidelines are an important driver and explanatory factor for the variations; however, further research is needed in this new field and factors such as the influence of cultural aspects should be the target of further research.

Correction to: Association between vaginal bulge and anatomical pelvic organ prolapse during pregnancy and postpartum: an observational study.

The last paragraph of the "Interpretation" section contains an error.