Assessing the prediction of type 2 diabetes risk using polygenic and clinical risk scores in South Asian study populations.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRSAI) and Europeans (PRSEU) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRSAI and PRSEU) successfully predicted the T2D risk. However, the PRSAI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63-1.97; p = 1.6 × 10-152] and 12.2% OR 1.38 (95% CI 1.30-1.46; p = 7.1 × 10-237) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRSAI showed about two-fold OR 20.73 (95% CI 10.27-41.83; p = 2.7 × 10-17) and 1.4-fold OR 3.19 (95% CI 2.51-4.06; p = 4.8 × 10-21) higher predictability to identify subgroups with higher genetic risk than the PRSEU. Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRSAI and 0.72 to 0.75 in PRSEU. Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.

Plasma AGE and Oxidation Products, Renal Function, and Preeclampsia in Pregnant Women with Type 1 Diabetes: A Prospective Observational Study.

Aims: We aimed to determine whether plasma advanced glycation end products or oxidation products (AGE/oxidation-P) predict altered renal function and/or preeclampsia (PE) in pregnant women with type 1 diabetes. Methods: Prospectively, using a nested case-control design, we studied 47 pregnant women with type 1 diabetes, of whom 23 developed PE and 24 did not. Nineteen nondiabetic, normotensive pregnant women provided reference values. In plasma obtained at ~12, 22, and 32 weeks' gestation (visits 1, 2, and 3; V1-V3), we measured five AGE products (carboxymethyllysine (CML), carboxyethyl-lysine (CEL), methylglyoxal-hydroimidazolone (MGH1), 3-deoxyglucosone hydroimidazolone (3DGH), and glyoxal-hydroimidazolone (GH1)) and four oxidation products (methionine sulfoxide (MetSO), 2-aminoadipic acid (2-AAA), 3-nitrotyrosine (3NT), and dityrosine (DT)), by liquid chromatography/mass spectroscopy. Clinical outcomes were "estimated glomerular filtration rate" (eGFR) at each visit and onset of PE. Results: In diabetic women, associations between AGE/oxidation-P and eGFR were found only in those who developed PE. In this group, CEL, MGH1, and GH1 at V2 and CML, CEL, MGH1, and GH1 at V3 were inversely associated with contemporaneous eGFR, while CEL, MGH1, 3DGH, and GH1 at V2 were inversely associated with eGFR at V3 (all p < 0.05). There were no associations of plasma AGE or oxidation-P with pregnancy-related development of proteinuria or PE. Conclusions: Inverse associations of second and early third trimester plasma AGE with eGFR among type 1 diabetic women who developed PE suggest that these patients constitute a subset susceptible to AGE-mediated injury and thus to cardiorenal complications later in life. However, AGE/oxidation-P did not predict PE in type 1 diabetic women.

The Early Effects of the Coronavirus Disease-19 Pandemic on Pediatric Resident Education: A National Assessment.

PURPOSE: Residency programs must ensure resident competence for independent practice. The coronavirus disease-19 (COVID-19) pandemic disrupted health care delivery, impacting pediatric residencies. This study examines the impact on pediatric resident education. METHODS: The authors conducted a mixed methods national survey of pediatric residency program directors (PDs) from May 2020 to July 2020. Data analysis included descriptive statistics, chi-square, and Wilcoxon rank sum tests. Multivariable modeling identified factors associated with resident preparation for more senior roles. Thematic analysis was performed on open-ended questions about PD COVID-19 pandemic recommendations to peers, Accreditation Council for Graduate Medical Education and American Board of Pediatrics. RESULTS: Response rate was 55% (110/199). PDs reported the COVID-19 pandemic negatively affected inpatient (n = 86, 78.2%), and outpatient education (n = 104, 94.5%), procedural competence (n = 64; 58.2%), and resident preparation for more senior roles (n = 50, 45.5%). In bivariate analyses, increasingly negative impacts on inpatient and outpatient education were associated with an increasingly negative impact on resident preparation for more senior roles (P = .03, P = .008), these relationships held true in multivariable analysis. Qualitative analysis identified 4 themes from PD recommendations: 1) Clear communication from governing bodies and other leaders; 2) Flexibility within programs and from governing bodies; 3) Clinical exposure is key for competency development; 4) Online platforms are important for education, communication, and support. CONCLUSIONS: The COVID-19 pandemic negatively impacted inpatient and outpatient education. When these were more negatively impacted, resident preparation for more senior roles was worse, highlighting the importance of competency based medical education to tailor experiences ensuring each resident is competent for independent practice.

Exploring Factors Associated with Decisions about Feminizing Genitoplasty in Differences of Sex Development.

STUDY OBJECTIVE: Infants with genital development considered atypical for assigned female sex may undergo feminizing genitoplasty (clitoroplasty and/or vaginoplasty) in early life. We sought to identify factors associated with parent/caregiver decisions regarding genitoplasty for their children with genital virilization. DESIGN: Longitudinal, observational study SETTING: Twelve pediatric centers in the United States with multidisciplinary differences/disorders of sex development clinics, 2015-2020 PARTICIPANTS: Children under 2 years old with genital appearance atypical for female sex of rearing and their parents/caregivers INTERVENTIONS/OUTCOME MEASURES: Data on the child's diagnosis and anatomic characteristics before surgery were extracted from the medical record. Parents/caregivers completed questionnaires on psychosocial distress, experience of uncertainty, cosmetic appearance of their child's genitalia, and demographic characteristics. Urologists rated cosmetic appearance. For 58 patients from the study cohort with genital virilization being raised as girls or gender-neutral, we compared these data across 3 groups based on the child's subsequent surgical intervention: (i) no surgery (n = 5), (ii) vaginoplasty without clitoroplasty (V-only) (n = 15), and (iii) vaginoplasty and clitoroplasty (V+C) (n = 38). RESULTS: Fathers' and urologists' ratings of genital appearance were more favorable in the no-surgery group than in the V-only and V+C groups. Clitorophallic length was greater in the V+C group compared with the V-only group, with substantial overlap between groups. Mothers' depressive and anxious symptoms were lower in the no-surgery group compared with the V-only and V+C groups. CONCLUSIONS: Surgical decisions were associated with fathers' and urologists' ratings of genital appearance, the child's anatomic characteristics, and mothers' depressive and anxious symptoms. Further research on surgical decision-making is needed to inform counseling practices.

Association of Renin Angiotensin Aldosterone System Inhibitors and Outcomes of Hospitalized Patients With COVID-19.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. SUBJECTS: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19-1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03-1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81-0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20-1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.

Bone Mass Accrual in First Six Months of Life: Impact of Maternal Diabetes, Infant Adiposity, and Cord Blood Adipokines.

The perinatal period is a time of substantial bone mass accrual with many factors affecting long-term bone mineralization. Currently it is unclear what effect maternal gestational/type 2 diabetes has on infant bone mass accrual. This is a prospective study of offspring of Native American and Hispanic mothers with normoglycemia (n = 94) and gestational diabetes or type 2 diabetes (n = 64). Infant anthropometrics were measured at birth, 1, and 6 months of age. Cord blood leptin, high-molecular weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF), vascular epithelium growth factor (VEGF), endoglin, and C-peptide were measured by ELISA. Infants had bone mineral density measurement at 1 month or/and 6 months of age using dual-energy x-ray absorptiometry scan. Mothers with diabetes were older (31 ± 6 years vs 25 ± 4 years) and had higher pre-pregnancy BMI (32.6 ± 5.8 vs 27.2 ± 6.4 kg/m2) than control mothers. Mean HbA1C of mothers with diabetes was 5.9 ± 1.0% compared to 5.1 ± 0.3% in controls early in pregnancy. Infants born to mothers with diabetes (DM-O) were born at a slightly lower gestational age compared to infants born to control mothers (Con-O). There was no difference in total body less head bone mineral content (BMC) or bone mineral density (BMD) between DM-O and Con-O. For both groups together, bone area, BMD, and BMC tracked over the first 6 months of life (r: 0.56, 0.38, and 0.48, respectively). Percent fat was strongly and positively correlated with BMC at 1 month of age (r = 0.44; p < 0.001) and BMC at both 1 and 6 months of age correlated strongly with birth weight. There were no associations between infant bone mass and cord blood leptin, PEDF, or VEGF, while C-peptide had a significant correlation with BMC at 1 and 6 months only in DM-O (p = 0.01 and 0.03, respectively). Infants born to mothers with well-controlled gestational/type 2 diabetes have normal bone mass accrual. Bone mineral content during this time is highly correlated with indices of infant growth and the association of bone mineral indices with percent body fat suggests that bone-fat crosstalk is operative early in life.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Post-operative complications following masculinizing genitoplasty in moderate to severe genital atypia: results from a multicenter, observational prospective cohort study.

INTRODUCTION: Differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. A phenotype of severe genital atypia in patients raised as male is a relatively rare occurrence and standards for management are lacking. Decision making for early surgical planning in these rare cases includes, but is not limited to, degree of atypia, location of testes, and presence of Mϋllerian remnants. In this study we describe surgical approaches and short-term outcomes for masculinizing genitoplasty in moderate to severe genital atypia in young patients raised male, for whom parents opted for early surgery. METHODS: This NIH-sponsored study is an ongoing, observational, multicenter investigation assessing medical, surgical and psychological outcomes in children and their parents affected by atypical genitalia due to DSD. Participants were prospectively enrolled from 12 children's hospitals across the United States that specialize in DSD care. Criteria for child enrollment were a Quigley score of 3-6 in those with a 46, XY or 45,X/46, XY chromosome complement, age <3 years with no previous genitoplasty; patients were included independent of whether genitoplasty was performed. Cosmesis was graded according to a 4-point Likert scale and complications per the Clavian-Dindo classification. RESULTS: Of the 31 participants, 30 underwent hypospadias repair and 1 patient did not undergo a genitoplasty procedure. The majority of participants (22) received a staged hypospadias repair. Seventeen complications were identified in 12 of the 31 children (41%) at 12 months of follow up. Glans dehiscence and urethrocutaneous fistula were the most common complications. Orchiopexy was performed in 14 (44%) and streak gonads were removed in 4 (13%) participants. Both parents and surgeons reported improved cosmesis after surgery when compared to baseline. CONCLUSION: Genitoplasty was chosen by parents for the majority of children eligible for study. No single surgical approach for masculinizing moderate to severe genital ambiguity in young patients with 46, XY or 45,X/46, XY DSD was adopted by all surgeons. Complications occurred in 41% of those who underwent genitoplasty for severe hypospadias. Overall, appearance of the genitals, as determined by parents and surgeons, improved following genitoplasty. Outcomes of early genitoplasty are needed to guide families when making decisions about such procedures for their young children.

Illness Uncertainty Longitudinally Predicts Distress Among Caregivers of Children Born With DSD.

OBJECTIVE: A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child's DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child's DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. METHODS: One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measures at baseline, 6 and 12 months following genitoplasty, or study entry if parents elected not to have surgery for their child. RESULTS: Caregiver illness uncertainty and both anxious and depressive symptoms were highest at baseline and decreased over time (ps < .05). Caregiver illness uncertainty predicted symptoms of anxious and depressive symptoms across all time points (ps < .05). CONCLUSIONS: Caregivers' perceptions of uncertainty about their child's DSD are highest soon after diagnosis, and uncertainty continues to predict both anxious and depressive symptoms across time. Thus, the initial diagnostic period is a critical time for psychological assessment and intervention, with parent illness uncertainty being an important clinical target.

The Role of GnRH Receptor Autoantibodies in Polycystic Ovary Syndrome.

OBJECTIVE: Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? DESIGN AND METHODS: We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. RESULTS: The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P < .01) the elevated GnRHR activity induced by IgG from 7 PCOS patients while the IgG activity level from 7 OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, 3 had normal or low activity while 2 had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The copresence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left (P < .01). CONCLUSIONS: GnRHR-ECL2-AAb are significantly elevated in patients with PCOS compared with NCs. Their presence raises important etiological, diagnostic, and therapeutic implications.

Post-operative complications following feminizing genitoplasty in moderate to severe genital atypia: Results from a multicenter, observational prospective cohort study.

Disorders/differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. While there remains controversy around the traditionally binary concept of sex, most patients with DSD are reared either male or female depending on their genetic sex, gonadal sex, genital phenotype and status of their internal genital tract. This study uses prospective data from 12 institutions across the United States that specialize in DSD care. We focused on patients raised female. Eligible patients had moderate to severe genital atypia (defined as Prader score >2), were ≤2 years of age at entry, and had no prior genitoplasty. The aim of this study is to describe early post operative complications for young patients undergoing modern approaches to feminizing genitoplasty. Of the 91 participants in the cohort, 57 (62%) were reared female. The majority had congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (n = 52), 1 had ovo-testicular syndrome, 2 had mixed gonadal dysgenesis and 2 had partial androgen insensitivity syndrome (PAIS). Of the 50 participants who received early genitoplasty, 43 (86%) had follow-up at 6-12 months post-surgery. Thirty-two participants (64%) received a clitoroplasty, 31 (62%) partial urogenital mobilization and 4 (8%) total urogenital sinus mobilization. Eighteen percent (9/50) experienced post-surgical complications with 7 (14%) being rated as Clavien-Dindo grade III. Both parents and surgeons reported improved satisfaction with genital appearance of participants following surgery compared to baseline. This information on post-operative complications associated with contemporary approaches to feminizing genitoplasty performed in young children will help guide families when making decisions about whether or not to proceed with surgery for female patients with moderate to severe genital atypia.

Vitamin D Metabolites and Binding Protein Predict Preeclampsia in Women with Type 1 Diabetes.

The risk for preeclampsia (PE) is enhanced ~4-fold by the presence of maternal type 1 diabetes (T1DM). Vitamin D is essential for healthy pregnancy. We assessed the total, bioavailable, and free concentrations of plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D binding protein (VDBP) at ~12, ~22, and ~32 weeks' gestation ("Visits" (V) 1, 2, and 3, respectively) in 23 T1DM women who developed PE, 24 who remained normotensive, and 19 non-diabetic, normotensive women (reference controls). 25(OH)D deficiency was more frequent in diabetic than non-diabetic women (69% vs. 22%, p < 0.05), but no measure of 25(OH)D predicted PE. By contrast, higher 1,25(OH)2D concentrations at V2 (total, bioavailable, and free: p < 0.01) and V3 (bioavailable: p < 0.05; free: p < 0.01), lower concentrations of VDBP at V3 (p < 0.05), and elevated ratios of 1,25(OH)2D/VDBP (V2, V3: p < 0.01) and 1,25(OH)2D/25(OH)D (V3, p < 0.05) were all associated with PE, and significance persisted in multivariate analyses. In summary, in women with T1DM, concentrations of 1,25(OH)2D were higher, and VDBP lower, in the second and third trimesters in women who later developed PE than in those who did not. 1,25(OH)2D may serve as a new marker for PE risk and could be implicated in pathogenesis.

Occurrence of Listeria monocytogenes in Ready-to-Eat Meat and Poultry Product Verification Testing Samples from U.S. Department of Agriculture-Regulated Producing Establishments, 2005 through 2017.

ABSTRACT: Ready-to-eat (RTE) meat and poultry product samples collected between 2005 and 2017 from RTE-producing establishments for the U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) ALLRTE/RTEPROD_RAND (random) and RTE001/RTEPROD_RISK (risk-based) sampling projects were tested for Listeria monocytogenes (Lm). Data for 45,897 ALLRTE/RTEPROD_RAND samples collected from 3,607 distinct establishments and 112,347 RTE001/RTEPROD_RISK samples collected from 3,283 distinct establishments were analyzed for the presence of Lm. These data were also analyzed based upon the percentages of establishments with positive samples, annual production volume, sanitation control alternatives, geographic location, and season or month of sample collection. Results revealed low occurrence of Lm-positive samples from the random and risk-based sampling projects, with 152 (0.33%) positive samples for ALLRTE/RTEPROD_RAND and 403 (0.36%) positive samples for RTE001/RTEPROD_RISK. The percentage of positive samples significantly decreased over time, from about 0.7% in 2005 and 2006 to about 0.2% in 2017 (P < 0.05). From 2005 to 2017, 3.9% of establishments sampled under the ALLRTE/RTEPROD_RAND sampling project had at least one Lm-positive sample. Similarly, 10.0% of establishments sampled under the RTE001/RTEPROD_RISK sampling project had at least one positive sample. Samples positive for Lm were found in all geographic regions in all months. Thus, in 13 years of RTE product sampling in FSIS-regulated establishments (2005 through 2017), <0.4% of samples were positive for Lm in both risk-based and random sampling projects. The low prevalence of Lm in these products suggests that the combination of FSIS policies and industry practices may be effective for controlling Lm contamination. Information obtained from these sampling projects is relevant to the ongoing prevention of foodborne Lm illnesses from RTE meat and poultry products.

Elevated activity levels of activating autoantibodies to the GnRH receptor in patients with polycystic ovary syndrome.

OBJECTIVES: 1) To confirm the correlation of GnRH receptor (GnRHR) activating autoantibody (AAb) activity with polycystic ovary syndrome (PCOS) diagnosis in large well defined cohorts; and 2) to evaluate suppression of AAb activity with GnRH antagonist medication in transfected GnRHR cells exposed to serum of PCOS patients. DESIGN: Cross-sectional matched case-control study. SETTING: University-based research facility. PATIENTS: Sera from 200 patients with PCOS from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial and from 200 race, parity-, age-, and body mass index (BMI)-matched ovulatory unexplained infertile control patients from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) trial were obtained and used for this study. INTERVENTIONS: GnRHR AAb activity was determined with the use of the GeneBlazer cell-based fluorescence resonance energy transfer assay with and without cetrorelix, a GnRH antagonist. MAIN OUTCOME MEASURES: 1) GnRHR AAb activity in PCOS patients compared with control subjects; and 2) effectiveness of GnRH antagonist in suppressing GnRHR AAb activity. RESULTS: GnRHR AAb activity levels in the PCOS group were significantly higher than in the control group. With cetrorelix, GnRHR AAb activity was largely suppressed in the PCOS group but not in the control group. These differences remained significant after adjusting for within-pair differences in age, BMI, and antimüllerian hormone (AMH) levels. CONCLUSIONS: We confirmed higher GnRHR AAb activity levels in the sera of a large cohort of PCOS patients compared with unexplained infertile control subjects. Addition of cetrorelix resulted in significant suppression of AAb activity levels in PCOS patients as a group whereas control subjects were unaffected. GnRHR AAb, along with patient age and AMH level, may provide a promising future diagnostic test for PCOS.

Incidence of Epinephrine Reactions With Local Anesthesia in Mohs Micrographic Surgery.

BACKGROUND: The incidence of reactions to epinephrine-containing local anesthetics in Mohs micrographic surgery (MMS) has not been established. OBJECTIVE: To estimate the incidence of epinephrine-induced reactions from local anesthetics in patients who undergo MMS for the removal of cutaneous malignancies. METHODS: From 2016 to 2018, 200 MMS patients were recruited from the authors' surgical center. Assessments were obtained throughout the entirety of the Mohs cases during a single visit. RESULTS: This study estimated the incidence of epinephrine reactions in patients who undergo MMS to be 2.0% (95% confidence interval: 0.1%-3.9%). No relationship between epinephrine dose and incidence of adverse effects was found. Patient age was a significant risk factor for the development of an epinephrine reaction. CONCLUSION: Systemic reactions to epinephrine from local anesthetics are an infrequent adverse event in MMS cases. The data suggest that the absolute dose of local anesthetic with epinephrine does not correlate with the risk of developing an epinephrine reaction. Older age seems to have a protective effect.

Validation of apixaban anti-factor Xa assay and impact of body weight.

BACKGROUND: Direct oral anticoagulants (DOACs) are widely used as therapies for venous thromboembolism and other cardiovascular diseases. However, routine coagulation monitoring is not required, but may be clinically indicated in high risk populations including obese patients. OBJECTIVES: The aims of this study were two fold; to validate a chromogenic assay for anti-factor Xa measurement in patients taking apixaban, and correlate it with PT/INR and PTT, and to measure anti-factor Xa levels in patients who weighed >120 kg. PATIENTS/METHODS: Patients who were taking apixaban had 3 blood samples drawn over a 4 h period. Apixaban levels were determined using an anti-factor Xa activity assay (STA-Liquid Anti-Xa) using STA-Apixaban Calibrator and STA-Apixaban Controls. The PT/INR was determined using standard methodology. Apix MS, using manufacturer provided apixaban standard, was performed on plasma. RESULTS AND CONCLUSIONS: 18 normal weight patients, 39 obese patients and 14 controls were enrolled. There was a strong correlation between apixaban anti-factor Xa activity compared to plasma Apix MS (r = 0.95). In patients >120 kg, there was a statistically significant decreased rate of change in anti-factor Xa levels after ingestion. Further, the area under the curve for apixaban anti-factor Xa levels was significantly lower in patients over 120 kg. While INR correlated with apixaban MS and apixaban anti-factor Xa activity in both normal weight and obese patients, the association was not sufficiently strong to clinically manage patients, normal weight or obese. Given these findings, research is necessary to investigate the clinical utility of apixaban anti-factor Xa activity measurement in selected populations.

Predictors of Psychosocial Distress in Parents of Young Children with Disorders of Sex Development.

PURPOSE: We evaluated demographic, financial and support predictors of distress for parents of young children with disorders of sex development including atypical genital development, and characterized early parental experiences. This work extends our previous findings to identify those parents at risk for distress. MATERIALS AND METHODS: Participants included mothers (76) and fathers (63) of a child (78) diagnosed with disorders of sex development characterized by moderate to severe genital atypia. Parents completed a demographic questionnaire, measures of anxious and depressive symptoms, quality of life, illness uncertainty and posttraumatic stress symptoms, and rated their satisfaction with the appearance of their child's genitalia. RESULTS: Depressive and posttraumatic stress symptoms of caregivers were comparable to standardized norms while levels of anxious symptoms were below norms. A subset of parents reported clinically elevated symptoms. Overall 26% of parents reported anxious symptoms, 24% reported depressive symptoms and 17% reported posttraumatic stress symptoms. Levels of illness uncertainty were lower than those of parents of children with other chronic illnesses. Differences by parent sex emerged, with mothers reporting greater distress. Lower income, increased medical care and travel expenses, and having no other children were related to increased psychosocial distress. CONCLUSIONS: Early psychosocial screening is recommended for parents of children with disorders of sex development. Clinicians should be aware that financial burden and lack of previous parenting experience are risk factors for distress.

Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women With Type 1 Diabetes.

CONTEXT: The incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease. OBJECTIVE: To investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks. DESIGN AND SETTING: Multicenter prospective study of T1DM pregnancy. PATIENTS: Pregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks' gestation (mean ± SD). MAIN OUTCOME MEASURES: Hp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE. RESULTS: Hp phenotype did not predict PE, but lipoprotein associations with subsequent PE were confined to women with Hp 2-2, in whom the following associations with PE were observed: increased low-density lipoprotein (LDL) cholesterol, LDL particle concentration, apolipoprotein B (APOB), triacylglycerol/high-density lipoprotein (HDL) cholesterol ratio, and APOB/apolipoprotein AI (APOA1) ratio; decreased HDL cholesterol, APOA1, large HDL particle concentration, and peripheral lipoprotein lipolysis (all P < 0.05). In women with one or two Hp-1 alleles, no such associations were observed. CONCLUSIONS: In women with T1DM, although Hp phenotype did not predict PE risk, lipoprotein-related risks for PE were limited to those with the Hp 2-2 phenotype. Hp phenotype may modulate PE risk in diabetes.