Diagnostic Ultrasound for Acute Appendicitis: The Gold Standard.

BACKGROUND: Acute appendicitis may present a diagnostic dilemma. The aim of this study was to review the accuracy of ultrasound in the diagnosis of paediatric acute appendicitis. METHOD: Ultrasound studies performed for investigation of appendicitis during 2015-2021 were retrieved from a tertiary paediatric hospital database and reviewed. Medical records were reviewed to determine operative intervention, further imaging, and final diagnosis. Diagnostic accuracy was assessed by sensitivity, specificity, predictivity, and overall accuracy. All appendicectomy specimens underwent histopathological confirmation. This study was approved by the local Human Research Ethics Committee. RESULTS: A total of 8555 consecutive ultrasound examinations were performed during the study period. Mean patient age was 10.8 years ( ± 3.7). Overall diagnostic accuracy was 96.1% (8221/8555) with a visualisation rate of 91.0%. Sensitivity and specificity were 96.2% (CI 95.3-97.0%) and 96.1% (CI 95.6-96.5%), respectively. When limited to positive/negative scans, sensitivity was 99.6% (CI 99.2-99.8%) and specificity 99.0% (CI 98.7-99.3%). Positive and negative predictive values were 96.9% and 99.9%, respectively. Repeat ultrasound following a non-diagnostic scan led to a definitive diagnosis in 76.1%. Negative appendicectomy rate was 5.5% overall in children who had undergone pre-operative ultrasound (107/1938), and 4.4% when other surgical pathologies were excluded. CONCLUSION: Ultrasound examination provides gold-standard accuracy in the diagnosis of paediatric appendicitis and reduces rates of negative appendicectomy. Given the disadvantages of computed tomography and magnetic resonance imaging, ultrasound should be considered the first-line investigation of choice in the diagnosis of acute appendicitis in children. LEVEL OF EVIDENCE: III.

Ultrasound guided hydrostatic enema reduction of ileocolic intussusception: a safe and effective technique.

BACKGROUND: Currently, the primary management of ileocolic intussusception in children is usually by non-operative image-guided enema reduction. In most centres around the world especially in Australasia the predominant technique is the pneumatic reduction under fluoroscopic guidance. At our institution, we have been performing ultrasound-guided hydrostatic reduction since 2012.This is an audit to determine the efficacy and safety of ultrasound-guided hydrostatic reduction for intussusception. METHODS: Following ethics approval, a retrospective review of all patients presenting to our institution with intussusception and subsequently undergoing hydrostatic reduction over a period of 9 years (2012 to-2020) was performed. The parameters studied included (i) successful reduction, (ii) recurrence, (iii) need for surgery and (iv) lead point at surgery. RESULTS: The mean age at presentation was 12 months. One hundred and eight children were diagnosed to have ileocolic intussusception. One hundred and six underwent ultrasound-guided hydrostatic reduction with successful reduction in 96 (90.5%) patients. Reduction was unsuccessful in 10 patients (9.5%). Of these eight were noted to have a pathological lead point (four-Meckel's diverticulum and four-Lymphoma) at the time of the surgery. The intussusception recurred in six patients (6.25%) within 24 h. No reduction related perforation occurred during the study period. CONCLUSION: Ultrasound-guided hydrostatic reduction is a safe and effective technique for managing intussusception as it allows continuous monitoring of the reduction of the intussusception without exposing the children to ionizing radiation.

Ultrasound diagnosis of hypertrophic pyloric stenosis - Time to change the criteria.

Introduction: Ultrasound is the examination of choice for the diagnosis of hypertrophic pyloric stenosis (HPS). A correct diagnosis is dependent on the technique and measurement accuracy. However, in the world literature there is a wide range of values suggested for the diagnosis of this condition. The current minimum measurements used to diagnose HPS seem excessively large, and therefore, we set out to redefine these values. Methods: A retrospective study was performed on 607 patients (615 scans) being investigated for HPS. The length and transverse diameter of the pyloric canal, and thickness of the pyloric muscle were measured. All results were correlated with clinical and surgical findings. Results: In this study, the muscle thickness in the normal group was <2.0 mm than in HPS infants having a muscle thickness of 2.0-5.0 mm. All the pyloric canal lengths in the normal group were <5.0 mm than in those with HPS having a length of 10.0-24.0 mm. The transverse diameters ranged from 6.0 to 11.0 mm in the normal group compared with those with HPS having a diameter between 8.0 and 16.0 mm. Conclusions: The current criteria for sonographic diagnosis of HPS should be redefined. The canal length is the single most important discriminator, with a clear separation between normal and abnormal. The commonly used 16.0-mm measurement is too long and should be reduced to 10.0 mm (without the risk of false positives). In many cases, the muscle thickness in those with HPS is as low as 2.0 mm, considerably less than the 3.0 mm that is currently used. The transverse diameter is not a useful discriminator for HPS. The use of current values will delay the diagnosis and timely treatment of this condition.

Vascular Function and Distribution of Adiponectin Isomers during Puberty in Children and Adolescents with Obesity.

INTRODUCTION: Youth with obesity have abnormal vascular function that relates to the anti-atherogenic adipose-derived hormone, adiponectin. The distribution of adiponectin isomers changes during normal puberty, but there are no data in relation to vascular function. We aimed to evaluate vascular function, adiponectin, and its isomers longitudinally in peri-pubertal youth with obesity and controls. METHODS: The study is a cohort longitudinal study involving 30 children and adolescents with obesity (body mass index [BMI] z-score 2.31 ± 0.24; age 12.8 ± 3 years, 17 male participants) and 28 age-/sex-matched healthy controls (12.8 ± 3 years, 14 male participants). Vascular function (flow-mediated dilatation [FMD], glyceryl trinitrate-mediated dilatation [GTN]), total adiponectin and isomers, and laboratory and clinical variables were assessed at 0, 18, and 36 months. RESULTS: FMD and GTN were stable during puberty in both groups, remaining consistently lower in obese children (p = 0.02, p < 0.001). The change in total (p = 0.02) and high-molecular weight (HMW) (p = 0.02) adiponectin differed between the groups: falling in controls by the end of puberty but not falling further during puberty in obesity. In obesity, impaired GTN was associated longitudinally with lower total (B = 7.85, p = 0.006) and HMW (B = 3.72, p = 0.03) adiponectin. In controls, more favourable GTN was longitudinally associated with a lower BMI z-score (B = -3.04, p = 0.027) and lower waist circumference (B = -0.35, p = 0.009). CONCLUSIONS: Vascular dysfunction and lower levels of adiponectin are associated in children and adolescents with obesity during puberty and do not deteriorate further. Healthy children's better vascular function, within the normal range, is associated with a lower BMI z-score and waist circumference.

Ultrasound imaging as the first line of investigation to diagnose intestinal malrotation in children: Safety and efficacy.

BACKGROUND: Upper gastrointestinal contrast study is considered the gold standard investigation to diagnose intestinal malrotation and midgut volvulus which is potentially devastating condition. Ultrasound imaging is an alternative but has been considered unreliable due to significant false negative results. At our institution we have been using ultrasound imaging as the first line investigation to diagnose malrotation since 2008 with a preliminary study of 139 patients published in 2014. This is an ongoing audit of a further much larger cohort of patients to determine the efficacy and safety of ultrasound imaging in the diagnosis of intestinal malrotation. MATERIALS AND METHODS: Following ethics approval, a retrospective analysis of a prospectively collected patient database undergoing ultrasound scans to exclude malrotation at our centre was performed from 2012 to 2019. RESULTS: 539 patients underwent ultrasound to assess for malrotation. The mean age of presentation was 365 days (median 30 days, mode 1 day). Malrotation was diagnosed in 17 with 5 having volvulus, with findings confirmed at surgery. 12 had equivocal findings and subsequent contrast studies ruled out malrotation. The remaining 510 patients with no evidence of malrotation were managed conservatively. CONCLUSION: We have shown ultrasound to be a safe and effective tool to assess intestinal malrotation without exposure to ionizing radiation. LEVEL OF EVIDENCE: Level IV.

The coronal aorto-mesenteric orientation theory for post-operative nausea and vomiting following scoliosis surgery in children: a pilot study.

BACKGROUND: Post-operative nausea and vomiting (PONV) is often encountered following corrective scoliosis surgery in children, frequently attributed to high-dose opiate administration. PONV is a frequent cause of prolonged hospital stay. Mechanisms related to transient partial duodenal compression by narrow angulation of the superior mesenteric artery (SMA) and aorta following scoliosis surgery are poorly understood and might be implicated in PONV. This study investigates relationships between biomechanical anatomic variations of the SMA and aorta, and its relationship with clinically significant PONV following scoliosis surgery in children. METHODS: Children undergoing elective spinal arthrodesis for adolescent idiopathic scoliosis were assessed by preoperative abdominal ultrasound and spinal X-ray prior to surgery. Post-operative assessment of clinically significant PONV is compared to preoperative imaging and clinical variables. RESULTS: Thirteen patients (11 female and two male), with a mean age of 14 years and 1 month were included. Five patients (38.5%) developed clinically significant PONV. A significant association was observed between the coronal aorto-mesenteric orientation and PONV (P = 0.035). Of the five patients who developed PONV, two had direct coronal angulation of the SMA, one had left angulation and two had right angulation. Patients with significant PONV had narrower aorto-mesenteric distances which approached significance (P = 0.06). No other preoperative variable reached significance. CONCLUSION: Patients with coronal aorto-mesenteric orientation preoperatively appear at greater risk of developing significant PONV following scoliosis surgery, independent of opiate requirements, prompting consideration of transient partial duodenal obstruction as an important factor in the mechanisms of PONV. A coronal aorto-mesenteric orientation theory (CAMOT) is proposed to explain this biomechanical vascular 'scissor'.

Early atherosclerosis is associated with retinal microvascular changes in adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: Adolescents with type 1 diabetes have early macrovascular changes (increased intima-media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross-sectionally and longitudinally in adolescents with type 1 diabetes. METHODS: Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. RESULTS: There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 µm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 µm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). CONCLUSIONS: The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention.

Diagnosis and management of omental infarction in children: Our 10 year experience with ultrasound.

AIM: To review children with Omental Infarction (OI) and the role of Ultrasound Scan (US) in its diagnosis and management. METHODS: Cases of OI were identified retrospectively from 2004 to 2014 through screening of admission coding, pathology databases and radiology records. Demographic, clinical and pathological data were extracted from case records. MAIN RESULTS: 30 cases were identified (17 male, 13 female). Mean age was 10.7years (range 3.5-17.2). The majority of the patients were grossly overweight, with 83.3% of patients weighing greater than the mean for their age. All patients underwent at least one US, 4 had a repeat US and 1 patient also had a CT to rule out appendicitis after a US demonstrating OI. OI was demonstrated in 26 initial USs; in 4 cases initial USs were negative but repeat USs correctly detected OI. In 34 USs the appendix was identified on 20 occasions (15 normal, equivocal in 5). 13 patients underwent surgery, while 17 were managed nonoperatively; 7 underwent omentectomy only, 5 had omentectomy plus appendicectomy and 1 underwent appendicectomy only. All 12 omentectomy specimens were confirmed as OI histologically while none of the 6 appendices showed inflammation histologically. There were no postoperative complications. CONCLUSION: In a large series we have demonstrated the efficacy of US in the diagnosis and management of OI in children. To our knowledge this is the largest series of its kind to date. No patient with OI was incorrectly diagnosed with acute appendicitis or vice versa. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Retrospective Case Series.

Dietary sodium intake relates to vascular health in children with type 1 diabetes.

BACKGROUND AND OBJECTIVE: Children with type 1 diabetes (T1D) have vascular dysfunction and frequently struggle to adhere to dietary recommendations. Limited data exist for the vascular consequences of poor diet quality in children. We aimed to evaluate the association between dietary components and vascular function in children with T1D. METHODS: Cross-sectional study including 90 children (13.6 [3.5] years, 41 boys) with T1D. They had evaluation of dietary micro and macronutrients (Australian Child and Adolescent Eating Survey), vascular endothelial and smooth muscle function (flow-mediated dilatation and glyceryl trinitrate mediated dilatation [GTN], respectively), clinical and biochemical variables. RESULTS: Children had a sodium intake of 3.013 (0.76) (mean [SD]) g/day. Vascular smooth muscle dysfunction, as measured by GTN, related to higher daily sodium intake (r = -0.31, P = .003), independent of the inverse relationships between GTN and total energy (r = -0.30, P = .005) and fat intake (r = -0.28, P = .007). Multiregression model showed that an increase in 1 g of daily sodium intake was independently associated with a deterioration of 3 percentage units in GTN (95% CI -4.3, -0.9; P = .003). There was an association between sodium intake and systolic blood pressure after adjustment for age and gender (regression coefficient 2.4; 95% CI 0.5, 4.3; P = .01). CONCLUSIONS: High dietary sodium intake in children with T1D is common and relates to vascular dysfunction, independently of other dietary intake, blood pressure, and glycemic control.

Children With Type 1 Diabetes Have Delayed Flow-Mediated Dilation.

OBJECTIVES: Children with type 1 diabetes have accelerated atherosclerosis with early endothelial dysfunction as measured by reduced flow-mediated dilation (FMD) at 60 seconds postischemic stress (early FMD). Delayed dilation may also occur in the presence of cardiovascular risk factors and may be a more sensitive marker. No data exist that evaluate FMD beyond 60 seconds (delayed FMD) in children with type 1 diabetes. We aimed to compare early and delayed FMD in children with type 1 diabetes and in healthy children. METHODS: We studied 66 children 13.5±2.8 years of age; 29 were males. Of the 66 children, 38 had type 1 diabetes, and 28 were healthy age- and gender-matched controls. Evaluation of brachial artery FMD was performed at 60 seconds (FMD60s) and 120 seconds (FMD120s) postischemic stress. Early FMD was defined as peak FMD60s and delayed FMD as peak FMD120s. RESULTS: Children with type 1 diabetes had diabetes durations of 5.4±4.6 years and median glycated hemoglobin levels of 8.8 (6.6 to 14)% (73 [49 to 130] mmol/mol). Of the children, 8 with type 1 diabetes and 1 healthy child had delayed FMD; a relationship was seen between the prevalence of early FMD and delayed FMD in children with type 1 diabetes and healthy children, respectively (p=0.019). Children with type 1 diabetes and delayed FMD had lower FMD60s than children without delayed FMD (2.50±3.61 vs. 6.14±3.83 percentage units; p=0.02). Children with type 1 diabetes had lower FMD60s than healthy children (5.38±4.0 percentage units; p=0.03) but not FMD120s (7.56±3.5 percentage units; p=0.47). CONCLUSIONS: Delayed FMD patterns occur in children with type 1 diabetes and detect children who have more severe vascular abnormalities. The standard FMD60s remains the better marker to identify children at increased risk for cardiovascular disease.

Effect of Metformin on Vascular Function in Children With Type 1 Diabetes: A 12-Month Randomized Controlled Trial.

Context: Children with type 1 diabetes have vascular dysfunction preceding atherosclerosis. Early interventions are needed to reduce cardiovascular disease. Objective: To evaluate the effect of metformin on vascular function in children with type 1 diabetes. Design: Twelve-month double-blind, randomized, placebo-controlled trial. Setting: Tertiary pediatric diabetes clinic. Participants: Ninety children (8 to 18 years of age), >50th percentile body mass index (BMI), with type 1 diabetes. Intervention: Metformin (up to 1 g twice a day) or placebo. Main Outcome Measure: Vascular function measured by brachial artery ultrasound [flow-mediated dilatation/glyceryl trinitrate-mediated dilatation (GTN)]. Results: Ninety participants were enrolled [41 boys, 13.6 (2.5) years of age, 45 per group], 10 discontinued intervention, and 1 was lost to follow-up. On metformin, GTN improved, independent of glycosylated hemoglobin (HbA1c), by 3.3 percentage units [95% confidence interval (CI) 0.3, 6.3, P = 0.03] and insulin dose reduced by 0.2 U/kg/d (95% CI 0.1, 0.3, P = 0.001) during 12 months, with effects from 3 months. Metformin had a beneficial effect on HbA1c at 3 months (P = 0.001) and difference in adjusted HbA1c between groups during 12 months was 1.0%; 95% CI 0.4, 1.5 (10.9 mmol/mol; 95% CI 4.4, 16.4), P = 0.001. There were no effects on carotid/aortic intima media thickness, BMI, lipids, blood pressure, or other cardiovascular risk factors. Median (95% CI) adherence, evaluated by electronic monitoring, was 75.5% (65.7, 81.5), without group differences. More gastrointestinal side effects were reported on metformin (incidence rate ratio 1.65, 95% CI 1.08, 2.52, P = 0.02), with no difference in hypoglycemia or diabetic ketoacidosis. Conclusions: Metformin improved vascular smooth muscle function and HbA1c, and lowered insulin dose in type 1 diabetes children. These benefits and good safety profile warrant further consideration of its use.

Benchmarking the value of ultrasound for acute appendicitis in children.

BACKGROUND: This study appraises the diagnostic quality of ultrasound for acute appendicitis in children and consequently challenges the perception of inferior accuracy and suitability compared to computed tomography (CT). METHODS: Radiologist reports for consecutive "query appendicitis" ultrasound studies were retrieved from a hospital database for the study period 2009-2014. Children who subsequently underwent appendicectomy were identified. Corresponding operative and histopathology findings were evaluated. Diagnostic accuracy of ultrasound was determined by analyzing overall accuracy, sensitivity, specificity, predictivity, and likelihood ratios. RESULTS: A total of 3799 ultrasound examinations were evaluated. Mean age was 11.5±3.8years. The proportion of patients investigated with preoperative ultrasound was 59.9% (1103/1840). Appendix visualization rate was 91.7%. Overall diagnostic accuracy was 95.5%. Sensitivity and specificity values were 97.1% (95.9-98.1; 95% CI) and 94.8% (93.9-95.6; 95% CI), respectively. Separate analysis of only ultrasound positive and negative examinations (i.e., excluding nondiagnostic examinations) confirmed sensitivity and specificity values of 98.8% and 98.3%. CONCLUSION: In this largest reported single institution series of ultrasound examinations for appendicitis, we report benchmark standard quality of diagnostic accuracy and visualization rates. Given the radiation and cost implications of CT, there is a strong argument to recommend ultrasound as the primary imaging modality. Diagnostic Study-Level II.

Lack of evidence for progression of atherosclerosis during puberty in type 1 diabetes.

OBJECTIVES: Children with type 1 diabetes have early changes in vascular structure with increased aortic intima-media thickness (aIMT) or carotid IMT (cIMT). aIMT may be an earlier, more sensitive marker; however, longitudinal data in type 1 diabetes are lacking. This study will aim to evaluate changes in vascular structure (aIMT and cIMT) over 2 yr during puberty in children with type 1 diabetes and compare them with those in healthy children. RESEARCH DESIGN AND METHODS: A total of 110 children (aged 10-18 yr, 55 males) participated in a prospective cohort study, including 77 children with type 1 diabetes and 33 age- and sex-matched healthy children. Ultrasound assessments of aIMT and cIMT; and clinical and biochemical data were collected at baseline and 2 yr later. RESULTS: Mean and maximal aIMT or cIMT did not worsen over time in children with type 1 diabetes compared with healthy children. Longer duration of diabetes related to an increase in aIMT. Improvement in HDL cholesterol and leptin related to a decrease in aIMT. Higher baseline IMT related to an improvement in IMT in children with type 1 diabetes (mean and maximal aIMT: ß = -0.52, p < 0.001; ß = -0.49, p = 0.001, and mean and maximal cIMT: ß = -0.36, p = 0.003; ß = -0.40, p = 0.001), independent of cardiovascular risk factors. CONCLUSIONS: Aortic and carotid IMT does not deteriorate during puberty in children with type 1 diabetes. This has implications for the design of interventional studies in this important age group.

Delayed brachial artery dilation response and increased resting blood flow velocity in young children with mild sleep-disordered breathing.

AIM: This study aimed to evaluate whether the vascular dysfunction perceived in adults with sleep-disordered breathing (SDB) was also evident in children with snoring referred for evaluation of clinically suspected SDB. OBJECTIVES: This study compared flow-mediated dilatation (FMD), measured at the brachial artery, at rest and during hyperaemic stress between children who snore [n = 23; mean standard deviation (SD) age = 7.51 (1.3) years] and healthy, non-snoring children [n = 11; age = 8.0 (1.3) years]. METHODS: Children with suspected obstructive sleep apnoea (OSA) and healthy non-snoring controls underwent overnight polysomnography (PSG). Using standard techniques, non-invasive FMD and brachial arterial blood flow velocity during rest and hyperaemia were subsequently measured by ultrasound imaging MEASUREMENTS: Resting and hyperaemic velocity time integral (area under the curve of mean systolic velocity × ejection time), maximal dilation response (highest percentage difference from baseline diameter) and the time taken to reach maximal dilation were calculated. RESULTS: Children awaiting adenotonsillectomy compared to healthy non-snoring control children had higher velocity time integrals at rest (14 ± 3 m vs. 20 ± 8 m, p < 0.01) and during hyperaemic stress (56 ± 6m vs. 63 ± 13m, p < 0.01) despite having only mild SDB on polysomnographic assessment. Lower nadir oxygen saturation values during non-rapid eye movement sleep were negatively associated with higher resting (r = -0.58, p <0.001) and hyperaemic (r = -0.36, p < 0.05) velocity time integrals. Maximal FMD dilatation response was not significantly different between snoring and non-snoring groups, but the estimated time to reach maximal dilation was significantly delayed in children who snored (60.7 ± 28.4 vs. 39.2 ± 13.2 s, p < 0.05). CONCLUSIONS: Children with mild SDB showed increased blood flow velocity at rest and during hyperaemic stress suggesting altered cardiovascular and haemodynamic function. The delay in time to maximal vessel dilatation in children who snored also suggests possible reduced vascular compliance in response to hyperaemic sheer stress. Mild SDB appears to alter the peripheral vascular response in young children. The long-term vascular implications of these changes in the growing child are unknown and warrant further investigation.

Flow-mediated dilatation, using time course data, shows maturation of the brachial artery from young children to mid-adolescents.

Flow-mediated dilatation (FMD) is a tool widely used to measure arterial responsiveness to sheer stress. However, there is scant literature to show how the peripheral arterial response changes as the vascular system matures. One reason for this is that the feasibility of measuring FMD in younger children has not been established. The aim of the present study was to assess brachial artery function at rest and during the FMD response after 4 min ischaemia of the forearm in children aged 6-15 years. Time to reach maximum FMD (FMDmax ) was found to be correlated with age (r = 0.4, P < 0.05), resting brachial artery diameter (r = 0.4, P < 0.05), height (r = 0.4, P < 0.05), body mass index (BMI; r = 0.45, P < 0.05), body surface area (r = 0.44, P < 0.05) and resting blood flow (r = 0.37, P < 0.05). However, there was no correlation between the traditional FMD response at 60 s or FMD maximal dilation and age, resting brachial artery diameter, height, weight, BMI, body surface area and resting blood flow. In conclusion, the time taken to reach the maximal dilation response is related to age, brachial artery luminal diameter and body habitus, but not the traditional measure of FMD response at 60 s or the maximal dilatation percentage.

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

OBJECTIVE: To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity. STUDY DESIGN: A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies. RESULTS: Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001). CONCLUSIONS: A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies.