Sex-Specific Differences in MicroRNA Expression During Human Fetal Lung Development.

Background: Sex-specific differences in fetal lung maturation have been well described; however, little is known about the sex-specific differences in microRNA (miRNA) expression during human fetal lung development. Interestingly, many adult chronic lung diseases also demonstrate sex-specific differences in prevalence. The developmental origins of health and disease hypothesis suggests that these sex-specific differences in fetal lung development may influence disease susceptibility later in life. In this study, we performed miRNA sequencing on human fetal lung tissue samples to investigate differential expression of miRNAs between males and females in the pseudoglandular stage of lung development. We hypothesized that differences in miRNA expression are present between sexes in early human lung development and may contribute to the sex-specific differences seen in pulmonary diseases later in life. Methods: RNA was isolated from human fetal lung tissue samples for miRNA sequencing. The count of each miRNA was modeled by sex using negative binomial regression models in DESeq2, adjusting for post-conception age, age2, smoke exposure, batch, and RUV factors. We tested for differential expression of miRNAs by sex, and for the presence of sex-by-age interactions to determine if miRNA expression levels by age were distinct between males and females. Results: miRNA expression profiles were generated on 298 samples (166 males and 132 females). Of the 809 miRNAs expressed in human fetal lung tissue during the pseudoglandular stage of lung development, we identified 93 autosomal miRNAs that were significantly differentially expressed by sex and 129 miRNAs with a sex-specific pattern of miRNA expression across the course of the pseudoglandular period. Conclusion: Our study demonstrates differential expression of numerous autosomal miRNAs between the male and female developing human lung. Additionally, the expression of some miRNAs are modified by age across the pseudoglandular stage in a sex-specific way. Some of these differences in miRNA expression may impact susceptibility to pulmonary disease later in life. Our results suggest that sex-specific miRNA expression during human lung development may be a potential mechanism to explain sex-specific differences in lung development and may impact subsequent disease susceptibility.

L-Citrulline increases nitric oxide and improves control in obese asthmatics.

BACKGROUNDThe airways of obese asthmatics have been shown to be NO deficient, and this contributes to airway dysfunction and reduced response to inhaled corticosteroids. In cultured airway epithelial cells, L-citrulline, a precursor of L-arginine recycling and NO formation, has been shown to prevent asymmetric dimethyl arginine-mediated (ADMA-mediated) NO synthase (NOS2) uncoupling, restoring NO and reducing oxidative stress.METHODSIn a proof-of-concept, open-label pilot study in which participants were analyzed before and after treatment, we hypothesized that 15 g/d L-citrulline for 2 weeks would (a) increase the fractional excretion of NO (FeNO), (b) improve asthma control, and (c) improve lung function. To this end, we recruited obese (BMI >30) asthmatics on controller therapy, with a baseline FeNO of ≤30 ppb from the University of Colorado Medical Center and Duke University Health System.RESULTSA total of 41 subjects with an average FeNO of 17 ppb (95% CI, 15-19) and poorly controlled asthma (average asthma control questionnaire [ACQ] 1.5 [95% CI, 1.2-1.8]) completed the study. Compared with baseline, L-citrulline increased whereas ADMA and arginase concentration did not (values represent the mean Δ and 95% CI): plasma L-citrulline (190 µM, 84-297), plasma L-arginine (67 µM, 38-95), and plasma L-arginine/ADMA (ratio 117, 67-167). FeNO increased by 4.2 ppb (1.7-6.7 ppb); ACQ decreased by -0.46 (-0.67 to 0.27 points); the forced vital capacity and forced exhalation volume in 1 second, respectively, changed by 86 ml (10-161 ml) and 52 ml (-11 to 132 ml). In a secondary analysis, the greatest FEV1 increments occurred in those subjects with late-onset asthma (>12 years) (63 ml [95% CI, 1-137]), in females (80 ml [95% CI, 5-154]), with a greater change seen in late-onset females (100 ml, [95% CI, 2-177]). The changes in lung function or asthma control were not significantly associated with the changes before and after treatment in L-arginine/ADMA or FeNO.CONCLUSIONShort-term L-citrulline treatment improved asthma control and FeNO levels in obese asthmatics with low or normal FeNO. Larger FEV1 increments were observed in those with late-onset asthma and in females.TRIAL REGISTRATIONClinicalTrials.gov NCT01715844.FUNDINGNIH NHLBI R01 HL146542-01.

Mentoring during Medical School and Match Outcome among Emergency Medicine Residents.

INTRODUCTION: Few studies have documented the value of mentoring for medical students, and research has been limited to more subjective (e.g., job satisfaction, perceived career preparation) rather than objective outcomes. This study examined whether having a mentor is associated with match outcome (where a student matched based on their rank order list [ROL]). METHODS: We sent a survey link to all emergency medicine (EM) program coordinators to distribute to their residents. EM residents were surveyed about whether they had a mentor during medical school. Match outcome was assessed by asking residents where they matched on their ROL (e.g., first choice, fifth choice). They were also asked about rank in medical school, type of degree (MD vs. DO), and performance on standardized tests. Residents who indicated having a mentor completed the Mentorship Effectiveness Scale (MES), which evaluates behavioral characteristics of the mentor and yields a total score. We assessed correlations among these variables using Pearson's correlation coefficient. Post-hoc analysis using independent sample t-test was conducted to compare differences in the MES score between those who matched to their first or second choice vs. third or higher choice. RESULTS: Participants were a convenience sample of 297 EM residents. Of those, 199 (67%) reported having a mentor during medical school. Contrary to our hypothesis, there was no significant correlation between having a mentor and match outcome (r=0.06, p=0.29). Match outcome was associated with class rank (r=0.13, p=0.03), satisfaction with match outcome (r= -0.37, p<0.001), and type of degree (r=0.12, p=0.04). Among those with mentors, a t-test revealed that the MES score was significantly higher among those who matched to their first or second choice (M=51.31, SD=10.13) compared to those who matched to their third or higher choice (M=43.59, SD=17.12), t(194)=3.65, p<0.001, d=0.55. CONCLUSION: Simply having a mentor during medical school does not impact match outcome, but having an effective mentor is associated with a more favorable match outcome among medical students applying to EM programs.