Nurturing the next generation of pediatric physician scientists: the Padova Physician Scientist Research Training for pediatric residents.

Less than 2% of physicians complete a research training (PhD) after the residency with a declining trend in those pursuing a clinical scientist pathway in pediatrics. The exposure to research methodology during the clinical training may play a role in engaging the next generations of pediatric physician scientist. Herein, we describe the experience of the Padova Physician Scientist Research Training (PPSRT) of the pediatric residency program at the University of Padova. The PPSRT was addressed to residents attending PGY2 to PGY4 of the pediatric program and consisted of two cores: a general one including in person or virtual lectures about research methodology in pediatrics including design of a clinical trial, writing of a scientific paper and statistical methods, and a subspecialties core for the discussion of research challenges in each area and the scientific writing activities. The perceived barriers to a research training and an evaluation of the program were assessed by an anonymized questionnaire. Sixty-four out 150 residents registered for the research training with 62/64 completing the two cores. The major perceived barrier to research during clinical training was the absence of protected time (89%) followed by the lack of specific funds (37%). The group activities lead to the publication of 24 papers.    Conclusion: This is the first experience in the Italian pediatric training of a dedicated research program within the frame of postgraduate medical education. Our report highlights the need for protected time to promote research interest and nurture a new generation of physician scientists. What is Known: • Training to medical research is not part of residency program. • The declining trend of physician scientists might be reverted by early exposure to research methodology and challenges during residency. What is New: • An early exposure to research training during pediatric residency increases the research engagement of pediatric residents. • The lack of protected time for research is perceived as the major barrier to research training during residency.

Impact of macronutrients intake on glycemic homeostasis of preterm infants: evidence from continuous glucose monitoring.

Nutritional intake could influence the blood glucose profile during early life of preterm infants. We investigated the impact of macronutrient intake on glycemic homeostasis using continuous glucose monitoring (CGM). We analyzed macronutrient intake in infants born ≤ 32 weeks gestational age (GA) and/or with birth weight ≤ 1500 g. CGM was started within 48 h of birth and maintained for 5 days. Mild and severe hypoglycemia were defined as sensor glucose (SG) < 72 mg/dL and <47 mg/dL, respectively, while mild and severe hyperglycemia were SG > 144 mg/dL and >180 mg/dL. Data from 30 participants were included (age 29.9 weeks (29.1; 31.2), birthweight 1230.5 g (1040.0; 1458.6)). A reduced time in mild hypoglycemia was associated to higher amino acids intake (p = 0.011) while increased exposure to hyperglycemia was observed in the presence of higher lipids intake (p = 0.031). The birthweight was the strongest predictor of neonatal glucose profile with an inverse relationship between the time spent in hyperglycemia and birthweight (p = 0.007).  Conclusions: Macronutrient intakes influence neonatal glucose profile as described by continuous glucose monitoring. CGM might contribute to adjust nutritional intakes in preterm infants. What is Known: • Parenteral nutrition may affect glucose profile during the first days of life of preterm infants. What is New: • Continuous glucose monitoring describes the relationship between daily parenteral nutrient intakes and time spent in hypo and hyperglycemic ranges.

The Impact of Antenatal Corticosteroids on the Metabolome of Preterm Newborns: An Untargeted Approach.

We analyzed and compared variations in the urinary metabolome, as well as postnatal clinical outcomes among preterm infants, based on the timing of antenatal corticosteroid (ACS) administration in response to preterm labor onset in their mothers. This was a prospective observational study held in the Neonatal Intensive Care Unit, Department of Woman's and Child's Health, Padova University Hospital (Italy). A urine sample was obtained from each patient within 24 h of birth; Mass Spectrometry-based untargeted metabolomics analysis was then conducted. We searched for any significant disparities in the metabolomic profile of preterm newborns subjected to antenatal corticosteroid (ACS) treatment at varying timings; their correlation with clinical outcomes were also evaluated. The group receiving ACS within the optimal time window (1-7 days before delivery) exhibited elevated levels of cysteine, N-acetylglutamine, propionyl carnitine and 5-hydroxyindolacetic acid, coupled with a decrease in pipecolic acid. Clinically, this group demonstrated a reduced need for invasive ventilation (p = 0.04). In conclusion, metabolomics analysis identified several metabolites that discriminated preterm infants whose mothers received ACS within the recommended time window. Elevated levels of cysteine and 5-Hydroxyindoleacetic acid, metabolites characterized by antioxidant and anti-inflammatory properties, were observed in these infants. This metabolic profile correlated with improved respiratory outcomes, as evidenced by a reduced necessity for invasive ventilation at birth.

Quantifying beta cell function in the preclinical stages of type 1 diabetes.

Clinically symptomatic type 1 diabetes (stage 3 type 1 diabetes) is preceded by a pre-symptomatic phase, characterised by progressive loss of functional beta cell mass after the onset of islet autoimmunity, with (stage 2) or without (stage 1) measurable changes in glucose profile during an OGTT. Identifying metabolic tests that can longitudinally track changes in beta cell function is of pivotal importance to track disease progression and measure the effect of disease-modifying interventions. In this review we describe the metabolic changes that occur in the early pre-symptomatic stages of type 1 diabetes with respect to both insulin secretion and insulin sensitivity, as well as the measurable outcomes that can be derived from the available tests. We also discuss the use of metabolic modelling to identify insulin secretion and sensitivity, and the measurable changes during dynamic tests such as the OGTT. Finally, we review the role of risk indices and minimally invasive measures such as those derived from the use of continuous glucose monitoring.

Obstructive sleep apnea (OSA) is associated with the impairment of beta-cell response to glucose in children and adolescents with obesity.

BACKGROUND: The main purpose of the study is to assess the association between obstructive sleep apnea (OSA) and insulin secretion in children with obesity. METHODS: We enrolled children and adolescents who attended our pediatric clinic because of obesity and OSA. Glucose homeostasis was assessed through standard 2-h oral glucose tolerance test (OGTT). Nocturnal cardio-respiratory polygraphy was performed for OSA diagnosis. Twenty-two patients underwent a 3-h OGTT to investigate insulin secretion and sensitivity through the oral-minimal model. RESULTS: seventy-seven children and adolescents were included in the study. Based on OSA severity, the cohort was divided into three groups (29 mild, 29 moderate, and 19 severe OSA). The group with mild OSA showed lower levels of 30-min glucose (p = 0.01) and 60-min glucose (p = 0.03), and lower prevalence of elevated 1-h glucose (10.4% versus 44.8% in moderate and 31.6% in severe OSA, p = 0.01). The odds for elevated 1-h plasma glucose was 6.2-fold (95%CI 1.6-23.4) higher in subjects with moderate and severe OSA compared to mild OSA (p = 0.007) independent of confounders. Spearman correlation test revealed a positive correlation between 30-min plasma glucose and apnea-hypopnea index (AHI, r = 0.31, p = 0.01), oxygen desaturation index (ODI, r = 0.31, p = 0.009), and mean desaturation (r = 0.25, p = 0.04). The 3-h OGTT study included 22 participants (7 mild, 9 moderate, and 6 severe OSA). The group with mild OSA showed a higher dynamic, static, and total insulin secretion compared to those with moderate and severe OSA (p < 0.0001, p = 0.007, p = 0.007, respectively). AHI was significantly correlated to dynamic insulin secretion (r = -0.48, p = 0.02). CONCLUSIONS: OSA might impair beta-cell function reducing the pool of promptly releasable insulin in children and adolescents with obesity, in the absence of an effect on insulin sensitivity.

Sumatriptan, a serotonin 5HT1B receptor agonist, acutely reduces insulin secretion and sensitivity and glucose effectiveness in overweight humans: A double-blinded placebo-controlled cross-over trial.

AIM: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B -receptor agonist) would alter glucose homeostasis in humans. MATERIALS AND METHODS: We conducted a two-visit random-order double-blinded placebo-controlled cross-over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60-min intravenous glucose tolerance test, followed by a 120-min hyperinsulinaemic euglycaemic clamp. RESULTS: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0-60 min 316 (268-333) vs. 251 (197-319) min/mmol/L p = .047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0-10 min 1626 (1103-2733) vs. 2336 (1702-3269) min/pmol/L, p = .005], reduced insulin sensitivity [M/I-value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p = .010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p = .027]. CONCLUSIONS: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness.

Glucose-to-lactate ratio and neurodevelopment in infants with hypoxic-ischemic encephalopathy: an observational study.

We aimed to assess the glucose and lactate kinetics during therapeutic hypothermia (TH) in infants with hypoxic-ischemic encephalopathy and its relationship with longitudinal neurodevelopment. We measured glucose and lactate concentrations before TH and on days 2 and 3 in infants with mild, moderate, and severe hypoxic-ischemic encephalopathy (HIE). Neurodevelopment was assessed at 2 years. Participants were grouped according to the neurodevelopmental outcome into favorable (FO) or unfavorable (UFO). Eighty-eight infants were evaluated at follow-up, 34 for the FO and 54 for the UFO group. Severe hypo- (< 2.6 mmol/L) and hyperglycemia (> 10 mmol/L) occurred in 18% and 36% from the FO and UFO groups, respectively. Glucose-to-lactate ratio on day 1 was the strongest predictor of unfavorable metabolic outcome (OR 3.27 [Formula: see text] 1.81, p = 0.032) when adjusted for other clinical and metabolic variables, including Sarnat score. CONCLUSION: Glucose-to-lactate ratio on day 1 may represent a new risk marker for infants with HIE undergoing TH. WHAT IS KNOWN: • Glucose and lactate are key metabolic fuels during neonatal hypoglycemia. This suggests that their concentrations may influence the neurodevelopmental outcome of neonates experiencing hypoxic-hischemic encephalopathy (HIE). WHAT IS NEW: • We describe the relative availbility of glucose and lactate before and during theraputic hypothermia in neonates with HIE.

Glucose variability increases during minimally invasive procedures in very preterm infants.

The objective of this study is to assess the effect of neonatal procedures on glucose variability in very preterm infants. Preterm infants (≤ 32 weeks gestation and/or birthweight ≤ 1500 g) were started on continuous glucose monitoring (CGM) on day 2 of birth and monitored for 5 days. Minimally invasive (heel stick, venipunctures) and non-invasive (nappy change, parental presence) procedures were recorded. CGM data were analyzed 30 min before and after each procedure. The primary outcome was the coefficient of glucose variation (CV = SD/mean) before and after the procedure; SD and median glucose were also evaluated. We analyzed 496 procedures in 22 neonates (GA 30.5 weeks [29-31]; birthweight 1300 g [950-1476]). Median glucose did not change before and after each procedure, while CV and SD increased after heel prick (p = 0.017 and 0.030), venipuncture (p = 0.010 and 0.030), and nappy change (p < 0.001 and < 0.001), in the absence of a difference during parental presence. CONCLUSIONS: Non-invasive and minimally invasive procedures increase glucose variability in the absence of changes of mean glucose. WHAT IS KNOWN: • Minimally invasive procedures - including nappy change - may increase neonatal stress in preterm infants. WHAT IS NEW: • Continuous glucose monitoring provides a quantitative measure of neonatal stress during neonatal care procedures demonstrating an increase of glucose variability.

Relation of glomerular filtration to insulin resistance and related risk factors in obese children.

BACKGROUND AND OBJECTIVE: Childhood obesity is associated with later development of significant renal morbidity. We evaluated the impact of the degree of insulin sensitivity on estimated glomerular filtration rate (eGFR) and determined the factors associated with eGFR in obese children. We further tested the relation of eGFR to clinical outcomes such as blood pressure and microalbuminuria. MATERIALS AND METHODS: We evaluated the relation of whole body insulin sensitivity and estimated glomerular filtration rate (eGFR) across the spectrum of obesity in children and adolescents. eGFR was calculated using the iCARE formula, which has been validated in obese children with varying glucose tolerance. RESULTS: 1080 children and adolescents with overweight and obesity (701 females and 379 males) participated. Insulin sensitivity was a strongly negatively associated with (B = -2.72, p < 0.001) eGFR), even after adjustment for potential confounders. Male sex emerged to be significantly associated with eGFR with boys having greater values than girls (B = 18.82, p < 0.001). Age was a positively associated (B = 2.86, p < 0.001) with eGFR. Whole body and hepatic insulin sensitivity decreased across eGFR quartiles. Adjusted eGFR was tightly positively associated with systolic blood pressure (B = 0.09, p = 0.003) and negatively associated with the presence of microalbuminuria (B = -2.18, p = 0.04). CONCLUSIONS: eGFR tends to increase with greater degrees of insulin resistance in children and adolescents representing hyperfiltration and is associated with cardiovascular risk factors. Longitudinal studies are needed to determine the natural history of childhood insulin resistance related hyperfiltration in regards to future kidney disease.

Inhibition of 11ß-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, phase II study.

AIM: To evaluate whether short-term treatment with a selective 11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D). MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion of 13 C cortisone to 13 C cortisol in the liver. RESULTS: A total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of 13 C cortisone to 13 C cortisol was blocked in all patients in the AZD4017 group. There were no significant between-group differences (AZD4017 vs. placebo) in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity. CONCLUSION: Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13 C cortisone to 13 C cortisol in the liver in all patients who received the drug. In patients with NASH and T2D, AZD4017 improved liver steatosis versus placebo.

A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinaemia by restoring insulin clearance in obese youth.

AIM: To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth. MATERIALS AND METHODS: Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging. RESULTS: Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of ß-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and ß-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, ß-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and ß-cell function. CONCLUSIONS: We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

Metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis.

Psoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3-10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance.Conclusion: Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known: • Psoriasis in adults is strongly associated with metabolic disease and insulin resistance. • Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis. What is New: • This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance. • In children with psoriasis metabolic syndrome risk factors should be assessed.

The aftermath of SARS-CoV-2 in NICU: saving or checking accounts? Projected cost-effectiveness analysis.

In the aftermath of the SARS-CoV-2 pandemic, we revised the cost-effectiveness of the exploited interventions in neonatal intensive care unit, to redefine future strategies for hospital management. Costs were revised with respect to the lockdown R0 or under different R0 scenarios to estimate the cost-effectiveness of the screening program adopted. Weekly nasopharyngeal swabs for parents, neonates, and personnel were the major cost during the pandemic, although they effectively reduced the number of cases in our unit.Conclusion: Parents and healthcare personnel testing appears to be an effective strategy due to the high number of contact they have within the hospital environment and outside, able to minimize the cases within our unit. What is Known: • Costs of universal COVID-19 tests for parents, neonates, and NICU personnel have not been evaluated during the COVID-19 pandemic in neonatal intensive care unit in Europe. What is New: • Weekly nasopharyngeal swabs for parents, neonates, and personnel were the major cost during the COVID-19 pandemic in NICU. • Parents and healthcare personnel testing was effective to reduce costs related to COVID-19 due to the high number of contact they have within the hospital environment and outside.

Continuous glucose monitoring for the prevention of morbidity and mortality in preterm infants.

BACKGROUND: Preterm infants are susceptible to hyperglycaemia and hypoglycaemia, which may lead to adverse neurodevelopment. The use of continuous glucose monitoring (CGM) devices might help in keeping glucose levels in the normal range, and reduce the need for blood sampling. However, the use of CGM might be associated with harms in the preterm infant. OBJECTIVES: To assess the benefits and harms of CGM versus intermittent modalities to measure glycaemia in preterm infants 1. at risk of hypoglycaemia or hyperglycaemia; 2. with proven hypoglycaemia; or 3. with proven hyperglycaemia. SEARCH METHODS: We searched CENTRAL (2021, Issue 4); PubMed; Embase; and CINAHL in April 2021. We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing the use of CGM versus intermittent modalities to measure glycaemia in preterm infants at risk of hypoglycaemia or hyperglycaemia; with proven hypoglycaemia; or with proven hyperglycaemia. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomization, blinding, loss to follow-up, and handling of outcome data). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) with 95% confidence intervals (CI) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included four trials enrolling 300 infants in our updated review. We included one new study and excluded another previously included study (because the inclusion criteria of the review have been narrowed). We compared the use of CGM to intermittent modalities in preterm infants at risk of hypoglycaemia or hyperglycaemia; however, one of these trials was analyzed separately because CGM was used as a standalone device, without being coupled to a control algorithm as in the other trials. We identified no studies in preterm infants with proven hypoglycaemia or hyperglycaemia.  None of the four included trials reported the neurodevelopmental outcome (i.e. the primary outcome of this review), or seizures. The effect of the use of CGM on mortality during hospitalization is uncertain (RR 0.59, 95% CI 0.16 to 2.13; RD -0.02, 95% CI -0.07 to 0.03; 230 participants; 2 studies; very low-certainty evidence). The certainty of the evidence was very low for all outcomes because of limitations in study design, and imprecision of estimates. One study is ongoing (estimated sample size 60 infants) and planned to be completed in 2022. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if CGM affects preterm infant mortality or morbidities.  We are very uncertain of the safety of CGM and the available management algorithms, and many morbidities remain unreported. Preterm infants at risk of hypoglycaemia or hyperglycaemia were enrolled in all four included studies. No studies have been conducted in preterm infants with proven hypoglycaemia or hyperglycaemia. Long-term outcomes were not reported. Events of necrotizing enterocolitis, reported in the study published in 2021, were lower in the CGM group. However, the effect of CGM on this outcome remains very uncertain. Clinical trials are required to determine the most effective CGM and glycaemic management regimens in preterm infants before larger studies can be performed to assess the efficacy of CGM for reducing mortality, morbidity, and long-term neurodevelopmental impairments.

Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus.

BACKGROUND: Poor glycemic control is associated with increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM); however, little is known about mechanisms specific to T1DM. In T1DM, myocardial injury can induce persistent cardiac autoimmunity. Chronic hyperglycemia causes myocardial injury, raising the possibility that hyperglycemia-induced cardiac autoimmunity could contribute to long-term CVD complications in T1DM. METHODS: We measured the prevalence and profiles of cardiac autoantibodies (AAbs) in longitudinal samples from the DCCT (Diabetes Control and Complications Trial) in participants with mean hemoglobin A1c (HbA1c) ≥9.0% (n=83) and ≤7.0% (n=83) during DCCT. We assessed subsequent coronary artery calcification (measured once during years 7-9 in the post-DCCT EDIC [Epidemiology of Diabetes Interventions and Complications] observational study), high-sensitivity C-reactive protein (measured during EDIC years 4-6), and CVD events (defined as nonfatal myocardial infarction, stroke, death resulting from CVD, heart failure, or coronary artery bypass graft) over a 26-year median follow-up. Cardiac AAbs were also measured in matched patients with type 2 diabetes mellitus with HbA1c ≥9.0% (n=70) and ≤7.0% (n=140) and, as a control for cardiac autoimmunity, patients with Chagas cardiomyopathy (n=51). RESULTS: Apart from HbA1c levels, the DCCT groups shared similar CVD risk factors at the beginning and end of DCCT. The DCCT HbA1c ≥9.0% group showed markedly higher cardiac AAb levels than the HbA1c ≤7.0% group during DCCT, with a progressive increase and decrease in AAb levels over time in the 2 groups, respectively ( P<0.001). In the HbA1c ≥9.0% group, 46%, 22%, and 11% tested positive for ≥1, ≥2, and ≥3 different cardiac AAb types, respectively, similar to patients with Chagas cardiomyopathy, compared with 2%, 1%, and 0% in the HbA1c ≤7.0% group. Glycemic control was not associated with AAb prevalence in type 2 diabetes mellitus. Positivity for ≥2 AAbs during DCCT was associated with increased risk of CVD events (4 of 6; hazard ratio, 16.1; 95% CI, 3.0-88.2) and, in multivariable analyses, with detectable coronary artery calcification (13 of 31; odds ratio, 60.1; 95% CI, 8.4-410.0). Patients with ≥2 AAbs subsequently also showed elevated high-sensitivity C-reactive protein levels (6.0 mg/L versus 1.4 mg/L in patients with ≤1 AAbs; P=0.003). CONCLUSIONS: Poor glycemic control is associated with cardiac autoimmunity in T1DM. Furthermore, cardiac AAb positivity is associated with an increased risk of CVD decades later, suggesting a role for autoimmune mechanisms in the development of CVD in T1DM, possibly through inflammatory pathways.

Protecting youth from the vaping epidemic.

E-cigarettes (e-cigs) have been initially proposed as an aid to smoke cessation in adults, whereas they turned into a paradoxical preferential gateway to tobacco and nicotine initiation for adolescents naïve to tobacco. More than 25% of US school-age students is an e-cigs user with a steep rise over the past years. A marketing strategy on media and social network targeting youths, in the absence of rules to protect the pediatric users, resulted in an unprecedented trend up in tobacco consumption among adolescents and gave rise to a new generation of nicotine-addicted teenagers. Flavored e-cigs liquids and aerosols contain airway irritants and toxicants, that, in turn, produced an increase in asthma prevalence and its exacerbations among adolescents. In addition, since August 2019 an outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) has been described. In view of this, e-cigs must no longer be considered harmless, especially in adolescents never used a tobacco product before. This is a call-for-action to establish effective rules and campaigns targeting youths aimed to limit their access to e-cigs, thereby preserving the potential benefit in quitting tobacco addiction described in adults. Behavioral and educational actions, out of the conventional primary care setting, have been described as a model for a youth-centered campaign. We call for stricter regulations on e-cigs products, with respect to their marketing to the youngest ones, along with public health and primary care interventions that could curb the spread of this "vaping" epidemic.

Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort.

AIM: To evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups. METHODS: The intrahepatic fat content (HFF%) was quantified by magnetic resonance imaging in a multi-ethnic cohort of 632 obese youths aged 7-18 years at baseline and after a 2-year follow-up. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C-peptide data during 3-hour, 9-point oral glucose tolerance tests. RESULTS: African American youths exhibited the lowest HFF% and a prevalence of non-alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose-stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group-specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist-hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow-up was associated with decreased EIC and increased HIRI across all groups. CONCLUSIONS: Intrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background.

Continuous glucose monitoring for the prevention of morbidity and mortality in preterm infants.

BACKGROUND: Preterm infants are susceptible to hyperglycemia and hypoglycemia, conditions which may lead to adverse neurodevelopment. The use of continuous glucose monitoring devices (CGM) might help keeping glucose levels in the normal range, and reduce the need for blood sampling. However, the use of CGM might be associated with harms in the preterm infant. OBJECTIVES: Objective one: to assess the benefits and harms of CGM alone versus standard method of glycemic measure in preterm infants. Objective two: to assess the benefits and harms of CGM with automated algorithm versus standard method of glycemic measure in preterm infants. Objective three: to assess the benefits and harms of CGM with automated algorithm versus CGM without automated algorithm in preterm infants. SEARCH METHODS: We adopted the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9), in the Cochrane Library; MEDLINE via PubMed (1966 to 25 September 2020); Embase (1980 to 25 September 2020); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 25 September 2020). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs in preterm infants comparing: 1) the use of CGM versus intermittent modalities to measure glycemia (comparison 1); or CGM associated with prespecified interventions to correct hypoglycemia or hyperglycemia versus CGM without such prespecified interventions (comparison 2). DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomization, blinding, loss to follow-up, and handling of outcome data). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: Four trials enrolling 138 infants met our inclusion criteria. Investigators in three trials (118 infants) compared the use of CGM to intermittent modalities (comparison one); however one of these trials was analyzed separately because CGM was used as a standalone device, without being coupled to a control algorithm like in the other trials. A fourth trial (20 infants) assessed CGM with an automated algorithm versus CGM with a manual algorithm. None of the four included trials reported the neurodevelopmental outcome, i.e. the primary outcome of this review. Within comparison one, the certainty of the evidence on the use of CGM on mortality during hospitalization is very uncertain (typical RR 3.00, 95% CI 0.13 to 70.30; typical RD 0.04, 95% CI -0.06 to 0.14; 50 participants; 1  study; very low certainty). The number of hypoglycemic episodes was reported in two studies with conflicting data. The number of hyperglycemic episodes was reported in one study (typical MD -1.40, 95% CI -2.84 to 0.04; 50 participants; 1 study). The certainty of the evidence was very low for all outcomes because of limitations in study design, and imprecision of estimates.  Three studies are ongoing. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if CGM improves preterm infant mortality or morbidities. Long-term outcomes were not reported. Clinical trials are required to determine the most effective CGM and glycemic management regimens in preterm infants before larger studies can be performed to assess the efficacy of CGM  for reducing mortality, morbidity and long-term neurodevelopmental impairments. The absence of CGM labelled for neonatal use is still a major limit in its use as well as the absence of dedicated neonatal devices.

A low visceral fat proportion, independent of total body fat mass, protects obese adolescent girls against fatty liver and glucose dysregulation: a longitudinal study.

BACKGROUND: The relative proportion of visceral fat (VAT) to subcutaneous fat (SAT) has been described as a major determinant of insulin resistance (IR). Our study sought to evaluate the effect of body fat distribution on glucose metabolism and intrahepatic fat content over time in a multiethnic cohort of obese adolescents. SUBJECTS/METHODS: We examined markers of glucose metabolism by oral glucose tolerance test, and body fat distribution by abdominal MRI at baseline and after 19.2 ± 11.4 months in a cohort of 151 obese adolescents (88 girls, 63 boys; mean age 13.3 ± 3.4 years; mean BMI z-score 2.15 ± 0.70). Hepatic fat content was assessed by fast-gradient MRI in a subset of 93 subjects. We used the median value of VAT/(VAT + SAT) ratio within each gender at baseline to stratify our sample into high and low ratio groups (median value 0.0972 in girls and 0.118 in boys). RESULTS: Female subjects tended to remain in their VAT/(VAT + SAT) category over time (change over follow-up P = 0.14 among girls, and P = 0.04 among boys). Baseline VAT/(VAT + SAT) strongly predicted the hepatic fat content, fasting insulin, 2-h glucose, and whole-body insulin sensitivity index at follow-up among girls, but not in boys. CONCLUSIONS: The VAT/(VAT + SAT) ratio is a major determinant of impaired glucose metabolism and hepatic fat accumulation over time, and its effects are more pronounced in girls than in boys.

Airway Histopathology of Adolescent Survivors of Bronchopulmonary Dysplasia.

Long-term survivors of bronchopulmonary dysplasia develop chronic obstructive lung disease. Herein we report in vivo histopathology from bronchial biopsies of 3 adolescent survivors of severe bronchopulmonary dysplasia. Thickened basement membranes with lymphocytic infiltrates and signs of immature neoangiogenesis in the absence of T-helper lymphocytes or eosinophils suggest the presence of an ongoing active airway process.