Effectiveness of BNT162b2 BA.4/5 Bivalent mRNA Vaccine Against Symptomatic COVID-19 Among Immunocompetent Individuals Testing at a Large US Retail Pharmacy.

BACKGROUND: Data on the effectiveness of BA.4/5 bivalent vaccine stratified by age and prior infection are lacking. METHODS: This test-negative study used data from individuals ≥5 years of age testing for SARS-CoV-2 with symptoms (15 September 2022 to 31 January 2023) at a large national retail pharmacy chain. The exposure was receipt of 2-4 wild-type doses and a BNT162b2 BA.4/5 bivalent vaccine (>2 months since last wild-type dose). The outcome was a positive SARS-CoV-2 test. Absolute (vs unvaccinated) and relative (vs 2-4 wild-type doses) vaccine effectiveness (VE) were calculated as (1 - adjusted odds ratio from logistic regression) × 100. VE was stratified by age and self-reported prior infection. RESULTS: Overall, 307 885 SARS-CoV-2 tests were included (7916 aged 5-11, 16 329 aged 12-17, and 283 640 aged ≥18 years). SARS-CoV-2 positivity was 39%; 21% were unvaccinated, 70% received 2-4 wild-type doses with no bivalent vaccine, and 9% received a BNT162b2 BA.4/5 bivalent dose. At a median of 1-2 months after BNT162b2 BA.4/5 bivalent vaccination, depending on age group, absolute VE was 22%-60% and was significantly higher among those reporting prior infection (range, 55%-79%) than not (range, no protection to 50%). Relative VE was 31%-64%. CONCLUSIONS: BNT162b2 BA.4/5 bivalent showed early additional protection against Omicron-related symptomatic COVID-19, with hybrid immunity offering greater protection.

Spectrum of Phenotypes and Causes of Type 2 Diabetes in Children.

Several factors, including genetics, family history, diet, physical activity, obesity, and insulin resistance in puberty, appear to increase the risk of type 2 diabetes in youth. Youth-onset type 2 diabetes is often thought of as a single entity but rather exists as a spectrum of disease with differences in presentation, metabolic characteristics, clinical progression, and complication rates. We review what is currently known regarding the risks associated with developing type 2 diabetes in youth. Additionally, we focus on the spectrum of phenotypes of pediatric type 2 diabetes, discuss the pathogenic underpinnings and potential therapeutic relevance of this heterogeneity, and compare youth-onset type 2 diabetes with type 1 diabetes and adult-onset type 2 diabetes. Finally, we highlight knowledge gaps in prediction and prevention of youth-onset type 2 diabetes.

Diabetes Technology in People with Type 2 Diabetes: Novel Indications.

PURPOSE OF REVIEW: Diabetes technology has been continuously evolving. Current versions of continuous glucose monitors (CGM) use minimally invasive designs, monitor glucose values with high accuracy, and can be used to guide insulin dosing. Extensive evidence supports the use of diabetes technology for monitoring and insulin administration in people with type 1 diabetes. However, there is emerging evidence for people with type 2 diabetes. In this review, we present the different technological devices used to monitor glucose and deliver insulin and the evidence supporting their use in people with type 2 diabetes. RECENT FINDINGS: The use of CGMs in people with type 2 diabetes treated with insulin or non-insulin therapies has been associated with improvements in glycemic control and time spent in hypoglycemia. Smart insulin pens and smart connected devices are options to track compliance and guide insulin delivery in people who do not require insulin pump therapy. Mechanical patch pumps can be used to reduce the burden of multiple daily insulin injections. Automated insulin delivery algorithms improve glycemic control without an increase in hypoglycemia. The use of technology in the management of type 2 diabetes generates glycemic data previously inaccessible, reduces barriers for insulin initiation, improves glycemic control, tracks adherence to therapy, and improves user satisfaction.

Diabetes complications and cognitive function in young adults with youth-onset type 1 or type 2 diabetes: the SEARCH for Diabetes in Youth Study.

Aims/hypotheses: People with type 1 (T1D) or type 2 diabetes (T2D) who also have diabetes complications can have pronounced cognitive deficits. It remains unknown, however, whether and how multiple diabetes complications co-occur with cognitive dysfunction, particularly in youth-onset diabetes. Methods: Using data from the SEARCH for Diabetes in Youth study cohort, a prospective longitudinal cohort, we examined clustering of complications and their underlying clinical factors with performance on cognitive tests in young adults with youth-onset T1D or T2D. Cognition was assessed via the NIH Toolbox Cognition Battery. The main cognitive variables were age-corrected scores for composite fluid cognition and associated cognitive subdomains. Diabetes complications included retinopathy, microalbuminuria, and peripheral neuropathy (PN). Lipids, systolic blood pressure (SBP), hemoglobin A1c, and other clinical factors were included in the analyses. Clustering was applied separately to each group (T1D=646; T2D=165). A three-cluster(C) solution was identified for each diabetes type. Mean values and frequencies of all factors were compared between resulting clusters. Results: The average age-corrected score for composite fluid cognition differed significantly across clusters for each group (p<0.001). People with T1D and the lowest average fluid cognition scores had the highest frequency of self-reporting at least one episode of hypoglycemia in the year preceding cognitive testing and the highest prevalence of PN. Persons with T2D and the lowest average fluid cognition scores had the highest SBP, the highest central systolic and diastolic blood pressures, and highest prevalence of PN. Conclusions/interpretations: These findings highlight shared (PN) and unique factors (hypoglycemia in T1D; SBP in T2D) that could be targeted to potentially mitigate cognitive issues in young people with youth-onset diabetes.

Household Food Insecurity and Cognition in Youth and Young Adults with Youth-Onset Diabetes.

Objective: We evaluated the association of household food insecurity (FI) with cognition in youth and young adults with type 1 diabetes (T1D) or type 2 diabetes (T2D). Design: In this cross-sectional study, age-adjusted scores for composite Fluid Cognition, and sub-domain scores for Receptive Language and Inhibitory Control and Attention, were modeled stratified by diabetes-type using linear regression, with FI in the past year as the predictor, controlling for covariates. Tests for processing speed, inhibitory control/attention, working memory, episodic memory, and cognitive flexibility were administered to measure composite Fluid Cognition score. The NIHT-CB Picture Vocabulary Test was used to assess Crystallized Cognition score and rapid identification of congruent versus noncongruent items were used to assess Inhibitory Control and Attention score. Setting: The SEARCH for Diabetes in Youth study, representative of 5 U.S. states. Participants: Included 1574 youth and young adults with T1D or T2D, mean age of 21 years, mean diabetes duration of 11 years, 51% non-Hispanic white, and 47% had higher HbA1c levels (>9% HbA1c). Results: Approximately 18% of the 1,240 participants with T1D and 31% of the 334 with T2D experienced FI. The food-insecure group with T1D had a lower composite Fluid Cognition score (ß= -2.5, 95% confidence interval (CI)= -4.8, -0.1) and a lower Crystallized Cognition score (ß= -3.4, CI= -5.6, -1.3) than food-secure peers. Findings were attenuated to non-significance after adjustment for demographics. Among T2D participants, no associations were observed. In participants with T1D effect modification by glycemic levels were found in the association between FI and composite Fluid Cognition score but adjustment for socioeconomic characteristics attenuated the interaction (p=0.0531). Conclusions: Food-insecure youth and young adults with T1D or T2D did not have different cognition compared to those who were food-secure after adjustment for confounders. Longitudinal research is needed to further understand relations amongst these factors.

Screening for Gastric Sensory Motor Abnormalities in Pediatric Patients With Type 1 Diabetes.

OBJECTIVE: To determine the frequency of gastric sensory motor symptoms in youth with type 1 diabetes. METHODS: A prospective cross-sectional study was performed to evaluate symptoms of delayed gastric emptying in participants with type 1 diabetes, aged 12 to 25 years, using the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire. In addition, a 5-year (January 2015 to December 2019), a retrospective study was completed on all gastric emptying scans performed in youth at our institution. RESULTS: A total of 359 participants (mean age, 17.7 ± 3.33 years) with type 1 diabetes completed the GCSI questionnaire. Compared with nonresponders, responders were more likely to be non-Hispanic White (90% vs 86%; P =.003) and female patients (58% vs 44%; P <.0001), with a lower HbA1c (8.1 ± 1.8 vs 9.0 ± 2.1; P <.0001). At least 1 gastrointestinal symptom was reported in 270 (75%) of responders, of which nausea was the most common (71%). A GCSI score of ≥1.9 suggestive of more severe gastrointestinal symptoms was reported in 17% of responders. Participants with scores ≥1.9 were older (19.1 ± 3.0 vs 17.8 ± 3.3 years; P =.01). In the retrospective study, 778 underwent gastric emptying scan, 29 participants had type 1 diabetes and 11 (38%) showed delayed gastric emptying. CONCLUSION: Gastrointestinal symptoms related to gastric sensory motor abnormalities are seen in youth and young adults with type 1 diabetes. In particular, for those with higher GCSI scores, earlier recognition and referral may be warranted.

Conformational flexibility of apolipoprotein A-I amino- and carboxy-termini is necessary for lipid binding but not cholesterol efflux.

Because of its critical role in HDL formation, significant efforts have been devoted to studying apolipoprotein A-I (APOA1) structural transitions in response to lipid binding. To assess the requirements for the conformational freedom of its termini during HDL particle formation, we generated three dimeric APOA1 molecules with their termini covalently joined in different combinations. The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1 molecules, respectively, using introduced cysteine residues to form disulfide linkages. We then tested the ability of these constructs to generate reconstituted HDL by detergent-assisted and spontaneous phospholipid microsolubilization methods. Using cholate dialysis, we demonstrate WT and all APOA1 mutants generated reconstituted HDL particles of similar sizes, morphologies, compositions, and abilities to activate lecithin:cholesterol acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously solubilizing short chain phospholipids into discoidal particles. We found lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1's ability to promote cholesterol efflux via the ATP binding cassette transporter A1, whereas d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute other postulated arrangements like the "double super helix." Furthermore, we conclude the conformational freedom of both the N- and C-termini of APOA1 is important in spontaneous microsolubilization of bulk phospholipid but is not critical for ABCA1-mediated cholesterol efflux.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

Lipids: a Potential Molecular Pathway Towards Diastolic Dysfunction in Youth-Onset Type 2 Diabetes.

PURPOSE OF THE REVIEW: Obesity and type 2 diabetes (T2D) with onset in youth are emerging public health concerns. Youth with obesity and T2D are at risk for the development of heart failure with preserved ejection fraction (HFpEF) due to diabetes-related cardiomyopathy with evidence of precursor stages, namely diastolic dysfunction, present in youth. We review the literature regarding diastolic dysfunction in youth with obesity and T2D; discuss the potential mechanisms including the role of lipids, contractile proteins and their post-translational modifications, and conclude with studies to guide future treatments. RECENT FINDINGS: The diabetes milieu namely hyperglycemia, hyperinsulinemia, and lipotoxicity favor development of diastolic dysfunction and HFpEF. Recent studies show HFpEF is associated with slow left ventricular relaxation and sarcomere stiffness induced by reduced calcium (Ca2+) and ß-adrenergic responses. There are currently no effective therapies available for treating HFpEF. Targeting the sarcomere is an area of ongoing research.

Cerebral blood flow is lower in youth with type 2 diabetes compared to obese controls: A pilot study.

AIM: The cerebral vasculature may be susceptible to the adverse effects of type 2 diabetes. In this pilot study, we compared cerebral blood flow (CBF) in youth with type 2 diabetes to obese, euglycemic controls, and explored the association between CBF and a non-invasive measure of atherosclerosis, carotid intima-medial thickness (IMT). METHODS: Global and regional CBF were compared between youth with type 2 diabetes (mean age 16.7 ± 2.0 years, n = 20) and age, race, and sex similar obese youth without diabetes (17.4 ± 1.9 years, n = 19) using arterial spin labeling magnetic resonance imaging. Mean CBF values were compared between groups. Voxel-wise results were evaluated for statistical significance (p < 0.05) after adjustment for multiple comparisons. Carotid IMT in the type 2 diabetes group was correlated with CBF. RESULTS: Compared to obese controls, the type 2 diabetes group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ± 11.5 ml/gm/min, p < 0.001). Significantly lower CBF was observed in multiple brain regions for the type 2 diabetes group, while no regions with higher CBF were identified. In the type 2 diabetes group, carotid IMT was inversely correlated with CBF, both globally (r = -0.70, p = 0.002) and in regional clusters. CONCLUSIONS: In this pilot study, lower CBF was seen in youth with type 2 diabetes compared to youth with obesity and IMT was inversely correlated with CBF. Cerebrovascular impairment may be present in youth with type 2 diabetes. These findings could represent a mechanistic link to explain previously reported brain volume and neurocognitive differences.

ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

A large-scale study reveals 24-h operational rhythms in hospital treatment.

Hospitals operate 24 h a day, and it is assumed that important clinical decisions occur continuously around the clock. However, many aspects of hospital operation occur at specific times of day, including medical team rounding and shift changes. It is unclear whether this impacts patient care, as no studies have addressed this. We analyzed the daily distribution of ∼500,000 doses of 12 separate drugs in 1,546 inpatients at a major children's hospital in the United States from 2010 to 2017. We tracked both order time (when a care provider places an electronic request for a drug) and dosing time (when the patient receives the drug). Order times were time-of-day-dependent, marked by distinct morning-time surges and overnight lulls. Nearly one-third of all 103,847 orders for treatment were placed between 8:00 AM and 12:00 PM. First doses from each order were also rhythmic but shifted by 2 h. These 24-h rhythms in orders and first doses were remarkably consistent across drugs, diagnosis, and hospital units. This rhythm in hospital medicine coincided with medical team rounding time, not necessarily immediate medical need. Lastly, we show that the clinical response to hydralazine, an acute antihypertensive, is dosing time-dependent and greatest at night, when the fewest doses were administered. The prevailing dogma is that hospital treatment is administered as needed regardless of time of day. Our findings challenge this notion and reveal a potential operational barrier to best clinical care.

Apolipoprotein A-I modulates HDL particle size in the absence of apolipoprotein A-II.

Human high-density lipoproteins (HDLs) are a complex mixture of structurally related nanoparticles that perform distinct physiological functions. We previously showed that human HDL containing apolipoprotein A-I (APOA1) but not apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two discretely sized populations. Here, we isolated these particles directly from human plasma by antibody affinity chromatography, separated them by high-resolution size-exclusion chromatography and performed a deep molecular characterization of each species. The large and small LpA-I populations were spherical with mean diameters of 109 Å and 91 Å, respectively. Unexpectedly, isotope dilution MS/MS with [15N]-APOA1 in concert with quantitation of particle concentration by calibrated ion mobility analysis demonstrated that the large particles contained fewer APOA1 molecules than the small particles; the stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively. MS/MS experiments showed that the protein cargo of large LpA-I particles was more diverse. Human HDL and isolated particles containing both APOA1 and APOA2 exhibit a much wider range and variation of particle sizes than LpA-I, indicating that APOA2 is likely the major contributor to HDL size heterogeneity. We propose a ratchet model based on the trefoil structure of APOA1 whereby the helical cage maintaining particle structure has two "settings"-large and small-that accounts for these findings. This understanding of the determinants of HDL particle size and protein cargo distribution serves as a basis for determining the roles of HDL subpopulations in metabolism and disease states.

A cross sectional study to compare cardiac structure and diastolic function in adolescents and young adults with youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study.

AIMS: To compare left ventricular structure (LV) and diastolic function in young adults with youth- onset diabetes by type, determine the prevalence of abnormal diastolic function by diabetes type using published values from age similar healthy controls, and examine the risk factors associated with diastolic function. METHODS: In a cross sectional analysis we compared LV structure and diastolic function from two dimensional echocardiogram in participants with type 1 (T1D) and type 2 diabetes (T2D) who participated in the SEARCH for Diabetes in Youth Study. Linear models were used to examine the risk factors associated with worse diastolic function. RESULTS: Of 479 participants studied, 258 had T1D (mean age 21.2 ± 5.2 years, 60.5% non-Hispanic white, 53.9% female) and 221 had T2D (mean age 24.8 ± 4.3 years, 24.4% non-Hispanic white, 73.8% female). Median diabetes duration was 11.6 years. Participants with T2D had greater LV mass index and worse diastolic function that persisted after adjustment for differences in risk factors compared with participants with T1D (all p < 0.05). Abnormal diastolic function, quantified using healthy controls, was pronounced in both groups but greater in those with T2D than T1D (T2D: 57.7% vs T1D: 47.2%, respectively), p < 0.05. Risk factors associated with worse diastolic function included older age at diabetes diagnosis, female sex, higher BP, heart rate and HbA1c and longer diabetes duration. CONCLUSIONS: LV structure and diastolic function is worse in individuals with T2D compared to T1D. However, abnormal diastolic function in seen in both groups compared to published values from age similar healthy controls.

The Difference Between High Density Lipoprotein Subfractions and Subspecies: an Evolving Model in Cardiovascular Disease and Diabetes.

PURPOSE OF REVIEW: The term high density lipoproteins (HDL) refers to an eclectic collection of subparticles that play diverse roles in physiology. Here, we define the term "HDL subspecies" and review recent work on their molecular characterization and relation to disease, focusing on cardiovascular disease and diabetes. RECENT FINDINGS: The HDL family contains over 200 proteins and nearly 200 lipids that partition into different particles in plasma. Simple subfractionation of HDL based on a particular physicochemical property has not risen to the challenge of revealing the roles of specific particles in disease. However, by targeting minor protein or lipid components, a handful of compositionally defined HDL subspecies have been described and characterized. By combining targeted particle isolation techniques with the power of large human studies, progress is being made in understanding HDL subspecies functions and implications for disease. However, much work remains before these advancements can be translated into disease mitigation strategies.

Glycemic control is associated with dyslipidemia over time in youth with type 2 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Dyslipidemia has been documented in youth with type 2 diabetes. There is a paucity of studies examining dyslipidemia over time in youth with type 2 diabetes and associated risk factors. OBJECTIVE: To evaluate lipids at baseline and follow-up and associated risk factors in youth with type 2 diabetes. METHODS: We studied 212 youth with type 2 diabetes at baseline and after an average of 7 years of follow-up in the SEARCH for Diabetes in Youth Study. Abnormal lipids were defined as high-density lipoprotein cholesterol (HDL-C) < 35, low-density lipoprotein cholesterol (LDL-C) > 100, or triglycerides >150 (all mg/dl). We evaluated participants for progression to abnormal lipids (normal lipids at baseline and abnormal at follow-up), regression (abnormal lipids at baseline and normal at follow-up), stable normal, and stable abnormal lipids over time for HDL-C, LDL-C, and triglycerides. Associations between hemoglobin A1c (HbA1c) and adiposity over time (area under the curve [AUC]) with progression and stable abnormal lipids were evaluated. RESULTS: HDL-C progressed, regressed, was stable normal, and stable abnormal in 12.3%, 11.3%, 62.3%, and 14.2% of participants, respectively. Corresponding LDL-C percentages were 15.6%, 12.7%, 42.9%, and 28.8% and triglycerides were 17.5%, 10.8%, 55.7%, and 16.0%. Each 1% increase in HbA1c AUC was associated with a 13% higher risk of progression and stable abnormal triglycerides and a 20% higher risk of progression and stable abnormal LDL-C. Higher adiposity AUC was marginally (p = 0.049) associated with abnormal HDL-C. CONCLUSIONS: Progression and stable abnormal LDL-C and triglycerides occur in youth with type 2 diabetes and are associated with higher HbA1c.

Progression of Vasculopathy in Young Individuals with Turner Syndrome.

Vasculopathy has been identified in young individuals with Turner syndrome (TS). No studies in young individuals with TS have investigated whether this vasculopathy progresses over time. The objective of this study is to describe the changes in vasculopathy over time in a cohort of young individuals with TS. Repeat ultrasound and SphygmoCor CPV® (AtCor Medical) measurements of carotid thickness and peripheral arterial stiffness were performed. Vascular measurements were compared at baseline and follow-up. Follow-up measurements were also compared to historical lean (L) and obese (O) age-, race-, and sex-matched non-TS controls. Thirty-five individuals with TS were studied at a mean age of 19.4 years (range, 13.9-27.5). Mean time to follow-up was 7.2 years (range, 7.1-7.8). Carotid intima media thickness increased by 0.03 ± 0.07 mm (p < 0.01) over time, but was less than L and O controls at follow-up. Pulse wave velocity carotid-femoral increased by 0.51 ± 0.86 m/s (p < 0.01) over time, but was similar to L and less than O controls at follow-up. Augmentation index (AIx) remained unchanged (p = 0.09) over time, but was significantly higher at follow-up than both control groups (p < 0.01 for both). There were no identified differences between 45,X and other TS genotypes. We demonstrate evidence of vascular thickening and stiffening over 7 years in a cohort of young individuals with TS, as well as a persistently increased augmentation index compared to L and O non-TS controls. It is unclear whether the increase in vascular structure and function are related to normal aging or if TS is a risk factor. Higher body mass index seems to be a risk factor. Early estrogen replacement and longer exposure to growth hormone therapy need to be further explored as potential protective factors.

The changing face of paediatric diabetes.

The purpose of this review is to provide an update on the changing face of paediatric type 1 diabetes and type 2 diabetes. Paediatric diabetes is on the rise, with extensive research dedicated to understanding its pathophysiology, comorbidities and complications. As obesity continues to increase among all youth, differentiating between type 1 diabetes and type 2 diabetes has become increasingly difficult but remains important for optimising treatment, anticipating complications and predicting disease risk. Novel treatments are emerging, with the ultimate goal being to achieve glycaemic control, limit weight gain, improve quality of life and reduce comorbidities. In this review, we focus on updates regarding the epidemiology, clinical presentation, comorbidities and complications of paediatric type 1 diabetes and type 2 diabetes and conclude with current and emerging treatments.

Proprotein Convertase Subtilisin/Kexin Type 9 Loss-of-Function Is Detrimental to the Juvenile Host With Septic Shock.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis. We sought to validate this association in children with septic shock and in a juvenile murine model of sepsis. DESIGN: Prospectively enrolled cohort of children with septic shock; experimental mice. SETTING: Seventeen participating institutions; research laboratory. PATIENTS AND SUBJECTS: Five-hundred twenty-two children with septic shock; juvenile (14 d old) and adult (10-14 wk) mice with constitutive proprotein convertase subtilisin/kexin type 9 null and wildtype control mice (C57BL/6). INTERVENTIONS: Proprotein convertase subtilisin/kexin type 9 single-nucleotide polymorphisms, serum proprotein convertase subtilisin/kexin type 9, and lipid profiles in patients. Cecal slurry murine model of sepsis; survival studies in juvenile and adult mice, assessment of lipoprotein fractions, bacterial burden, and inflammation in juvenile mice. MEASUREMENTS AND MAIN RESULTS: PCSK9 loss-of-function genetic variants were independently associated with increased odds of complicated course and mortality in children with septic shock. PCSK9, low-density lipoprotein, and high-density lipoprotein concentrations were lower among patients with complicated course relative to those without. PCSK9 concentrations negatively correlated with proinflammatory cytokine interleukin-8. Proprotein convertase subtilisin/kexin type 9 loss-of-function decreased survival in juvenile mice, but increased survival in adult mice with sepsis. PCSK9 loss-of-function resulted in low lipoproteins and decreased hepatic bacterial burden in juvenile mice. CONCLUSIONS: In contrast to the adult host, proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. PCSK9 loss-of-function, in the context of low lipoproteins, may result in reduced hepatic bacterial clearance in the juvenile host with septic shock. Our data indicate that children should be excluded in sepsis clinical trials involving proprotein convertase subtilisin/kexin type 9 inhibitors.

Integrating quality improvement into the ECHO model to improve care for children and youth with epilepsy.

OBJECTIVE: Project ECHO (Extension for Community Healthcare Outcomes), a telementoring program, utilizes lectures, case-based learning, and an "all teach-all learn" approach to increase primary care provider (PCP) knowledge/confidence in managing chronic health conditions. The American Academy of Pediatrics (AAP) Epilepsy and Comorbidities ECHO incorporated quality improvement (QI) methodology to create meaningful practice change, while increasing PCP knowledge/self-efficacy in epilepsy management using the ECHO model. METHODS: Monthly ECHO sessions (May 2018 to December 2018) included lectures, case presentations/discussion, and QI review. Pediatric practices were recruited through the AAP. Practices engaged in ECHO sessions and improvement activities including monthly Plan-Do-Study-Act cycles, team huddles, chart reviews, and QI coaching calls to facilitate practice change. They were provided resource toolkits with documentation templates, safety handouts, and medication side effects sheets. QI measures were selected from the American Academy of Neurology Measurement Set for Epilepsy. The AAP Quality Improvement Data Aggregator was used for data entry, run chart development, and tracking outcomes. Participants completed retrospective surveys to assess changes in knowledge and self-efficacy. RESULTS: Seven practices participated across five states. Average session attendance was 14 health professionals (range = 13-17). A total of 479 chart reviews demonstrated improvement in six of seven measures: health care transition (45.3%, P = .005), safety education (41.6%, P = .036), mental/behavioral health screening (32.2% P = .027), tertiary center referral (26.7%, not significant [n.s.]), antiseizure therapy side effects (23%, n.s.), and documenting seizure frequency (7.1%, n.s.); counseling for women of childbearing age decreased by 7.8%. SIGNIFICANCE: This project demonstrated that integrating QI into an ECHO model results in practice change and increases PCP knowledge/confidence/self-efficacy in managing epilepsy.