Coronary Artery Calcium and Cognitive Decline in the Diabetes Prevention Program Outcomes Study.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience.

OBJECTIVE: To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS: By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20-0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46-1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS: DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Managing Atherosclerotic Cardiovascular Risk in Young Adults: JACC State-of-the-Art Review.

There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians identify and address high-risk conditions in the 20- to 39-year age range (young adults). These include tobacco use, elevated blood pressure/hypertension, family history of premature ASCVD, primary severe hypercholesterolemia such as familial hypercholesterolemia, diabetes with diabetes-specific risk-enhancing factors, or the presence of multiple other risk-enhancing factors, including in females, a history of pre-eclampsia or menopause under age 40. The authors update current thinking on lipid risk factors such as triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, or lipoprotein (a) that are useful in understanding an individual's long-term ASCVD risk. The authors review emerging strategies, such as coronary artery calcium and polygenic risk scores in this age group, that have potential clinical utility, but whose best use remains uncertain. Finally, the authors discuss both the obstacles and opportunities for addressing prevention in early adulthood.

Augmented Reality-Assisted Video Laryngoscopy and Simulated Neonatal Intubations: A Pilot Study.

BACKGROUND: For novice providers, achieving competency in neonatal intubation is becoming increasingly difficult, possibly because of fewer intubation opportunities. In the present study, we compared intubation outcomes on manikins using direct laryngoscopy (DL), indirect video laryngoscopy (IVL) using a modified disposable blade, and augmented reality-assisted video laryngoscopy (ARVL), a novel technique using smart glasses to project a magnified video of the airway into the intubator's visual field. METHODS: Neonatal intensive care nurses (n = 45) with minimal simulated intubation experience were randomly assigned (n = 15) to the following 3 groups: DL, IVL, and ARVL. All participants completed 5 intubation attempts on a manikin using their assigned modalities and received verbal coaching by a supervisor, who viewed the video while assisting the IVL and ARVL groups. The outcome and time of each attempt were recorded. RESULTS: The DL group successfully intubated on 32% of attempts compared to 72% in the IVL group and 71% in the ARVL group (P < .001). The DL group intubated the esophagus on 27% of attempts, whereas there were no esophageal intubations in either the IVL or ARVL groups (P < .001). The median (interquartile range) time to intubate in the DL group was 35.6 (22.9-58.0) seconds, compared to 21.6 (13.9-31.9) seconds in the IVL group and 20.7 (13.2-36.5) seconds in the ARVL group (P < .001). CONCLUSIONS: Simulated intubation success of neonatal intensive care nurses was significantly improved by using either IVL or ARVL compared to DL. Future prospective studies are needed to explore the potential benefits of this technology when used in real patients.

The use of supplemental hydrocortisone in the management of persistent pulmonary hypertension of the newborn.

OBJECTIVE: Characterize association between hydrocortisone receipt and hospital outcomes of infants with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: Cohort study of infants ≥34 weeks with PPHN who received inhaled nitric oxide at <7 days of age (2010-2016). We generated propensity scores, and performed inverse probability-weighted regression to estimate hydrocortisone effect on outcomes: death, chronic lung disease (CLD), oxygen at discharge. RESULTS: Of 2743 infants, 30% received hydrocortisone, which was associated with exposure to mechanical ventilation, sedatives, paralytics, or vasopressors (p < 0.001). There was no difference in death, CLD, or oxygen at discharge. In infants with meconium aspiration syndrome, hydrocortisone was associated with decreased oxygen at discharge (odds ratio 0.56; 95% confidence interval 0.21, 0.91). CONCLUSIONS: There was no association between hydrocortisone receipt and death, CLD, or oxygen at discharge in our cohort. Prospective studies are needed to evaluate the effectiveness of hydrocortisone in infants with PPHN.

Survival, Morbidities, and Developmental Outcomes among Low Birth Weight Infants with Congenital Heart Defects.

OBJECTIVE: Prematurity and low birth weight (LBW) are risk factors for increased morbidity and mortality in infants with congenital heart defects (CHDs). We sought to describe survival, inhospital morbidities, and 2-year neurodevelopmental follow-up in LBW infants with CHD. STUDY DESIGN: We included infants with birth weight (BW) <2,500 g diagnosed with CHD (except isolated patent ductus arteriosus) admitted January 2013 to March 2016 to a single level-IV academic neonatal intensive care unit. We reported CHD prevalence by BW and gestational age; selected in-hospital morbidities and mortality by infant BW, CHD type, and surgical intervention; and developmental outcomes by Bayley's scales of infant and toddler development, third edition (BSID-III) scores at age 2 years. RESULTS: Among 420 infants with CHD, 28 (7%) underwent cardiac surgery. Median (25th and 75th percentiles) gestational age was 30 (range: 27-33) weeks and BW was 1,258 (range: 870-1,853) g. There were 134 of 420 (32%) extremely LBW (<1,000 g) infants, 82 of 420 (20%) were small for gestational age, and 51 of 420 (12%) multiples. Most common diagnosis: atrial septal defect (260/420, 62%), followed by congenital anomaly of the pulmonary valve (75/420, 18%). Most common surgical procedure: pulmonary artery banding (5/28, 18%), followed by the tetralogy of Fallot corrective repair (4/28, 14%). Survival to discharge was 88% overall and lower among extremely LBW (<1,000 g, 81%) infants and infants undergoing surgery (79%). Comorbidities were common (35%); retinopathy of prematurity and bronchopulmonary dysplasia were most prevalent. BSID-III scores were available on 148 of 176 (84%); any scores <85 were noted in 73 of 148 (49%), with language being most commonly affected. CONCLUSION: Among LBW infants with congenital heart disease, hospital mortality varied by BW and cardiac diagnosis. KEY POINTS: · In low birth weight infants with congenital heart disease, survival varied by birth weight and cardiac diagnosis.. · Overall survival was higher than previously reported.. · There were fewer morbidities than previously reported.. · Bayley's scale-III scores at 2 years of age were <85 for nearly half..

Clinical Approach to Assessment and Amelioration of Atherosclerotic Vascular Disease in Diabetes.

Atherosclerotic cardiovascular disease is increased on average 2-3-fold in people with diabetes as compared to their non-diabetic counterparts and is the major cause of the increased morbidity and mortality in this disease. There is however heterogeneity in cardiovascular risk between individuals based on demographic, cardiometabolic and clinical risk factors in the setting of hyperglycemia, insulin resistance and obesity that needs to be taken into consideration in planning preventive interventions. Randomized clinical trials of agents or procedures used for amelioration of augmented CVD risk in diabetes have been pivotal in providing evidenced-based treatments. Improvement in hyperglycemia in both type 1 and type 2 diabetes is considered to be central in the prevention of microvascular and macrovascular complications although selected antihyperglycemic agents have demonstrated beneficial as well as possible deleterious off-target effects. Lowering low density lipoprotein cholesterol, treating hypertension and stopping smoking each play important roles in preventing cardiovascular disease in diabetes as they do in the general population and low dose aspirin is overall beneficial in high risk individuals. Hypertriglyceridemia may represent another important marker for augmented cardiovascular risk in diabetes and newer agents targeting dyslipidemia appear promising. The fall in cardiovascular events over the past two decades offers hope that modern intervention strategies as well as novel approaches such as those targeting inflammation may contribute to a continued reduction of cardiovascular disease in people with diabetes.

Gastrostomy Tube Feeding in Extremely Low Birthweight Infants: Frequency, Associated Comorbidities, and Long-term Outcomes.

OBJECTIVE: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes. STUDY DESIGN: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables. RESULTS: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up. CONCLUSIONS: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions.

AIMS/HYPOTHESIS: We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.

Prolonged furosemide exposure and risk of abnormal newborn hearing screen in premature infants.

BACKGROUND: At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. AIMS: Evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants. STUDY DESIGN: Using propensity scoring, infants with prolonged (≥28 days) exposure to furosemide were matched to infants never exposed. The matched sample was used to estimate the impact of prolonged furosemide exposure on the probability of an abnormal hearing screen prior to hospital discharge. SUBJECTS: A cohort of infants 501-1250 g birth weight and 23-29 weeks gestational age discharged home from 210 neonatal intensive care units in the United States (2004-2013). OUTCOME MEASURES: We defined abnormal hearing screen as a result of either "fail" or "refer" for either ear. RESULTS: Altogether, 1020 infants exposed to furosemide for ≥28 days were matched to 790 unique infants never exposed, yielding a total of 1042 matches due to sampling with replacement and propensity score ties. Matching resulted in a population similar in baseline characteristics. After adjusting for covariates, the proportion of infants with an abnormal hearing screen in the furosemide-exposed group was not significantly higher than the never-exposed group (absolute difference 3.0% [95% CI -0.2-6.2%], P = 0.07). CONCLUSIONS: Prolonged furosemide exposure was associated with a positive, but not statistically significant, difference in abnormal hearing screening in premature infants. Additional studies with post-hospital discharge audiology follow-up are needed to further evaluate the safety of furosemide in this population.

Androgens, Irregular Menses, and Risk of Diabetes and Coronary Artery Calcification in the Diabetes Prevention Program.

Context: It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant. Research Design and Methods: We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IM was associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c. Results: Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06; 95% CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed. Conclusions: Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC.

Depressive Symptoms, Antidepressant Medication Use, and Inflammatory Markers in the Diabetes Prevention Program.

OBJECTIVE: Antidepressant medication use (ADM) has been shown to predict diabetes. This article assessed the role of inflammatory markers in this relationship within the Diabetes Prevention Program (DPP). METHODS: DPP participants randomized to metformin (MET), life-style intervention (ILS), or placebo (PLB) were assessed for depression (Beck Depression Inventory [BDI]) annually, ADM use semiannually, serum inflammatory markers (C-reactive protein [CRP], interleukin 6 [IL-6]) at baseline and year 1, and diagnosis of type 2 diabetes mellitus (T2DM) semiannually (for 3.2 years). RESULTS: At baseline (N = 3187), M (SD) body mass index was 34 (6) kg/m and the median (interquartile range) BDI score was 3 (1-7). One hundred eighty-one (5.7%) reported ADM use and 328 (10%) had BDI scores of 11 or higher. CRP and IL-6 levels did not differ by treatment group. Baseline ADM, but not BDI score, was associated with higher levels of baseline CRP adjusted for demographic, anthropometric variables, and other medications (20% higher, p = .01). Year 1 CRP decreased for non-ADM users in the MET (-13.2%) and ILS (-34%) groups and ADM users in the ILS group (-29%). No associations were found with IL-6. CRP and continuous use of ADM predicted incident T2DM in the PLB group. In the ILS group, continuous and intermittent ADM, but not CRP, predicted T2DM. In the MET group, CRP predicted incident T2DM. CRP did not mediate the risk of T2DM with ADM use in any group. CONCLUSIONS: ADM was significantly associated with elevated CRP and incident T2DM. In the PLB group, ADM and CRP independently predicted onset of T2DM; however, CRP did not significantly mediate the effect of ADM.

Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease. OBJECTIVE: We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks' postmenstrual age. STUDY DESIGN: Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks' gestational age with a birthweight of ≥401 g born from Jan. 1, 2006, through Dec. 31, 2014, were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks' postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch. RESULTS: Infants exposed to any antenatal corticosteroids had a lower rate of death (2193/9670 [22.7%]) compared to infants without exposure (540/1302 [41.5%]) (adjusted relative risk, 0.71; 95% confidence interval, 0.65-0.76; P < .0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death (654/2520 [26.0%]) compared to infants without exposure (540/1302 [41.5%]); (adjusted relative risk, 0.77; 95% confidence interval, 0.70-0.85; P < .0001). In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23-27 weeks' gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks' gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure. CONCLUSION: Among infants 22-28 weeks' gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ.

Markers of Successful Extubation in Extremely Preterm Infants, and Morbidity After Failed Extubation.

OBJECTIVES: To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. STUDY DESIGN: This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Network's Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks' gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. RESULTS: Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non-small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/ bronchopulmonary dysplasia (OR 3.27). CONCLUSIONS: Higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00233324.

A Shift in ApoM/S1P Between HDL-Particles in Women With Type 1 Diabetes Mellitus Is Associated With Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex.

OBJECTIVE: Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. APPROACH AND RESULTS: ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1- receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. CONCLUSIONS: ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

Mechanism of inhibition of botulinum neurotoxin type A light chain by two quinolinol compounds.

Quinolinol-based compounds are a promising starting point for discovery of effective inhibitors of the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism of inhibition by quinolinol compounds facilitate interpretation of docking data and inhibitor optimization. In this study, a fluorogenic substrate of BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 µM and 5.8 µM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors of BoNT/A LC with inhibition constants (KI) 3.2 µM and 6.2 µM for MSU58 and MSU84, respectively. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding of the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis.

New JAG1 Mutation Causing Alagille Syndrome Presenting With Severe Hypercholesterolemia: Case Report With Emphasis on Genetics and Lipid Abnormalities.

Context: Alagille syndrome is a rare autosomal-dominant genetic disorder caused by defects in the Notch signaling pathway, which involves multiple organ systems. Bile duct paucity is the main characteristic feature of the disease, which often leads to cholestatic hypercholesterolemia. Case Description: We report the case of a male infant who had developed failure to thrive, jaundice, intermittent pruritus, and multiple diffuse symmetrical skin xanthomas at 1 year of age. He was diagnosed with pulmonary stenosis, butterfly vertebrae of T4, T6, and T8; horseshoe kidney, and embryotoxon in the left eye. Laboratory workup revealed severe hypercholesterolemia. Alagille syndrome was suspected and confirmed by genetic testing, which identified a previously undescribed frameshift pathogenic heterozygous variant in the JAG1 gene, p.Arg486Lysfs*5. Conclusions: Here, we report a unique case of a patient diagnosed with Alagille syndrome who was found to have a previously undescribed frameshift pathogenic mutation in the JAG1 gene and who presented with xanthomatosis and levels of hypercholesterolemia more than 2 times higher than those previously reported in the literature. We also provide a review of the different pathophysiologic mechanisms associated with the increase in serum cholesterol and low-density lipoprotein cholesterol concentrations seen in cholestatic liver disease in general and in Alagille syndrome in particular.

Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants.

OBJECTIVE: To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. STUDY DESIGN: We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. RESULTS: The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. CONCLUSIONS: Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.