Unique Associations of DNA Methylation Regions With 24-Hour Blood Pressure Phenotypes in Black Participants.

BACKGROUND: Epigenetic marks (eg, DNA methylation) may capture the effect of gene-environment interactions. DNA methylation is involved in blood pressure (BP) regulation and hypertension development; however, no studies have evaluated its relationship with 24-hour BP phenotypes (daytime, nighttime, and 24-hour average BPs). METHODS: We examined the association of whole blood DNA methylation with 24-hour BP phenotypes and clinic BPs in a discovery cohort of 281 Blacks participants using reduced representation bisulfite sequencing. We developed a deep and region-specific methylation sequencing method, Bisulfite ULtrapLEx Targeted Sequencing and utilized it to validate our findings in a separate validation cohort (n=117). RESULTS: Analysis of 38 215 DNA methylation regions (MRs), derived from 1 549 368 CpG sites across the genome, identified up to 72 regions that were significantly associated with 24-hour BP phenotypes. No MR was significantly associated with clinic BP. Two to 3 MRs were significantly associated with various 24-hour BP phenotypes after adjustment for age, sex, and body mass index. Together, these MRs explained up to 16.5% of the variance of 24-hour average BP, while age, sex, and BMI explained up to 11.0% of the variance. Analysis of one of the MRs in an independent cohort using Bisulfite ULtrapLEx Targeted Sequencing confirmed its association with 24-hour average BP phenotype. CONCLUSIONS: We identified several MRs that explain a substantial portion of variances in 24-hour BP phenotypes, which might be excellent markers of cumulative effect of factors influencing 24-hour BP levels. The Bisulfite ULtrapLEx Targeted Sequencing workflow has potential to be suitable for clinical testing and population screenings on a large scale.

Does Supply Equal Demand? The Workforce of Direct Patient Care Genetic Counselors in Wisconsin.

BACKGROUND: Recent studies documented a shortage of direct patient care (DPC) genetic counselors in the United States. We aimed to survey genetic counselor members of the Wisconsin Genetic Counselors Association (WIGCA) to determine if the supply and demand was met within the state and where access to services can improve. METHODS: An email invitation was sent to all genetic counselor members of the WIGCA with a link to a confidential online survey. Survey questions addressed the workforce composition, elements that impact services, and professional satisfaction of practicing genetic counselors. RESULTS: The Wisconsin workforce currently has half of the projected need for full-time DPC genetic counselors. One-third of genetic counselors reported changing from direct to non-direct patient care positions. In-person services are concentrated within Milwaukee and Madison. Appointment wait times are decreased when patients meet with a genetic counselor only, and half of the genetic counselors reported moderate to high stress levels. DISCUSSION/CONCLUSION: A shortage of DPC genetic counselors in Wisconsin is confirmed due to the total full-time effort in direct patient care. Data provided here can be used to identify targets for increasing the number of DPC genetic counselors, maximizing time spent on patient care, and improving access.

Infants with esophageal atresia and right aortic arch: Characteristics and outcomes from the Midwest Pediatric Surgery Consortium.

PURPOSE: Right sided aortic arch (RAA) is a rare anatomic finding in infants with esophageal atresia with or without tracheoesophageal fistula (EA/TEF). In the presence of RAA, significant controversy exists regarding optimal side for thoracotomy in repair of the EA/TEF. The purpose of this study was to characterize the incidence, demographics, surgical approach, and outcomes of patients with RAA and EA/TEF. METHODS: A multi-institutional, IRB approved, retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals in the United States over a 5-year period (2009 to 2014) was performed. All patients had a minimum of one-year follow-up. RESULTS: In a cohort of 396 infants with esophageal atresia, 20 (5%) had RAA, with 18 having EA with a distal TEF and 2 with pure EA. Compared to infants with left sided arch (LAA), RAA infants had a lower median birth weight, (1.96 kg (IQR 1.54-2.65) vs. 2.57 kg (2.00-3.03), p = 0.01), earlier gestational age (34.5 weeks (IQR 32-37) vs. 37 weeks (35-39), p = 0.01), and a higher incidence of congenital heart disease (90% vs. 32%, p < 0.0001). The most common cardiac lesions in the RAA group were ventricular septal defect (7), tetralogy of Fallot (7) and vascular ring (5). Seventeen infants with RAA underwent successful EA repair, 12 (71%) via right thoracotomy and 5 (29%) through left thoracotomy. Anastomotic strictures trended toward a difference in RAA patients undergoing right thoracotomy for primary repair of their EA/TEF compared to left thoracotomy (50% vs. 0%, p = 0.1). Side of thoracotomy in RAA patients undergoing EA/TEF repair was not significantly associated with mortality, anastomotic leak, recurrent laryngeal nerve injury, recurrent fistula, or esophageal dehiscence (all p > 0.29). CONCLUSION: RAA in infants with EA/TEF is rare with an incidence of 5%. Compared to infants with EA/TEF and LAA, infants with EA/TEF and RAA are more severely ill with lower birth weight and higher rates of prematurity and complex congenital heart disease. In neonates with RAA, surgical repair of the EA/TEF is technically feasible via thoracotomy from either chest. A higher incidence of anastomotic strictures may occur with a right-sided approach. LEVEL OF EVIDENCE: Level III.

Relationship between perioperative blood transfusion and surgical site infections in pediatric general and thoracic surgical patients.

BACKGROUND: Recently, perioperative transfusions were demonstrated to be associated with higher rate of surgical site infections (SSIs) in neonates. We sought to examine whether a similar relationship exists between perioperative blood transfusions and SSI among non-neonatal pediatric general surgical patients. METHODS: We conducted an IRB-approved retrospective study reviewing non-neonatal patients (age greater than 28days and less than 18years) who underwent a general or thoracic surgical procedure in 2012, 2013, 2014, in the American College of Surgeons National Safety and Quality Improvement Project-Pediatric (ACS-NSQIP-P) Participant User Files. We used Chi-square analyses to perform a bivariate analysis comparing proportions of SSI's between patients who received blood transfusion to those who did not. Multiple logistic regression analyses compared the odds of SSIs in transfused versus nontransfused patients controlling for organ failure, steroid use, nutritional status, current infection, American Society of Anesthesiologists (ASA) Physical Status classification, and wound classification. RESULTS: There were 55,133 patients with 1779 patients who received blood transfusion (≥25ml/kg body weight) during or within 72h of surgery. Bivariate analysis showed at least twice the rate of infection in transfused patients compared to nontransfused patients (p<0.01): superficial SSI 3.5% vs 1.5%; deep SSI 0.8% vs 0.2%, organ space SSI 3.8% vs 1.6%; deep dehiscence 2% vs 0.3%. Total wound infections and dehiscence for transfused patients were 10.5% vs 3.8% in nontransfused patients (p<0.01). Multiple regression analysis showed that nutritional issue, current infection, and wounds not classified as "clean" have statistically significant correlation with SSI. Although there was significant interaction between ASA and transfusion (p<0.0001), we found statistically significant associations between transfusions and SSI for ASA class 1-2 (OR=5.51, 95% CI 3.47-7.52), ASA class 3 (OR=2.06, 95% CI 1.63-2.61), and ASA class 4-5 (OR=1.67, 95% CI 1.15-2.42). CONCLUSION: In non-newborn pediatric general and thoracic surgery patients, transfusions were associated with higher risk of SSI or wound dehiscence. Although there was a significant interaction between ASA and transfusion, OR for SSI was stronger for lower ASA classes. TYPE OF STUDY: Retrospective Review. LEVEL OF EVIDENCE: II.

Challenging surgical dogma in the management of proximal esophageal atresia with distal tracheoesophageal fistula: Outcomes from the Midwest Pediatric Surgery Consortium.

PURPOSE: Perioperative management of infants with esophageal atresia and tracheoesophageal fistula (EA/TEF) is frequently based on surgeon experience and dogma rather than evidence-based guidelines. This study examines whether commonly perceived important aspects of practice affect outcome in a contemporary multi-institutional cohort of patients undergoing primary repair for the most common type of esophageal atresia anomaly, proximal EA with distal TEF. METHODS: The Midwest Pediatric Surgery Consortium conducted a multicenter, retrospective study examining selected outcomes on infants diagnosed with proximal EA with distal TEF who underwent primary repair over a 5-year period (2009-2014), with a minimum 1-year follow up, across 11 centers. RESULTS: 292 patients with proximal EA and distal TEF who underwent primary repair were reviewed. The overall mortality was 6% and was significantly associated with the presence of congenital heart disease (OR 4.82, p=0.005). Postoperative complications occurred in 181 (62%) infants, including: anastomotic stricture requiring intervention (n=127; 43%); anastomotic leak (n=54; 18%); recurrent fistula (n=15; 5%); vocal cord paralysis/paresis (n=14; 5%); and esophageal dehiscence (n=5; 2%). Placement of a transanastomotic tube was associated with an increase in esophageal stricture formation (OR 2.2, p=0.01). Acid suppression was not associated with altered rates of stricture, leak or pneumonia (all p>0.1). Placement of interposing prosthetic material between the esophageal and tracheal suture lines was associated with an increased leak rate (OR 4.7, p<0.001), but no difference in the incidence of recurrent fistula (p=0.3). Empiric postoperative antibiotics for >24h were used in 193 patients (66%) with no difference in rates of infection, shock or death when compared to antibiotic use ≤24h (all p>0.3). Hospital volume was not associated with postoperative complication rates (p>0.08). Routine postoperative esophagram obtained on day 5 resulted in no delayed/missed anastomotic leaks or a difference in anastomotic leak rate as compared to esophagrams obtained on day 7. CONCLUSION: Morbidity after primary repair of proximal EA and distal TEF patients is substantial, and many common practices do not appear to reduce complications. Specifically, this large retrospective series does not support the use of prophylactic antibiotics beyond 24h and empiric acid suppression may not prevent complications. Use of a transanastomotic tube was associated with higher rates of stricture, and interposition of prosthetic material was associated with higher leak rates. Routine postoperative esophagram can be safely obtained on day 5 resulting in earlier initiation of oral feeds. STUDY TYPE: Treatment study. LEVEL OF EVIDENCE: III.

Pepsin as a biomarker for laryngopharyngeal reflux in children with laryngomalacia.

OBJECTIVES/HYPOTHESIS: Laryngomalacia is a common cause of newborn stridor. Laryngopharyngeal reflux (LPR) has been associated with laryngomalacia. Although pepsin, a component of LPR, has been associated with inflammatory diseases of the aerodigestive tract, its presence in the airways of laryngomalacia patients is unknown. STUDY DESIGN: Prospective case-control study comparing patients under age 3 years with laryngomalacia to children without laryngomalacia. METHODS: Children less than 3 years old undergoing supraglottoplasty for laryngomalacia or surgery unrelated to the airway, without a history of laryngomalacia, reflux, or respiratory disease, were offered enrollment. Supraglottic lavage samples (3 mL) were obtained from all subjects. Two-millimeter arytenoid biopsies were collected from laryngomalacia patients. Pepsin Western blot and enzyme-linked immunosorbent assay were performed. RESULTS: Ten laryngomalacia and five control subjects were enrolled. Pepsin was detected in lavages of laryngomalacia patients (8/10) but absent in controls (0/5; P = .007). Pepsin was observed more frequently in lavages (8/10) than biopsies (4/10; P = .046) of laryngomalacia subjects. Higher median pepsin concentration was observed in laryngomalacia than control lavages (P = .025). CONCLUSIONS: Pepsin in supraglottic specimens demonstrated an association with laryngomalacia, supporting a role for refluxed pepsin in laryngomalacia. These data corroborate previous work implicating pepsin in inflammatory diseases of the upper airways. Further studies are warranted to investigate the contribution of pepsin to the pathophysiology of laryngomalacia. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:2413-2417, 2017.

Relationship between perioperative blood transfusion and surgical site infections in the newborn population: An ACS-NSQIP-Pediatrics analysis.

BACKGROUND: Adult data suggest that perioperative transfusion may have deleterious effects through immunomodulation. Limited data regarding the effect of transfusions exist in the pediatric population. We hypothesized that perioperative transfusions may be associated with surgical site infections (SSI) in newborns. METHODS: The 2012 and 2013 American College of Surgeons National Safety and Quality Improvement Project-Pediatric (ACS-NSQIP-P) Participant User Files were queried to include all neonates that underwent surgical procedures. SSI rates in infants who had a perioperative blood transfusion were compared to those who were not transfused using a Fisher's Exact Test. Logistic regression analysis compared the odds of SSIs in transfused patients versus nontransfused patients. p Values <0.05 were statistically significant. RESULTS: The study population included 6499 patients, of which 1109 (17.1%) had transfusions. Transfused patients had increased SSIs. In the multivariate analysis, patients with nutritional issues (OR=1.58, 95%CI 1.24-2.00), current infection (OR=1.98, 95%CI 1.52-2.57), and perioperative transfusion (OR=2.08, 95%CI 1.59-2.72) were associated with increased risk of SSI after controlling for all other variables. CONCLUSIONS: Perioperative transfusions are associated with increased risk of SSIs. Further work to determine possible mechanisms of this association may be warranted.