The human leukocyte antigen (HLA)-A2-restricted zinc transporter (ZnT)8186–194 and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. Here, we show that clonal ZnT8186–194-reactive CD8+ T cells express private T-cell receptors and display equivalent functional properties in T1D and healthy subjects. Ex-vivo analyses further revealed that CD8+ T cells reactive to ZnT8186–194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186–194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children vs. adults, irrespective of disease status. Moreover, some ZnT8186–194-reactive CD8+ T-cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. While ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expressions levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186–194-reactive cells were enriched in the pancreata of T1D donors vs. non-diabetic and type 2 diabetic controls. Thus, islet-reactive CD8+ T cells circulate in most individuals, but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T-cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a pro-inflammatory islet microenvironment.

Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.

We report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.

Neonatal CDI may be transient or permanent. These vulnerable patients have high rates of comorbidity and require careful monitoring.

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This randomized control trial investigated glucose control with closed-loop (CL) versus threshold-low-glucose-suspend (TLGS) insulin pump delivery in pre-pubertal children with type 1 diabetes in supervised hotel conditions. The patients [n = 24, age range: 7-12, HbA1c: 7.5 ± 0.5% (58 ± 5 mmol/mol)] and their parents were admitted twice at a 3-week interval. CL control to range or TLGS set at 3.9 mmoL/L were assessed for 48 hour in randomized order. Admissions included three meals and one snack, and physical exercise. Meal boluses followed individual insulin/carb ratios. While overnight (22:00-08:00) per cent continuous glucose monitoring (CGM) time below 3.9 mmol/L (primary outcome) was similar, time in ranges 3.9 to 10.0 and 3.9 to 7.8 mmoL/L and mean CGM were all significantly improved with CL (P < 0.001). These results were confirmed over the whole 48 hour. Disconnections between devices and limited accuracy of glucose sensors in the hypoglycaemic range appeared as limiting factors for optimal control. CL mode was well accepted while fear of hypoglycaemia was unchanged. CL did not minimize nocturnal hypoglycaemia exposure but improved time in target range compared to TLGS. Although safe and well-accepted, CL systems would benefit from more integrated devices.

No difference in the risk of diabetes was found between GH-treated patients and the reference population. These results are reassuring, but further studies with a longer follow-up are required to evaluate the risk of diabetes with age in these patients.

No abstract