Substance Use Affects Type 1 Diabetes Pancreas Pathology: Implications for Future Studies.

Access to human pancreas samples from organ donors has greatly advanced our understanding of type 1 diabetes pathogenesis; however, previous studies have shown that donors have a high rate of substance use, and its impact on pancreatic histopathology in this disease is not well described. One-hundred-thirty-one type 1 diabetes and 111 control organ donor pancreata from persons 12-89 years of age (mean 29.8 ± 15.5 years) within the Network for Pancreatic Organ donors with Diabetes (nPOD) were examined for insulin positivity, insulitis, amyloid staining, acute and chronic pancreatitis, and chronic exocrine changes (acinar atrophy, fibrosis, fatty infiltration, or periductal fibrosis); findings were compared by history of substance use. A secondary analysis compared exocrine pancreatic histopathologic findings in type 1 diabetes versus control organ donors regardless of substance use history. We observed a high but congruent rate of substance use in type 1 diabetes and control organ donors (66.4% and 64% respectively). Among donors with type 1 diabetes (but not controls), islet amyloid (OR 9.96 [1.22, 81.29]) and acute pancreatitis (OR 3.2 [1.06, 9.63]) were more common in alcohol users while chronic exocrine changes (OR 8.86 [1.13, 69.31]) were more common in cocaine users. Substance use impacted the pancreata of donors with type 1 diabetes more than controls. Overall, despite similar rates of substance use, acute pancreatitis (15.3% versus 4.5%, p=0.0061), chronic pancreatitis (29.8% versus 9.9%, p=0.0001), and chronic exocrine changes (73.3% versus 36.9%, p<0.0001) were more common in type 1 diabetes donors than controls. Alcohol and/or cocaine use in type 1 diabetes organ donors increases exocrine pancreas pathology and islet amyloid deposition but does not affect insulitis or insulin positivity. Exocrine pathology in type 1 diabetes donors is common, and further study of the pathophysiology of these changes is needed.

Multisite Examination of Depression Screening Scores and Correlates Among Adolescents and Young Adults With Type 2 Diabetes.

OBJECTIVES: Our aim was to evaluate self-reported depressive symptoms and clinical outcomes during routine screening for adolescents and young adults with type 2 diabetes (T2D), and examine associations among depressive symptoms and demographic and clinical characteristics. METHODS: The Patient Health Questionnaire (PHQ) was administered to 197 adolescents and young adults with T2D using the PHQ-2 or PHQ-9 in routine pediatric diabetes care at 4 academic medical centres. Data from electronic health records were extracted from the screening date and 12 months earlier. RESULTS: Adolescents and young adults with T2D (mean age, 16.85 years; 57% male; 77.2% non-Caucasian) completed the PHQ as part of routine diabetes care. On the PHQ, 19.3% of adolescents and young adults endorsed elevated depressive symptoms (PHQ score ≥10) and, among a subsample with item-level data (n=53), 18.9% endorsed thoughts of self-harm. Subsequently, 50.0% of those with depressive symptoms had a documented referral for mental health treatment in the electronic health record after the positive screening outcome. Older age, shorter diabetes duration, higher glycated hemoglobin level, being non-Hispanic white, more blood glucose checks per day and being prescribed oral medications were significantly associated with more depressive symptoms. CONCLUSIONS: Screening for depressive symptoms identifies individuals in need of referral for mental health treatment. A focus on self-harm assessment, standardized methods for documentation of symptoms and mental health referrals and increased referral resources are needed.

How Do We Move Type 1 Diabetes Immunotherapies Forward During the Current COVID-19 Pandemic?

Research-based immunotherapy trials seeking to prevent or reverse a number of autoimmune diseases, including type 1 diabetes, have seen near universal suspension due to the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diabetes and hyperglycemia are now appreciated as significant risk factors for COVID-19 morbidity and mortality; however, the vast majority of studies have reported on adults. Recent data in children and adolescents with type 1 diabetes suggest no increased risk of COVID-19. Even with immense appreciation for COVID-19 morbidity and mortality, we believe compelling arguments exist to carefully and thoughtfully resume certain type 1 diabetes phase 2-3 immunotherapy trials. In this Perspective, we consider the experience of trials that never halted or have resumed in the oncology and rheumatology fields, and advocate for staged type 1 diabetes immunotherapy trial resumption. With this, we present recommendations to achieve equipoise and mitigate risks for SARS-CoV-2 infection in the weeks surrounding infusion. Given the fact that the COVID-19 pandemic is expected to persist for some time, it is in the best interest of our patients that we find ways to safely move our field forward.

A retrospective multisite examination of depression screening practices, scores, and correlates in pediatric diabetes care.

Psychosocial guidelines recommend routine screening of depressive symptoms in adolescents and young adults (AYA) with diabetes. Best practices for screening in routine care and patient characteristics associated with depressive symptoms require further investigation. The purpose of this study was to examine psychometric properties of the Patient Health Questionnaire (PHQ-2 and PHQ-9); document rates of depressive symptoms and related clinical actions; and evaluate associations with patient characteristics. The Patient Health Questionnaire (PHQ-2 or PHQ-9) was administered at five pediatric academic medical centers with 2,138 youth with type 1 diabetes. Screening was part of routine clinical care; retrospective data from electronic health records were collected for the first screening date as well as 12 months prior. The PHQ demonstrated good psychometric properties. Evaluation of item-level PHQ-9 data identified 5.0% of AYA with at least moderate depressive symptoms who would not have been flagged for further screening using the PHQ-2 only. On the PHQ-9, 10.0% of AYA with type 1 diabetes endorsed elevated depressive symptoms and 7.0% endorsed thoughts of self-harm. Patients with moderate or greater depressive symptoms had a 43.9% documented referral rate for mental health treatment. Higher BMI, older age, public insurance, shorter diabetes duration, higher HbA1C, and a diabetic ketoacidosis (DKA) event in the past year were associated with depressive symptoms. The PHQ-9 identified AYA with elevated depressive symptoms that would not have been identified using the PHQ-2. Depressive symptoms were associated with negative diabetes indicators. To improve referral rates, standardized methods for provision and documentation of referrals are needed.

The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening.

AIMS/HYPOTHESIS: Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status. METHODS: Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1-49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study. RESULTS: Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%. CONCLUSIONS/INTERPRETATION: Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.

Who Is Enrolling? The Path to Monitoring in Type 1 Diabetes TrialNet's Pathway to Prevention.

OBJECTIVE: To better understand potential facilitators of individual engagement in type 1 diabetes natural history and prevention studies through analysis of enrollment data in the TrialNet Pathway to Prevention (PTP) study. RESEARCH DESIGN AND METHODS: We used multivariable logistic regression models to examine continued engagement of eligible participants at two time points: 1) the return visit after screening to confirm an initial autoantibody-positive (Ab+) test result and 2) the initial oral glucose tolerance test (OGTT) for enrollment into the monitoring protocol. RESULTS: Of 5,387 subjects who screened positive for a single autoantibody (Ab), 4,204 (78%) returned for confirmatory Ab testing. Younger age was associated with increased odds of returning for Ab confirmation (age <12 years vs. >18 years: odds ratio [OR] 2.12, P < 0.0001). Racial and ethnic minorities were less likely to return for confirmation, particularly nonwhite non-Hispanic (OR 0.50, P < 0.0001) and Hispanic (OR 0.69, P = 0.0001) relative to non-Hispanic white subjects. Of 8,234 subjects, 5,442 (66%) were identified as eligible to be enrolled in PTP OGTT monitoring. Here, younger age and identification as multiple Ab+ were associated with increased odds of returning for OGTT monitoring (age <12 years vs. >18 years: OR 1.43, P < 0.0001; multiple Ab+: OR 1.36, P < 0.0001). Parents were less likely to enroll into monitoring than other relatives (OR 0.78, P = 0.004). Site-specific factors, including site volume and U.S. site versus international site, were also associated with differences in rates of return for Ab+ confirmation and enrollment into monitoring. CONCLUSIONS: These data confirm clear differences between successfully enrolled populations and those lost to follow-up, which can serve to identify strategies to increase ongoing participation.

Islet amyloidosis in a child with type 1 diabetes.

Histopathology based studies of the pancreas obtained from organ donors are increasing our awareness of islet phenotypic heterogeneity during development and aging, as well as in settings of type 1 diabetes, type 2 diabetes, monogenic diabetes or other forms of this metabolic disease. Islet amyloidosis represents a histopathological feature classically ascribed to patients with type 2 diabetes. Herein, the occurrence of islet amyloidosis and its severity are reported in a child with type 1 diabetes along with histological comparisons of islet amyloidosis in two young adults with recent-onset type 1 diabetes. Islet amyloidosis was infrequent yet widely distributed throughout the pancreas in the child with type 1 diabetes and both adults with type 1 diabetes, with no such pathology seen in matched control donors. Analysis of these cases add to the increasing appreciation of islet heterogeneity in children and young adults with type 1 diabetes. Such knowledge also supports a notion that multiple pathophysiological mechanisms underlie the loss of functional ß-cell mass in the spectrum of clinical phenotypes in patients with type 1 diabetes.

Type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic ß-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of ß-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in ß-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent ß-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.

Errors in the diagnosis and management of necrotizing otitis externa.

OBJECTIVE: Necrotizing otitis externa (NOE) is a life-threatening condition that may be difficult to distinguish from other clinical entities. The purpose of this study was to assess the pitfalls associated with contemporary diagnosis and management of NOE. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Patients given the diagnosis of NOE or one of its typical presenting complaints over the past 14 years were identified by diagnostic and radiology codes. Charts were reviewed for history, findings, treatment, and outcomes. RESULTS: Fifty-one patients with NOE were identified. The annual case numbers rose steadily. A risk factor was known in 46 patients. Gallium single-photon emission computed tomography was accurate for the presence (44 of 46 patients) and resolution of disease. Prolonged systemic antimicrobial therapy (mean 15 weeks, range 4-59 weeks) was required. Microbial cultures influenced therapy in only 50 percent. Two diabetic men died with disease. Of the cases seen at the request of otolaryngologists, 68 percent were for indications other than NOE (e.g., chronic otitis media). With a known risk such as diabetes, the mean time to diagnosis was 6.9 months. History of and clinical appearance overlapping with benign otitis were the primary reasons for diagnostic delay. CONCLUSION: NOE remains a life-threatening condition that requires prolonged antimicrobial therapy. Its incidence may be on the rise. NOE may develop in patients with benign otitis media and externa, and must be considered in all patients with temporal bone inflammation, especially those with risk factors and those who fail to improve with more conservative measures.