Factors Impacting Long-Term Gastrostomy Tube Dependence in Infants with Congenital Heart Disease.

BACKGROUND: Infants with congenital heart disease (CHD) often experience oral feeding intolerance requiring gastrostomy (GT). Complications related to GT use are common. The study aim was to identify factors associated with continued GT use at one-year. METHODS: A retrospective cohort study was performed at a tertiary children's hospital using the Society of Thoracic Surgeons database and patients' electronic medical record. Infants <1-year with CHD who underwent cardiac and GT surgery between January 2014-October 2019 were identified. Patient demographics, preoperative feeding, clinical variables, and GT use at one-year was evaluated. A separate cohort discharged with a nasogastric tube (NGT) was identified for longitudinal comparisons. RESULTS: Of 137 infants who received a GT, 115 (84%) continued using their GT at one-year. Factors associated with continued GT use included lower median percent of goal oral feeding before GT placement (0% IQR 0-6.5 versus 3.7% IQR 0-31), prolonged hospitalization after GT placement (36% versus 14%, P-value = 0.048), and failure to take oral feeds at discharge (69% versus 27%, P-value <0.001). There was no difference in demographics or clinical comorbidities between groups. Clinic/emergency room visits for GT complications were common (72%). Eight infants discharged with a NGT did not require GT placement. CONCLUSIONS: Patients with CHD tolerating minimal oral nutrition before GT placement, prolonged hospitalization after GT, and difficulty with oral feeds at discharge were more likely to use their GT at 1-year. Outpatient NGT feeding is feasible for select infants with CHD. Efforts to optimize care for this complex, device-dependent population are warranted to minimize risks and facilitate family engagement for long-term care.

NH2-terminal deletion of specific phosphorylation sites on PHOX2B disrupts the formation of enteric neurons in vivo.

Mutations in the paired-like homeobox 2 b (PHOX2B) gene are associated with congenital central hypoventilation syndrome (CCHS), which is a rare condition in which both autonomic dysregulation with hypoventilation and an enteric neuropathy may occur. The majority of patients with CCHS have a polyalanine repeat mutation (PARM) in PHOX2B, but a minority of patients have nonpolyalanine repeat mutations (NPARMs), some of which have been localized to exon 1. A PHOX2B-Y14X nonsense mutation previously generated in a human pluripotent stem cell (hPSC) line results in an NH2-terminus truncated product missing the first 17 or 20 amino acids, possibly due to translational reinitiation at an alternate ATG start site. This NH2-terminal truncation in the PHOX2B protein results in the loss of two key phosphorylation residues. Though the deletion does not affect the potential for PHOX2BY14X/Y14X mutant hPSC to differentiate into enteric neural crest cells (ENCCs) in culture, it impedes in vivo development of neurons in an in vivo model of human aganglionic small intestine.NEW & NOTEWORTHY A mutation that affects only 17-20 NH2-terminal amino acids in the paired-like homeobox 2 b (PHOX2B) gene hinders the subsequent in vivo establishment of intestinal neuronal cells, but not the in vitro differentiation of these cells.

Postoperative Opioid Analgesia Impacts Resource Utilization in Infants Undergoing Pyloromyotomy.

BACKGROUND: Opioid analgesia is often avoided in infants undergoing pyloromyotomy. Previous studies highlight an association between opioid use and prolonged hospitalization after pyloromyotomy. However, the impact of opioid use on healthcare resource utilization and cost is unknown. We hypothesized that use of opioids after pyloromyotomy is associated with increased resource utilization and costs. METHODS: A retrospective cohort study was conducted identifying healthy infants aged <6 mo with a diagnosis of pyloric stenosis who underwent pyloromyotomy from 2005 to 2015 among 47 children's hospitals using the Pediatric Health Information System database. Time of opioid exposure was categorized as day of surgery (DOS) alone, postoperative use alone, or combined DOS and postoperative use. Primary outcomes were the standardized unit cost, a proxy for resource utilization, billed charges to the patient/insurer, and hospital costs. A multivariable log-linear mixed-effects model was used to adjust for patient and hospital level factors. RESULTS: Overall, 11,008 infants underwent pyloromyotomy with 2842 (26%) receiving perioperative opioids. Most opioid use was confined to the DOS alone (n = 2,158, 19.6%). Infants who received opioids on DOS and postoperatively exhibited 13% (95% confidence interval [CI]: 7%-20%, P-value <0.001) higher total resource utilization compared with infants who did not receive any opioids. Billed charges were 3% higher (95% CI: 0%-5%, P-value = 0.034) for infants receiving opioids isolated to the postoperative period alone and 6% higher (95% CI: 2%-11%, P-value = 0.004) for infants receiving opioids on the DOS and postoperatively. CONCLUSIONS: Postoperative opioid use among infants who underwent pyloromyotomy was associated with increased resource utilization and costs.

A 10-Month-Old Infant Presenting With Signs of Precocious Puberty Secondary to a Sclerosing Stromal Tumor of the Ovary in the Absence of Hormonal Elevation.

Precocious puberty in an infant is an alarming and infrequent finding, making the differential diagnosis difficult for practitioners. Precocious puberty secondary to a sclerosing stromal tumor (SST) of the ovary is rare. We present a case of a child that began precocious puberty at 3 months of age including development of breast buds, pubic hair, growth spurt, and menarche 5 days prior to presenting to pediatric endocrinology at 10 months. She underwent right salpingo-oophorectomy which demonstrated a soft tissue mass occupying almost the entire ovary with a tan-pink fleshy cut surface. Histological examination confirmed a variant of SST. This case represents an extremely young onset of precocious puberty secondary to a variant of SST without hormonal elevation.

Minimally invasive repair of asymmetric pectus excavatum: An alternative technique to treating asymmetric morphology.

Minimally invasive repair of pectus excavatum or the Nuss procedure has become the standard operation for pectus excavatum repair. Pectus excavatum can be broadly divided into two categories: symmetric or asymmetric morphology. To optimize surgical outcomes of asymmetric pectus excavatum repair, previous work has proposed morphology-tailored bar shaping technique; the bar to be inserted is shaped asymmetrically to counter-balance the outer contour of the chest prior to the passage of the introducer across the chest. We describe an alternate approach that emphasizes precise introducer chest insertion and extraction and that highlights the direction of the introducer passage is from the higher asymmetric side to the lower contralateral side. The shape of the bar is determined after the introducer has been placed into the chest. This technique allows simultaneous compression of the higher asymmetric chest and elevation of the contralateral depressed side by the metal bar achieving excellent symmetric chest appearance. LEVEL OF EVIDENCE: Level V, Operative Technique.

A Novel Thoracic Ultrasound Measurement After Congenital Diaphragmatic Hernia Repair Identifies Decreased Diaphragmatic Excursion Associated With Adverse Respiratory and Surgical Outcomes.

Background and Aim: Congenital diaphragmatic hernia (CDH) is a rare defect often associated with pulmonary hypoplasia and abnormal pulmonary vascular development. Even after successful hernia repair, pulmonary disease may persist into adulthood. Impaired diaphragmatic motility may lead to compromised respiratory function long after index repair. This study investigates whether a novel ultrasound measurement, the diaphragmatic excursion ratio, can be a simple and non-invasive method to evaluate routine diaphragmatic motion after CDH repair, and whether it correlates with adverse surgical and respiratory outcomes. Materials and Methods: A cross-sectional study was conducted in consecutive patients who presented at medium-term follow-up visit between December 2017 and December 2018 after CDH repair at single pediatric hospital. Transthoracic ultrasound was performed with craniocaudal diaphragmatic excursion measured bilaterally during routine breathing. Diaphragmatic excursion ratios (diaphragmatic excursion of repaired vs. unrepaired side) were calculated and retrospectively compared with clinical data including demographics, length of stay, respiratory adjuncts, oral feeding, and need for gastrostomy. Results: Thirty-eight patients (median age at ultrasound, 24 months, interquartile range 11-60) were evaluated. Nine patients underwent primary repair, 29 had non-primary repair (internal oblique muscle flap or mesh patch). Patients with a diaphragmatic excursion ratio below the median (0.54) had longer hospital stays (median 77 vs. 28 days, p = 0.0007) more ventilator days (median 16 vs. 9 days, p =0.004), and were more likely to have been discharged on oxygen (68 vs. 16%, p = 0.001). They were also less likely to be exclusively taking oral feeds at 1-year post-surgery (37 vs. 74%, p = 0.02) and more likely to require a gastrostomy tube in the first year of life (74 vs. 21%, p = 0.003). Conclusions: Transthoracic ultrasound after CDH repair is practical method to assess diaphragm motion, and decreased diaphragm excursion ratio is associated with worse respiratory outcomes, a longer length of stay, and dependence on gastrostomy tube feeding within 1 year. Further prospective studies may help validate this novel ultrasound measurement and offer prognostic value.

Laparoscopic Treatment of Slipping Rib Syndrome in Pediatric Patients.

Background: Slipping rib syndrome (SRS) is an often unrecognized cause of lower chest and upper abdominal pain in children and adolescents. Surgical resection of the cartilaginous portions of the slipping rib often provides permanent pain relief, with the standard surgical approach being an open resection. A minimally invasive approach has not been reported previously; we report a novel laparoscopic technique for the treatment of SRS with satisfactory results. Materials and Methods: A retrospective review of all consecutive pediatric patients who underwent laparoscopic cartilage resection during the year 2019 and open cartilage resection during the year 2018 was included. Following data were recorded: age of patients, length of symptoms, length of procedure, length of cartilage resection, length of stay, resolution of pain, cosmetic acceptability, and postoperative complications. Results: Four patients underwent laparoscopic slipping rib resection without complication during the year 2019. The mean age of symptom onset was 15 (range 14-16) years old, mean length of symptoms was 1.4 (0.5-2.0) years, and mean age at operation was 16.5 (16-18) years old. The average length of the procedure was 72.8 (55-102) minutes, and mean length of cartilage removed was 2.3 (1.9-3.0) cm. Three patients underwent standard open operation during the year 2018. All patients reported complete resolution of their chronic pain at their 6-month follow-up visit. Conclusions: Laparoscopic technique can be used to treat SRS. All patients reported high satisfaction from resolution of chronic pain and the cosmetic appearance of their surgical scars.

A Giant Childhood Mesenteric Lipoblastoma With Extensive Maturation.

Abdominal lipoblastomas are uncommon soft tissue tumors in children and rarely arise from the mesentery. Due to intraabdominal location and slow growth, these masses can go unnoticed for long periods of time and often found on surgical exploration. We present a case of a 12-year-old male with years of abdominal distension accompanied by new onset early satiety that was found to have an intra-abdominal mass. He underwent an exploratory laparotomy revealing a large 33 x 27 x 15 cm rubbery mesenteric mass displacing the entire intra-abdominal contents, connected by a single vascular pedicle and encasing a loop of small intestine. The mass was resected and the patient did well without signs of recurrence. Histology confirmed the presence of mature adipocytes but on further cytogenetic analysis, a translocation between chromosomes 2 and 8 at the 12q arm was detected, which is often associated with lipoblastomas. This case represents the one of the largest mesenteric lipoblastomas that matured extensively to lipoma-like histology at the time of surgical resection.

R-Spondin 1 (RSPO1) Increases Mouse Intestinal Organoid Unit Size and Survival in vitro and Improves Tissue-Engineered Small Intestine Formation in vivo.

Introduction: Cell therapy and tissue engineering has recently emerged as a new option for short bowel syndrome (SBS) treatment, generating tissue engineered small intestine (TESI) from organoid units (OU) and biodegradable scaffolds. The recombinant human R-Spondin 1 (rhRSPO1) protein may be a key player in this process due to its mitogenic activity in intestinal stem cells. Objective: Aiming at optimizing the TESI formation process and advancing this technology closer to the clinic, we evaluated the effects of rhRSPO1 protein on OU culture and TESI formation. Methods: Intestinal OU were isolated from C57BL/6 mice and cultured in Matrigel in the presence or absence of recombinant human rhRSPO1. Throughout the culture, OU growth and survival rates were evaluated, and cells were harvested on day 3. OU were seeded onto biodegradable scaffolds, in the presence or absence of 5 µg of rhRSPO1 and implanted into the omentum of NOD/SCID mice in order to generate TESI. The explants were harvested after 30 days, weighed, fixed in formalin and embedded in paraffin for histological analysis and immunofluorescence for different cell markers. Results: After 3 days, rhRSPO1-treated OU attained a larger size, when compared to the control group, becoming 5.7 times larger on day 6. Increased survival was observed from the second day in culture, with a 2-fold increase in OU survival between days 3 and 6. A 4.8-fold increase of non-phosphorylated ß-catenin and increased relative expression of Lgr5 mRNA in the rhRSPO1-treated group confirms activation of the canonical Wnt pathway and suggests maintenance of the OU stem cell niche and associated stemness. After 30 days of in vivo maturation, rhRSPO1-treated TESI presented a larger mass than constructs treated with saline, developing a more mature intestinal epithelium with well-formed villi and crypts. In addition, the efficiency of OU-loaded rhRSPO1-treated scaffolds significantly increased, forming TESI in 100% of the samples (N = 8), of which 40% presented maximum degree of development, as compared to 66.6% in the control group (N = 9). Conclusion: rhRSPO1 treatment improves the culture of mouse intestinal OU, increasing its size and survival in vitro, and TESI formation in vivo, increasing its mass, degree of development and engraftment.

Induced pluripotent stem cell-derived enteric neural crest cells repopulate human aganglionic tissue-engineered intestine to form key components of the enteric nervous system.

Models for enteric neuropathies, in which intestinal nerves are absent or injured, are required to evaluate possible cell therapies. However, existing options, including transgenic mice, are variable and fragile. Here immunocompromised mice were implanted with human pluripotent stem cell-derived tissue-engineered small intestine 10 weeks prior to a second survival surgery in which enteric nervous system precursor cells, or saline controls, were injected into the human intestinal organoid-derived tissue-engineered small intestine and analyzed 4 weeks later. Human intestinal organoid-derived tissue-engineered small intestine implants injected with saline as controls illustrated formation of intestinal epithelium and mesenchyme without an enteric nervous system. Second surgical introduction of human pluripotent stem cell-generated enteric nervous system precursors into developing human intestinal organoid-derived tissue-engineered small intestine implants resulted in proliferative migratory neuronal and glial cells, including multiple neuronal subtypes, and demonstrated function in contractility assays.

Spleen Organoid Units Generate Functional Human and Mouse Tissue-Engineered Spleen in a Murine Model.

Introduction: Splenectomy is common after trauma or hematologic disease, and alters immune protection against pathogens, which may lead to fulminant infection with high mortality. Yet the spleen has demonstrable regenerative capacity and cells might be recovered and reimplanted at the time of injury or excision to avoid these risks. Methods: Tissue-engineered spleen (TESp) was generated from ActinGFP mice (mTESp) or human donor spleen (hTESp) through implantation of spleen organoid units (spleen OU), in NOD/SCID mice with concurrent splenectomy, on a biodegradable scaffold. Explants were evaluated and blood smears were obtained to investigate the presence of target cells or Howell-Jolly bodies, which are erythrocyte sequelae of asplenia. Results: TESp was generated from mouse (mTESp) and human (hTESp) donor cells with essential splenic components: red and white pulp with trabeculae. mTESp and hTESp demonstrated green fluorescent protein- or lamin-positive costaining with proliferating cell nuclear antigen, CD4, and CD11c, identifying proliferative donor cells and key immune components of the spleen of donor origin. Animals with hTESp and mTESP combined with splenectomy had significantly fewer Howell-Jolly bodies on blood smears than controls. Conclusion: TESp from mouse and human donor cells can be generated by 4 weeks and contains donor immune cells identified by CD4 and CD11c. TESp reduces postsplenectomy erythrocyte inclusions, indicating possible function. Impact Statement Overwhelming postsplenectomy infection is rare but highly mortal. Tissue-engineered spleen (TESp) was generated from murine (mTESp) and human (hTESp) donors and appeared histologically similar to native spleen. Both mTESp and hTESp demonstrated proliferative cells of donor spleen origin. Importantly, functional cells were demonstrated on imaging with a corresponding reduction in the number of erythrocyte inclusions in blood smears that are typically identified in patients with asplenia and indicate a lack of clearance by functional spleen tissue. Taken together, these findings indicate that this approach might be clinically relevant as a future human therapy.

Managing Procedural Pain in the Neonate Using an Opioid-sparing Approach.

PURPOSE: Pain in the neonate is often challenging to assess but important to control. Physicians often must balance the need for optimal pain control with the need to minimize oversedation and prolonged opioid use. Both inadequate pain control and overuse of opioids can have long-term consequences, including poor developmental outcomes. The aim of this review is to introduce a comprehensive approach to pain management for physicians, nurses, and surgeons caring for critically ill neonates, focusing on nonopioid alternatives to manage procedural pain. FINDINGS: After review, categories of opioid-sparing interventions identified included (1) nonopioid pharmacologic agents, (2) local and regional anesthesia, and (3) nonpharmacologic alternatives. Nonopioid pharmacologic agents identified for neonatal use included acetaminophen, NSAIDs, dexmedetomidine, and gabapentin. Local and regional anesthesia included neuraxial blockade (spinals and epidurals), subcutaneous injections, and topical anesthesia. Nonpharmacologic agents uniquely available in the neonatal setting included skin-to-skin care, facilitated tucking, sucrose, breastfeeding, and nonnutritive sucking. IMPLICATIONS: The use of various pharmacologic and interventional treatments for neonatal pain management allows for the incorporation of opioid-sparing techniques in neonates who are already at risk for poor neurodevelopmental outcomes. A multifactorial approach to pain control is paramount to optimize periprocedural comfort and to minimize the negative sequelae of uncontrolled pain in the neonate.

Emergent Repair of Paraesophageal Hernias and the Argument for Elective Repair.

BACKGROUND AND OBJECTIVES: A feared complication of large paraesophageal hernias is incarceration necessitating emergent repair. According to previous studies, patients who require an emergent operation are subject to increased morbidity compared with patients undergoing elective operations. In this study, we detail patients who underwent hernia repair emergently and compare their outcomes with elective patients. METHODS: A retrospective analysis was performed of the paraesophageal hernia repair operations between 2010 and 2016. Patients were divided into 2 groups: patients with hernias that were repaired electively and patients with hernias that were repaired emergently. Perioperative complications and follow-up data regarding morbidity, mortality, and recurrence were also recorded. A propensity analysis was used to compare emergent and elective groups. RESULTS: Thirty patients had hernias repaired emergently, and 199 patients underwent elective procedures. Patients undergoing emergent repair were more likely to have a type IV hernia, have a partial gastrectomy or gastrostomy tube insertion as part of their procedure, have a postoperative complication, and have a longer hospital stay. However, propensity analysis was used to demonstrate that when characteristics of the emergent and elective groups were matched, differences in these factors were no longer significant. Having an emergent operation did not increase a patient's risk for recurrence. CONCLUSION: Patients who had their hernias repaired emergently experienced complications at similar rates as those of elective patients with advanced age or comorbid conditions as demonstrated by the propensity analysis. The authors therefore recommend evaluation of all paraesophageal hernias for elective repair, especially in younger patients who are otherwise good operative candidates.

The Association Between Opioid Use and Outcomes in Infants Undergoing Pyloromyotomy.

PURPOSE: The purpose of this study was to describe the frequency and variation of opioid use across hospitals in infants undergoing pyloromyotomy and to determine the impact of opioid use on postoperative outcomes. METHODS: A retrospective cohort study (2005-2015) was conducted by using the Pediatric Health Information System (PHIS) database, including infants (aged <6 months) with pyloric stenosis who underwent pyloromyotomy. Infants with significant comorbidities were excluded. Opioid use was classified as a patient receiving at least 1 opioid medication during his or her hospital stay and categorized as preoperative, day of surgery, or postoperative (≥1 day after surgery). Outcomes included prolonged hospital length of stay (LOS; ≥3 days) and readmission within 30 days. FINDINGS: Overall, 25,724 infants who underwent pyloromyotomy were analyzed. Opioids were administered to 6865 (26.7%) infants, with 1385 (5.4%) receiving opioids postoperatively. In 2015, there was significant variation in frequency of opioid use by hospital, with 0%-81% of infants within an individual hospital receiving opioids (P < 0.001). Infants only receiving opioids on the day of surgery exhibited decreased odds of prolonged hospital LOS (odds ratio [OR], 0.85; 95% CI, 0.78-0.92). Infants who received an opioid on both the day of surgery and postoperatively exhibited increased odds of a prolonged hospital LOS (OR, 1.71; 95% CI, 1.33-2.20). Thirty-day readmission was not associated with opioid use (OR, 1.03; 95% CI, 0.93-1.14). IMPLICATIONS: There is national variability in opioid use for infants undergoing pyloromyotomy, and postoperative opioid use is associated with prolonged hospital stay. Nonopioid analgesic protocols may warrant future investigation.

Laparoscopic repair of paraesophageal hernias.

BACKGROUND AND OBJECTIVES: Laparoscopy has quickly become the standard surgical approach to repair paraesophageal hernias. Although many centers routinely perform this procedure, relatively high recurrence rates have led many surgeons to question this approach. We sought to evaluate outcomes in our cohort of patients with an emphasis on recurrence rates and symptom improvement and their correlation with true radiologic recurrence seen on contrast imaging. METHODS: We retrospectively identified 126 consecutive patients who underwent laparoscopic repair of a large paraesophageal hernia between 2000 and 2010. Clinical outcomes were reviewed, and data were collected regarding operative details, perioperative and postoperative complications, symptoms, and follow-up imaging. Radiologic evidence of any size hiatal hernia was considered to indicate a recurrence. RESULTS: There were 95 female and 31 male patients with a mean age (±standard deviation) of 71±14 years. Laparoscopic repair was completed successfully in 120 of 126 patients, with 6 operations converted to open procedures. Crural reinforcement with mesh was performed in 79% of patients, and 11% underwent a Collis gastroplasty. Fundoplications were performed in 90% of patients: Nissen (112), Dor (1), and Toupet (1). Radiographic surveillance, obtained at a mean time interval of 23 months postoperatively, was available in 89 of 126 patients (71%). Radiographic evidence of a recurrence was present in 19 patients (21%). Reoperation was necessary in 6 patients (5%): 5 for symptomatic recurrence (4%) and 1 for dysphagia (1%). The median length of stay was 4 days. CONCLUSION: Laparoscopic paraesophageal hernia repair results in an excellent outcome with a short length of stay when performed at an experienced center. Radiologic recurrence is observed relatively frequently with routine surveillance; however, many of these recurrences are small, and few patients require correction of the recurrence. Furthermore, these small recurrent hernias are often asymptomatic and do not seem to be associated with the same risk of severe complications developing as the initial paraesophageal hernia.

Simultaneous laparoscopic paraesophageal hernia repair and sleeve gastrectomy in the morbidly obese.

BACKGROUND: Morbid obesity is associated with increased rates of hiatal and paraesophageal hernias. Although laparoscopic sleeve gastrectomy is gaining popularity as the procedure of choice for morbid obesity, there is little data regarding the management of paraesophageal hernias found intraoperatively. The aim of this study was to evaluate the feasibility and benefits of a combined sleeve gastrectomy and paraesophageal hernia repair in morbidly obese patients. METHODS: From May 2011 to February 2013, 23 patients underwent laparoscopic sleeve gastrectomy combined with the repair of a paraesophageal hernia. Only 4 patients had a large hiatal hernia documented preoperatively on esophagogastroduodenoscopy (EGD). The body mass index (BMI), operative time, length of stay, and complications were evaluated. RESULTS: The average operative time was 165 minutes (115-240 minutes) and length of stay was 2.83 days (2-6 days). All patients were female except for one, with an average age of 53.4 years and a BMI of 41.9 kg/m(2). There were no complications during the procedures. Mean follow-up was 6.16 months (1-19 months), and mean excess weight loss was 39%. The average cost of admission for a combined procedure ($10,056), was slightly higher than a laparoscopic sleeve gastrectomy ($8905) or laparoscopic paraesophageal hernia repair ($8954) done separately. CONCLUSIONS: Laparoscopic sleeve gastrectomy combined with a paraesophageal hernia repair is well-tolerated and feasible in morbidly obese patients. Surgeons should be aware that preoperative EGD is not effective at diagnosing large hiatal or paraesophageal hernias. Surgeons with the skill set to repair paraesophageal hernias should do a combined procedure because it is well-tolerated, feasible, and can reduce the cost of multiple hospital admissions.

Periodontal infection, systemic inflammation, and insulin resistance: results from the continuous National Health and Nutrition Examination Survey (NHANES) 1999-2004.

OBJECTIVE: Adverse microbial exposures might contribute to diabetogenesis. We hypothesized that clinical periodontal disease (a manifestation of microbial exposures in dysbiotic biofilms) would be related to insulin resistance among diabetes-free participants. The roles of inflammatory mediation and effect modification were also studied. RESEARCH DESIGN AND METHODS: The continuous National Health and Nutrition Examination Survey 1999-2004 enrolled 3,616 participants (51% women) who received a periodontal examination and fasting blood draw. Participants were mean age (± SD) 43 ± 17 years and 28% Hispanic, 52% Caucasian, 17% African American, and 3% other. Log-transformed values of the homeostasis model assessment of insulin resistance (HOMA-IR) or HOMA-IR ≥3.30 (75th percentile) were regressed across full-mouth periodontal probing depth (PD) levels using linear and logistic models. White blood cell (WBC) count and C-reactive protein (CRP) were considered as either mediators or effect modifiers in separate analyses. Risk ratios (RRs) stem from marginal predictions derived from the logistic model. Results were adjusted for multiple periodontal disease and insulin resistance risk factors. RESULTS: In linear regression, geometric mean HOMA-IR levels increased by 1.04 for every 1-mm PD increase (P = 0.007). WBC mediated 6% of the association (P < 0.05). Among participants with WBC ≤6.4 × 10(9), PD was unrelated to HOMA-IR ≥3.30. Fourth-quartile PD was associated with HOMA-IR ≥3.30 among participants with WBC >7.9 × 10(9); RR 2.60 (1.36-4.97) (P for interaction = 0.05). Findings were similar among participants with CRP >3.0 mg/L (P for interaction = 0.04). CONCLUSIONS: Periodontal infection was associated with insulin resistance in a nationally representative U.S. sample of diabetes-free adults. These data support the role of inflammation as both mediator and effect modifier of the association.