Normal sex differences in prenatal growth and abnormal prenatal growth retardation associated with 46,XY disorders of sex development are absent in newborns with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

<p>Abstract</p> <p>Background</p> <p>Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the most common presentation of a disorder of sex development (DSD) in genetic females. A report of prenatal growth retardation in cases of 46,XY DSD, coupled with observations of below-optimal final height in both males and females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, prompted us to investigate prenatal growth in the latter group. Additionally, because girls with congenital adrenal hyperplasia are exposed to increased levels of androgens in the absence of a male sex-chromosome complement, the presence or absence of typical sex differences in growth of newborns would support or refute a hormonal explanation for these differences.</p> <p>Methods</p> <p>In total, 105 newborns with congenital adrenal hyperplasia were identified in our database. Gestational age (weeks), birth weight (kg), birth length (cm) and parental heights (cm) were obtained. Mid-parental height was considered in the analyses.</p> <p>Results</p> <p>Mean birth weight percentile for congenital adrenal hyperplasia was 49.26%, indicating no evidence of a difference in birth weight from the expected standard population median of 50th percentile (<it>P </it>> 0.05). The expected sex difference in favor of heavier males was not seen (<it>P </it>> 0.05). Of the 105 subjects, 44 (27%; 34 females, 10 males) had birth length and gestational age recorded in their medical chart. Mean birth length for this subgroup was 50.90 cm (63rd percentile), which differed from the expected standard population median of 50th percentile (<it>P </it>= 0.0082). The expected sex difference in favor of longer males was also not seen (<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>The prenatal growth retardation patterns reported in cases of 46,XY disorders of sex development do not generalize to people with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Sex differences in body weight and length typically seen in young infants were not seen in the subjects who participated in this study. We speculate that these differences were ameliorated in this study because of increased levels of prenatal androgens experienced by the females infants.</p

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Price-Induced Patterns of Competition

This research focuses on how price changes influence the observed pattern of brand competition. The paper begins with a basic utility model formulation and examines the implications of three major classes of preference distributions on the expected patterns of competition. A price-tier model is proposed to operationalize the theory and to allow predictive testing. The price-tier model is estimated on 28 brands across four product categories. The results show a specific asymmetric pattern of price competition. Higher-price, higher quality brands steal share from other brands in the same price-quality tier, as well as from brands in the tier below. However, lower-price, lower-quality brands take sales from their own tier and the tier below brands, but do steal significant share from the tiers above. The results are consistent with a bimodal preference distribution, with the regular price indifference point being located toward the lower-quality end of the preference distribution for the categories analyzed.promotional analyses, market structure models, price competition

Dynamic Analysis of Consumer Response to Marketing Strategies

This paper develops a methodology for modeling consumer response that integrates previous research in stochastic brand selection, diffusion of innovation, test market analysis, and new product design. The methodology makes it practical to extend brand selection models to include diffusion phenomena such as awareness, trial, and information flow. Purchase timing and brand selection are interdependent and both phenomena depend jointly on managerial controls such as advertising, coupons, price-off promotion, product positioning, and consumer characteristics. Within this general structure, we provide practical estimation procedures (a least squares approximation to the maximum likelihood estimates) to determine the parameters which link managerial controls to consumer response. Closed form solutions are derived for cumulative awareness, cumulative trial, penetration, expected sales, and purchases due to promotion---all as a function of time. We also provide simplified expressions for equilibrium (t -> \infty ) market share. Tradeoffs among complexity of the diffusion process, number of managerial variables, nonstationarity, complexity of purchase timing, consumer segmentation, and sample size are made explicit so that the marketing scientist can customize his analyses to the managerial problems that he faces. The effects of sample size, data interval frequency, and collinearity in the explanatory variables are investigated with simulations based on a five-state consumer response process which depends on 8--10 marketing variables. The paper closes with a brief description of the application and predictive test of a consumer response model based on the methodology.marketing, consumer behavior, Markov analysis

Application, predictive test, and strategy implications for a dynamic model of consumer response to marketing

HD28 .M414 no.1244-, 81,

Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides

Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl₂ precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd₂(dba)₃. Twenty-two substituted benzonitriles have been synthesized using this method

Establishing the inter-rater reliability of spinal cord damage manual measurement using magnetic resonance imaging

Study design: Retrospective study. Objectives: To establish the inter-rater reliability in the quantitative evaluation of spinal cord damage following cervical incomplete spinal cord injury (SCI) utilizing magnetic resonance imaging (MRI). MRI was used to perform manual measurements of the cranial and caudal boundaries of edema, edema length, midsagittal tissue bridge ratio, axial damage ratio, and edema volume in 10 participants with cervical incomplete SCI. Setting: Academic university setting. Methods: Structural MRIs of 10 participants with SCI were collected from Northwestern University's Neuromuscular Imaging and Research Lab. All manual measures were performed using OsiriX (Pixmeo Sarl, Geneva, Switzerland). Intraclass correlation coefficients (ICC) were used to determine inter-rater reliability across seven raters of varying experience. Results: High-to-excellent inter-rater reliability was found for all measures. ICC values for cranial/caudal levels of involvement, edema length, midsagittal tissue bridge ratio, axial damage ratio, and edema volume were 0.99, 0.98, 0.90, 0.84, and 0.93, respectively. Conclusions: Manual MRI measures of spinal cord damage are reliable between raters. Researchers and clinicians may confidently utilize manual MRI measures to quantify cord damage. Future research to predict functional recovery following SCI and better inform clinical management is warranted