Introduction The COVID-19 pandemic has had an unprecedented ef- fect on hospital systems. Policy changes lead to de- creased hospital visits as well as surgical case volume. The literature on pediatric surgical case volume during the pandemic is sparse. Throughout the country, hospitals sought various policies to preserve personal protective equipment and other hospital resources, and to minimize avoidable peri- and postoperative sequelae due to COVID-19 infection. Our hospital first placed a hold on all elective surgeries. Later, all elective cases required a preoperative negative COVID test prior to proceed- ing. We sought to review the sequelae of our hospital’s policy in response to COVID-19. We identified trends in surgical case volume and cancellations due to a positive COVID-19 test. We also reviewed postoperative out- comes of cases with a positive test. Material and Methods This study was approved by the institutional IRB. Data was retrospectively collected on all surgical cases at our children’s hospital between March 2019 and March 2021. We marked the start of the COVID-19 pandemic as March 2020, when elective cases were suspended. A required preoperative negative COVID-19 test was im- plemented in May 2020. We identified pre-operative COVID-19 test results,the posted urgency of each case and 30-day outcomes from medical records. Results From March 2019 to March 2021, we identified 25,496 completed surgeries and 3,503 cancellations. 12,024 ca- ses proceeded during the first year of the pandemic, which appeared lower, compared to pre-pandemic case numbers. Of those, 2,785 (23%) cases were considered urgent or emergent. The average number of completed monthly cases fell from a pre-pandemic number of 1,123 to a pandemic number of 925. When comparing to a pre- pandemic month, average monthly case volume declined by 19%, with the largest decline noted to be 66%. There was a monthly average of 189 total cancellations between March 2020 and March 2021. 34 (18%) of those were for a positive preoperative COVID test. A total of 139 sur- geries commenced despite concomitant COVID-19 in- fection. 25 (18 %) had identifiable respiratory symptomsdocumented preoperatively. 13 (9 %) were deemed to have a respiratory complication afterward. Of those, three patients (2%) had a prolonged, and one (1%) had an unexpected reintubation. The remaining nine (6%) pa- tients had a prolonged oxygen requirement. Conclusion The COVID pandemic left operating rooms struggling to determine how to safely provide care to patients. This study demonstrated how the policies of one hospital af- fected the operating room case volume and how conco- mitant COVID infection affected outcomes in those that proceeded with surgery.

Information regarding the prevalence and risk of osteoporosis among American Indian (AI) women is limited. This study showed that with increasing AI blood quantum, the prevalence of osteoporosis at the hip based on BMD T-scores decreased and this appeared to be independent of other risk factors.

Introduction Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. Objective The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. Study design This 11-site, prospective study included children aged <= 2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. Results Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. Discussion In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. Conclusion In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management.

To evaluate the stability over time of recently identified gonadotropin-releasing hormone receptor autoantibodies (GnRHR-AAbs) found in the serum of infertile patients with polycystic ovary syndrome (PCOS). Our assay may hold promise in future diagnostic testing for PCOS, however currently no data exists regarding antibody level stability. Case series. Serum samples from a convenience sample of seven women with PCOS and infertility were assessed for GnRHR-AAbs levels over multiple time points (17 total) spanning, on average, a two year timeframe for all patients. All timepoints represent baseline AAb levels as the patients were not on hormonally modulating medications at the seleted times. The de-identified samples were screened by enzyme linked immunosorbent assay (ELISA) for GnRHR-AAbs using a synthetic 28-mer peptide (LifeTein, Somerset, NJ) from the second extracellular loop (ECL2) of human GnRHR as coating antigen and evaluated for optical density (OD) values. Statistical analyses were performed with paired t-tests using all sequential pairs of GnRHR values for evaluation of GnRHR AAb level total absolute change over time (TAC/T). There was no significant difference between GnRHR AAb level values over time for each patient, p=0.39. Additionally, increased variation in AAb level over time (higher TAC/T) was not associated with higher GnRHR AAbs levels, p=0.23. Lastly, when evaluating the relationship of AAb level variation with other measures also averaged over time (estradiol level, age, body mass index (BMI), and antimullerian hormone level), only estradiol was found to have a significant association with higher estradiol levels and GnRHR AAb TAC/T, p=0.048.Tabled 1Demographics of case series patientsMeanRangeAge (years)33.225-40BMI (kg/m2)32.118.9-40.6AMH (ng/ml)7.04-9.2Estradiol (pg/ml)56.027.8-95.5 Open table in a new tab Our initial investigations have shown that most patients in our study with PCOS have activating AAbs to GnRHR compared to ovulatory controls (1). In this case series we have demonstrated that GnRHR AAb levels are stable over time and AAb level consistency does not vary by baseline AAb level. Additionally, there may be an association between higher estradiol levels and GnRHR AAb level TAC/T.

Polycystic ovary syndrome (PCOS) is a diagnosis of exclusion with unknown etiology. We recently identified autoantibodies (AAbs) to the second extracellular loop (ECL-2) of the gonadotropin releasing hormone receptor (GnRHR) in a majority of patients with PCOS compared to ovulatory controls in baseline serum measurements. The present assay may represent the desired serological test needed to effectively screen subjects for possible PCOS. Currently, no data exists regarding autoantibody activity over time or with changes in the hormonal milieu associated with infertility treatments, specifically controlled ovarian hyperstimulation (COH) with in vitro fertilization (IVF). To evaluate the levels of AAbs to GnRHR in the serum of eleven subjects with PCOS and infertility over time and observe for changes relative to hormonal fluctuations occurring over the course of infertility treatment. Sera samples from eleven women with PCOS and infertility drawn over multiple time points (0: not on medications, 1: down-regulation phase of an IVF cycle (oral contraceptives or lupron), 2: IVF stimulation day five, 3: day of hCG trigger, and 4: day of pregnancy test) during infertility treatments were assessed for GnRHR-AAbs. The de-identified samples were screened by ELISA for GnRHR-AAbs using a synthetic 28-mer peptide (LifeTein, Somerset, NJ) from the ECL2 of human GnRHR as coating antigen. Optical density (OD) values were read at 405 nm at 60 minutes. Covariates evaluated include age, body mass index (BMI), anti-Mullerian hormone (AMH) level, antral follicle count (AFC), IVF protocol (GnRH antagonist or agonist), estradiol level, and hormonal down-regulation during IVF preparation. Statistical analyses were performed using generalized estimating equations within a generalized linear modeling framework to account for the repeated measures within each patient. AAb levels did not differ significantly by patient age (range 25-40 years; p=0.85) or BMI (range 19.3-41.8; p=0.89). After taking into account inter-patient variation and inter-time point variation, there was an association between GnRHR-AAb levels and estradiol levels (higher AAb level with lower estradiol; p<0.0001). Also, the GnRH antagonist protocol was associated with lower AAb levels (p=0.019). Most inter-patient variation could not be attributed to any of the patient characteristics. However, after taking into account inter-time point variation only, inter-patient variation in AAb levels was partially attributable to an interaction between BMI and AMH (p<0.0001) but not to age (p=0.70) or AFC (p=0.97). There was significant intra-patient variation in AAb levels at both baseline (time point 0, not on meds, p=0.042) and during the down-regulation phase (time point 1, p<0.0001) that could not be attributed to any of the measured covariates. Our initial investigations have shown that most patients in our study with PCOS have activating AAbs to GnRHR compared to ovulatory controls. Our pilot study has demonstrated that there is inter-patient variation of GnRHR-AAb levels on no medications and while in the down-regulation phase in preparation for IVF. Additionally, the fluctuation in AAb levels with estradiol levels in GnRH antagonist protocol would suggest an association between the two clinical time points and potentially a relationship between estradiol and the GnRHR-AAbs.

Polycystic ovary syndrome (PCOS), a disease of unknown etiology, is characterized by a variable elevation of luteinizing hormone. We previously showed presence and activity of autoantibodies (AAbs) to the second extracellular loop (ECL2) of other G-protein receptors (similar to GnRH). Our objective was to compare the presence and activity of AAbs directed to the ECL2 of the GnRH receptor (GnRHR) in PCOS patients compared to ovulatory controls. Case-cohort study Infertile PCOS subjects based on Rotterdam criteria and infertile ovulatory controls seen at an academic fertility clinic 2012-2016 were included in the study if they had stored serum prior to beginning treatment. Serum was screened by ELISA for AAbs to GnRHR using a synthetic 28-mer peptide (GenScript, Piscataway, NJ) from the ECL2 of human GnRHR as coating antigen. Optical density (OD) values were read at 405 nm at 60 minutes. Activity of GnRHR AAb in IgG purified from sera of 4 subjects with PCOS and 4 controls was analyzed with a GnRHR-transfected Chem-1 cell-based calcium flux assay (Eurofins, St Charles, MO). AAb specific effect was tested by GnRHR blockade. Group data are presented as mean ±SD or percent. Groups were compared using Student t or Pearson chi-squared tests. OD values were converted to z-scores for analysis, and are reported as such. An ROC curve was used to assess OD as a diagnostic test for PCOS. 79 PCOS patients and 73 controls were included. There were no significant (p>0.05) differences between the groups in age (overall 29±3), race (74% white) or BMI (29±8). Standardized OD in PCOS patients (0.53±1.00) was significantly higher (p<0.001) than in ovulatory controls (-0.55±0.62). Using OD to determine a ROC curve for PCOS the Area Under the Curve was 0.83 (±0.03;p<0.001). As a predictor of PCOS, OD alone had 74% sensitivity and 84% specificity for PCOS. There was a significant calcium flux response to IgG isolated from PCOS patients compared to controls (67.1±6.4 vs 30.9±1.5, % of maximum response, p<0.01). This PCOS (but not control) IgG-induced GnRHR activation was effectively suppressed by specific GnRHR blockade with cetrorelix (p<0.01). We developed a sensitive and specific biomarker for PCOS, activating AAb to the ECL2 of the GnRHR. At the hypothalamic/pituitary level, AAbs will likely be contributive and possibly causative of the menstrual dysfunction and metabolic disturbances demonstrated in PCOS subjects, and may represent the long-desired identifying diagnostic test for PCOS. We plan to evaluate the association between these AAbs and the PCOS-associated metabolic abnormalities in humans, in animal models and in pregnancy outcomes with ovulation induction.

IntroductionLittle data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center.ObjectiveThe present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery.Study designThis prospective, observational study included children aged <2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children's hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child's genitalia prior to and 6 months after genitoplasty.ResultsOf the 37 children meeting eligibility criteria, 20 (54%) had a 46, XX karyotype, 15 (40%) had a 46, XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child's genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P < 0.001) and fathers (P <= 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P < 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings. Discussion This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant preoperatively, they were generally concordant postoperatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life.ConclusionIn this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.

Study design: An observational study based on retrospective review of the medical charts and death records of 163 individuals with traumatic spinal cord injuries (SCI). Objectives: To determine whether HMG coA Reductase Inhibitor (‘statin’) use in a cohort of patients with traumatic SCI reduced overall and cause-specific mortality. Setting: An outpatient clinic designated for veterans with SCI at the Oklahoma City Veterans Administration Hospital. Methods: Review and analysis of the medical records of 163 veterans with traumatic SCI cared for between the years 2000 and 2014. Data collected included statin use, duration of statin use and intensity of statin therapy, as well as cause-specific mortality. Results: Seventy five participants had taken statins for an average of 5.7±3.7 years, and had greater cardiovascular risk burdens than those who had not taken statins ( n =88). Statin use was associated with a reduced risk of death. The mortality rate for those patients on statins was 33.8–49.9 per 1000 person-years, depending on assumptions made regarding residual effects of statin use. Under most assumptions this was significantly lower than the mortality rate seen in those not on statins (47.4–66.8 deaths per 1000 person-years). Within the statin group, neither duration nor average intensity of statin therapy affected mortality. Conclusion: Statin use among a cohort of veterans with traumatic SCI reduced all-cause mortality. This retrospective study ought to spur further investigations into the potential benefits of statin use among people with chronic SCI, and begin a discussion as to whether individuals with injuries should routinely be offered statin therapy.

SummaryFluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve‐to‐treatment veterans. Thirty‐seven naïve‐to‐treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention‐to‐treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve‐to‐treatment genotype 1 HCV patients.

Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, Torjesen P, Scholz H, Henriksen T, Lorentzen B, Garg S, Menard M, Hammad S, Scardo J, Stanley J, Wu M, Basu A, Aston C, Lyons T. Reduced soluble receptor for advanced glycation end‐products (sRAGE) scavenger capacity precedes pre‐eclampsia in Type 1 diabetes. BJOG 2012;119:1512–1520. Objective Increased advanced glycation end‐products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre‐eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four‐fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM ( n = 118; 26 developed PE) and healthy nondiabetic pregnant controls ( n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), N ε ‐(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal‐modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE−). Results In DM PE+ versus DM PE−, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE ( P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester ( P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester ( P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.

Background: Superficial thrombophlebitis can produce pain and result in a deep vein thrombosis (DVT) if not treated. Conservative therapies including prescription of non-steroidal anti-inflammatory drugs (NSAID) and heat have been standard care. Recently, studies have been published reporting efficacy and safety of low-molecular-weight heparin for the treatment of superficial thrombophlebitis. However, there are few comparative trials to conservative therapy. We studied the effectiveness and safety of treatment with dalteparin compared with ibuprofen in patients with confirmed superficial thrombophlebitis. Methods: Consecutive patients were randomized to receive daily dalteparin vs. ibuprofen three times daily for up to 14 days. The primary outcome measure was the incidence of extension of thrombus or new symptomatic venous thromboembolism during the 14-day and 3-month follow-up period. The secondary outcome was a reduction in pain. The outcome measure of safety was the incidence of major and minor bleeding. Results: Of 302 consecutive patients screened, 72 were enrolled. Four patients receiving ibuprofen compared with no patients receiving dalteparin had thrombus extension at 14 days (P = 0.05), however, there was no difference in thrombus extension at 3 months. Both treatments significantly reduced pain. There were no episodes of major or minor bleeding during the treatment period. Conclusions: Dalteparin is superior to the NSAID ibuprofen in preventing extension of superficial thrombophlebitis during the 14-day treatment period with similar relief of pain and no increase in bleeding. However, questions concerning the optimal treatment duration should be explored in future trials.

Two common variants (rs1387153, rs10830963) in MTNR1B have been reported to have independent effects on fasting blood glucose (FBG) levels with increased risk to type 2 diabetes (T2D) in recent genome-wide association studies (GWAS). In this investigation, we report the association of these two variants, and an additional variant (rs1374645) within the GWAS locus of MTNR1B with FBG, 2h glucose, insulin resistance (HOMA IR), β-cell function (HOMA B), and T2D in our sample of Asian Sikhs from India. Our cohort comprised 2222 subjects [1201 T2D, 1021 controls]. None of these SNPs was associated with T2D in this cohort. Our data also could not confirm association of rs1387153 and rs10830963 with FBG phenotype. However, upon stratifying data according to body mass index (BMI) (low ≤ 25 kg/m(2) and high > 25 kg/m(2)) in normoglycemic subjects (n = 1021), the rs1374645 revealed a strong association with low FBG levels in low BMI group (β = -0.073, p = 0.002, Bonferroni p = 0.01) compared to the high BMI group (β = 0.015, p = 0.50). We also detected a strong evidence of interaction between rs1374645 and BMI with respect to FBG levels (p = 0.002). Our data provide new information about the significant impact of another MTNR1B variant on FBG levels that appears to be modulated by BMI. Future confirmation on independent datasets and functional studies will be required to define the role of this variant in fasting glucose variation.

Aims/hypothesis Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGF beta 1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia.Methods Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial-derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term.Results Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n=26) vs those without hypertensive complications (diabetic normotensive, n=95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p<0.05) and the normal rise of PlGF during pregnancy was blunted (p<0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r(2)=42%, p<0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p<0.0001).Conclusions/interpretation Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.