ISPAD Clinical Practice Consensus Guidelines 2024: Screening, Staging, and Strategies to Preserve Beta Cell Function in Children and Adolescents with Type 1 Diabetes.

Introduction This guideline serves as an update to the 2022 International Society for Pediatric and Adolescent Diabetes (ISPAD) consensus guideline on staging for Type 1 Diabetes (T1D). Key additions include an evidence-based summary of recommendations for screening for risk of T1D and monitoring those with early-stage T1D. In addition, a review of clinical trials designed to delay progression to Stage 3 T1D and efforts seeking to preserve beta cell function in those with Stage 3 T1D is included.

Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop.

The approval of teplizumab to delay the onset of type 1 diabetes is an important inflection point in the decades-long pursuit to treat the cause of the disease rather than its symptoms. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop of the Diabetes Mellitus Interagency Coordinating Committee titled "Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes" to review this accomplishment and identify future goals. Speakers representing Type 1 Diabetes TrialNet (TrialNet) and the Immune Tolerance Network emphasized that the ability to robustly identify individuals destined to develop type 1 diabetes was essential for clinical trials.

Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings.

Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb) children and adults who are at risk of (confirmed single IAb) or living with (multiple IAb) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings.

Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.

Objective: Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

Objective: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.

Research Design And Methods: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months.

Transient vs Permanent Congenital Hypothyroidism in Ontario, Canada: Predictive Factors and Scoring System.

Context: The apparent increased incidence of congenital hypothyroidism (CH) is partly due to increased detection of transient disease.

Objective: This work aims to identify predictors of transient CH (T-CH) and establish a predictive tool for its earlier differentiation from permanent CH (P-CH).

Methods: A retrospective cohort study was conducted of patients diagnosed with CH from 2006 to 2015 through Newborn Screening Ontario (NSO).

A rare unbalanced translocation (trisomy 5q33.3-qter, monosomy 13q34-qter) results in growth hormone deficiency and brain anomalies.

Background: Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation.

Methods: Karyotype analysis was performed on the proband and their parents.

Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample.

Aims/hypothesis: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw.

GAD-alum immunotherapy in type 1 diabetes expands bifunctional Th1/Th2 autoreactive CD4 T cells.

Aims/hypothesis: Antigen-specific therapy aims to modify inflammatory T cell responses in type 1 diabetes and restore immune tolerance. One strategy employs GAD65 conjugated to aluminium hydroxide (GAD-alum) to take advantage of the T helper (Th)2-biasing adjuvant properties of alum and thereby regulate pathological Th1 autoimmunity. We explored the cellular and molecular mechanism of GAD-alum action in the setting of a previously reported randomised placebo-controlled clinical trial conducted by Type 1 Diabetes TrialNet.

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: ) the return visit after screening to confirm an initial autoantibody-positive (Ab) test result and ) 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.

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.

Background: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

Methods: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease.

Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes.

What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes? Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health-funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial-Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes.

GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis.

Aims/hypothesis: GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results.

Methods: In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine).

Prediction of congenital hypothyroidism based on initial screening thyroid-stimulating-hormone.

Background: In thyroid-stimulating-hormone (TSH)-based newborn congenital hypothyroidism (CH) screening programs, the optimal screening-TSH cutoff level is critical to ensuring that true cases of CH are not missed. Screening-TSH results can also be used to predict the likelihood of CH and guide appropriate clinical management. The purpose of this study is to evaluate the predictive value of various screening-TSH levels in predicting a diagnosis of CH in the Ontario Newborn Screening Program (ONSP).

Alternate approaches for pediatric type 1 diabetes drug development and potential regulatory approval: a perspective.

The incidence and prevalence of pediatric type 1 diabetes are increasing globally, including in the U.S. While the increasing number of cases of pediatric diabetes makes expeditious availability of new medical products and therapies for diabetes care essential, there have been many barriers encountered in bringing some drugs and devices to pediatric patients who may benefit.

Defining pathways for development of disease-modifying therapies in children with type 1 diabetes: a consensus report.

Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care.

Approach to the Infant with a Suspected Disorder of Sex Development.

A newborn with genital ambiguity requires careful diagnostic evaluation to identify the underlying etiology in an efficient manner and assign gender without lengthy delay. The infant's family needs comprehensive psychosocial support. Such infants should be referred to a multidisciplinary team with expertise in disorders of sex development.