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Current guidelines recommending preoperative transfusion to a hemoglobin level of 9 to 10 g/dL for patients with sickle cell disease (SCD) are based on imperfect evidence. The benefit of preoperative transfusion in children specifically is not known. This study aimed to evaluate whether preoperative RBC transfusion is associated with different rates of sickle cell crisis and surgical complications, compared with no preoperative transfusion, among children with SCD undergoing common abdominal operations.The NSQIP-Pediatrics database (2013 to 2019) was queried. Patients who underwent cholecystectomy, splenectomy, or appendectomy with a preoperative Hct level of less than 30% were included. The primary outcome was 30-day readmission for sickle cell crisis. Secondary outcomes were 30-day surgical complications and hospital length of stay. Propensity score matching methods were used to obtain two statistically similar cohorts of patients comprised of those who were preoperatively transfused and those who were not.Among 357 SCD patients, 200 (56%) received preoperative transfusion. In the matched cohort of 278 patients (139 per group), there was no statistically significant difference in 30-day readmission for sickle cell crisis in the transfused and non-transfused groups (5.8% vs 7.2%, p = 0.80). The rate of 30-day surgical complications did not differ between matched groups (10.8% vs 9.4%, p = 0.84). Subgroups defined by presenting Hct levels of 27.3% or greater or less than 27.3%, American Society of Anesthesiologists classification, wound class, and index operation were not associated with an altered risk of sickle cell crisis or surgical complications after preoperative transfusion compared with no transfusion.Preoperative transfusion for children with SCD undergoing semi-elective abdominal operations was not associated with improved outcomes. Prospective investigation is warranted to strengthen guidelines and minimize unnecessary perioperative transfusions in this population.

Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacologic SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared to controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared to controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically.

ImportanceThere is some data to suggest that racial and ethnic minority infants with congenital diaphragmatic hernia (CDH) have poorer clinical outcomes.ObjectiveTo determine what patient- and institutional-level factors are associated with racial and ethnic differences in CDH mortality.Design, Setting, and ParticipantsMulticenter cohort study of 49 US children’s hospitals using the Pediatric Health Information System database from January 1, 2015, to December 31, 2020. Participants were patients with CDH admitted on day of life 0 who underwent surgical repair. Patient race and ethnicity were guardian-reported vs hospital assigned as Black, Hispanic (White or Black), or White. Data were analyzed from August 2021 to March 2022.ExposuresPatient race and ethnicity: (1) White vs Black and (2) White vs Hispanic; and institutional-level diversity (as defined by the percentage of Black and Hispanic patients with CDH at each hospital): (1) 30% or less, (2) 31% to 40%, and (3) more than 40%.Main Outcomes and MeasuresThe primary outcomes were in-hospital and 60-day mortality. The study hypothesized that hospitals managing a more racially and ethnically diverse population of patients with CDH would be associated with lower mortality among Black and Hispanic infants.ResultsAmong 1565 infants, 188 (12%), 306 (20%), and 1071 (68%) were Black, Hispanic, and White, respectively. Compared with White infants, Black infants had significantly lower gestational ages (mean [SD], White: 37.6 [2] weeks vs Black: 36.6 [3] weeks; difference, 1 week; 95% CI for difference, 0.6-1.4; P P 21 = 3.9; P = .05). Black infants had higher 60-day (White: 99 patients [9%] vs Black: 29 patients [15%]; χ21 = 6.7; P = .01) and in-hospital (White: 133 patients [12%] vs Black: 40 patients [21%]; χ21 = 10.6; P = .001) mortality . There were no mortality differences in Hispanic patients compared with White patients. On regression analyses, institutional diversity of 31% to 40% in Black patients (hazard ratio [HR], 0.17; 95% CI, 0.04-0.78; P = .02) and diversity greater than 40% in Hispanic patients (HR, 0.37; 95% CI, 0.15-0.89; P = .03) were associated with lower mortality without altering outcomes in White patients.Conclusions and RelevanceIn this cohort study of 1565 who underwent surgical repair patients with CDH, Black infants had higher 60-day and in-hospital mortality after adjusting for disease severity. Hospitals treating a more racially and ethnically diverse patient population were associated with lower mortality in Black and Hispanic patients.

Pediatric appendicitis accounts for a notable proportion of health care use and cost in the United States. To identify opportunities for cost savings during pediatric laparoscopic appendectomy, this study assessed whether surgeons' use of costlier disposable supplies correlated with procedure duration and patient outcomes.This retrospective cross-sectional study assessed laparoscopic appendectomy for uncomplicated pediatric appendicitis at 2 tertiary-care academic hospitals. The cost of disposable surgical supplies, procedure duration, and patient outcomes were obtained from medical records. The correlation between average supply cost and procedure duration among surgeons was assessed using Pearson's correlation coefficient. Associations between use of specific disposable supplies and supply cost or procedure duration were assessed using Student's t tests.A total of 380 laparoscopic appendectomies were performed by 11 surgeons. Mean normalized supply cost varied between surgeons (range: 60.6%-151.1%) and was not correlated with procedure duration (R = 0.2951, P = .378). The use of energy-based sealing devices (76.7% increase, P.001), staplers (38.4% increase, P.001), endoscopic specimen pouches (45.3% increase, P.001), and disposable ports (43.6% increase, P.001) increased overall disposable supply cost. None of the disposable supplies in this analysis were associated with shorter procedures. Based on Medicaid reimbursement, the interquartile range of supply cost was 9.2% and 6.0% of hospital revenue at each site.Surgeons varied in their use of disposable supplies for pediatric laparoscopic appendectomy, but the cost of supplies used did not influence outcomes. Incentivizing more judicious supply use may reduce costs related to pediatric appendicitis.

In response to the opioid overdose crisis in the United States, many states implemented policies to guide opioid prescribing, but their impact on overdose mortality (prescription and non-prescription) remains poorly understood. We examined the impact of U.S. state opioid-prescribing policies on opioid overdose mortality following implementation.We calculated opioid overdose mortality rates from 1999-2016 by U.S. state using the CDC WONDER database, overall and separately for overdose deaths from prescription and non-prescription opioids. For each state, policies active on 1/1/2014 were reviewed for the presence and strength of six provisions recommending judicious opioid prescribing practices; "strong" provisions used the words "should," "shall," or "must". Interrupted time series (ITS) tested the association of each strong provision with overdose mortality, overall and separately for prescription and non-prescription opioids, in the two years following implementation. Sensitivity analyses compared between states, used time-lagged analyses, and excluded synthetic opioids from non-prescription opioid deaths.All six provisions had consistent direction of effect in ITS and sensitivity analyses. Strong provisions for prescriber training and limits on opioid dose reduced the slope of overall and prescription opioid overdose mortality in both ITS and sensitivity analyses. Reduced non-prescription opioid overdose mortality was only associated with strong provision for prescriber training. Some provisions had a negative impact. In ITS, strong provision for prescriber response to misuse increased the slope of non-prescription opioid overdose mortality. Strong provision for mandatory prescription drug monitoring program use had no relationship with overdose mortality in ITS and was associated with increased overall, prescription and non-prescription opioid overdose mortality in between-state sensitivity analysis.Opioid prescribing policies in U.S. states at the peak of the prescription opioid epidemic had modest mortality benefit, and did not reduce non-prescription opioid overdose mortality. A strong provision for prescriber training was the only provision associated with reduced prescription and non-prescription opioid overdose mortality. These findings can inform future efforts addressing prescription drug epidemics.

The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as “butyrate paradox”, in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate’s anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate’s cellular function into clinical therapies.