Baricitinib and ß-Cell Function in Patients with New-Onset Type 1 Diabetes.

BACKGROUND: Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves ß-cell function in type 1 diabetes is unclear. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration-time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring. RESULTS: A total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal-stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo. CONCLUSIONS: In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve ß-cell function as estimated by the mixed-meal-stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.).

Is there an optimal approach to elective stabilisation of glycaemic control in children and adolescents with type 1 diabetes mellitus?

AIM: To investigate the effectiveness of inpatient and outpatient interventions in attaining improved glycaemic control in children/adolescents with type 1 diabetes mellitus and persistently high/deteriorating HbA1c. METHODS: A retrospective study at a tertiary paediatric centre. Admitted individuals who had prior attempts at ambulatory stabilisation were matched with intervention naïve controls who underwent outpatient intervention. The mean age was 14.6 years in the admitted group and 14.7 years in the ambulatory group. Mean duration of diabetes was 6.1 years in the admitted group and 7.3 years in the ambulatory group. Change in HbA1c from baseline was assessed to 12 months. RESULTS: Mean baseline HbA1c was 11.3% (100 mmol/mol), with 11.4% in the admitted group and 11.2% in the ambulatory group. Sustained reduction in HbA1c at 12 months was seen in both groups (n = 35 in each): mean (standard deviation) 10.1% (1.5) in admitted (mean reduction in HbA1c 1.4%) and 9.7% (1.4) in ambulatory (mean reduction in HbA1c 1.5%). Proportions achieving delta HbA1c ≥2% (22 mmol/mol) at 12 months were 25 and 31% in admitted and ambulatory groups, respectively. A sustained reduction in HbA1c of ≥2% (22 mmol/mol) after 12 months was more likely in those who attained this reduction by 6 months (17/24 who achieved this at 6 months vs. 3/41 who had not). CONCLUSIONS: Both inpatient and outpatient stabilisation strategies achieved sustained improvements in HbA1c. We recommend an individualised approach to stabilisation, with review of the intervention's success at 6 months with further intensification as needed.

Sex Hormone Treatment for Female Children and young Adults with Disorders Affecting Hypothalamic Pituitary and Ovarian Function.

BACKGROUND: Normal hypothalamic-pituitary-ovarian (HPO) endocrine function is essential for female pubertal and psychosocial development and for ongoing adult physical, sexual and psychosocial health. Girls with hypogonadism, any endocrine disorder causing abnormal uterine bleeding (AUB) or with contraception needs may require sex hormone treatment. Challenges include evolving needs of a young girl through the course of sexual maturation, potential health risks related to the use of sex hormones for pubertal induction, hormone replacement therapy (HRT), menstrual management and/or contraception. SUMMARY: To ensure optimal sex hormone treatment, both a comprehensive understanding of the underlying disorder affecting HPO endocrine function and a professional communication with the patient and physicians involved are warranted. In this narrative mini-review, we discuss pubertal induction and HRT for girls with hypogonadism and the management of AUB and contraception for young women up to age 30 years. Additionally, we provide advice on management of AUB and contraception in young women with common conditions including polycystic ovary syndrome, congenital adrenal hyperplasia and others. A PubMed-literature search including articles published over the last 20 years, together with clinical experience of the authors was integrated to provide treatment recommendations. KEY MESSAGE: Sex hormone treatment, where needed, requires comprehensive understanding of a range of available options. When tailored to individual needs, with flexibility to accommodate changing circumstance in young women it is safe, well tolerated and provides both physical and psychosocial health.

Establishing a Molecular Genetic Diagnosis in Children with Differences of Sex Development: A Clinical Approach.

BACKGROUND: Despite distinct underlying aetiologies, the clinical phenotypes and hormonal profiles of children with various differences of sex development (DSD) are often similar, which presents challenges to ascertaining an accurate diagnosis on clinical grounds alone. Associated features and important clinical outcomes can, however, vary significantly in different DSD, thus establishing an accurate molecular diagnosis may have important implications for decision-making and management planning in a given individual. SUMMARY: The wider availability of next-generation sequencing techniques in recent years has led to recommendations for earlier integration of genetic testing in the diagnostic pathway of children with DSD. This review provides a practical overview of the clinical applications, advantages, and limitations of the more commonly available diagnostic genetic tests and outlines a suggested approach to testing. The potential clinical implications of a confirmed genetic diagnosis, subsequent management pathways for individuals with DSD, and challenges that remain to be addressed are also outlined. KEY MESSAGES: Despite significant improvements in our understanding of the complex genetic pathways that underlie DSD, an accurate diagnosis still eludes many affected individuals. Establishing a molecular diagnosis provides aetiological certainty, enabling improved information for families and individualized clinical management, including monitoring or prophylactic intervention where additional health risks exist. A stepwise approach to genomic testing is recommended to afford highest diagnostic yield from available resources. Looking forward, collaborative multicentre prospective studies will be required to assess the true impact of a genetic diagnosis on improving clinical care pathways and health, well-being and patient-reported outcomes for individuals with DSD.

Targeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development.

Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient's non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

The clinical features that contribute to poor bone health in young Australians living with cystic fibrosis: A recommendation for BMD screening.

BACKGROUND: For Australians living with cystic fibrosis (CF), increased longevity means greater consideration needs to be given to long-term endocrine sequelae such as CF-related bone disease. Deficits in bone mass accrual are most likely to occur during childhood and adolescence. Current guidelines in Australia suggest repeat dual-energy X-ray absorptiometry (DXA) scans every 2 years. This study aims to stratify clinical factors that determine future bone health in the Australian CF population and use this to guide a more streamlined approach to bone health screening. METHODS: This study was a retrospective audit of all patients diagnosed with CF who were treated at the Royal Children's Hospital Melbourne, Australia from 2000 to 2016 (n = 453). Two hundred and two patients had a DXA scan in the study period (191 with height-adjusted data) and 111 patients had more than one scan (108 with height-adjusted data). An investigation into the associations between bone mineral density (BMD) Z score and potential risk factors was conducted using DXA and historical data. RESULTS: The main predictor of future BMD was the previous BMD Z score (p < .001). Other factors found to be determinants of BMD included nutritional status, lung function (FEV1 ), age, history of previous fracture, oral corticosteroid use, and the number of hospital admissions. However, after adjusting for previous BMD, evidence of an association remained only with nutritional status, FEV1 , and number of hospital admissions. CONCLUSION: Second yearly scans may be unnecessary in children with an adequate DXA score on the initial scan who remain clinically stable. However, clinical deterioration in those whose BMD was previously normal, may require closer monitoring of bone health. We propose a guideline for the frequency of DXA monitoring in relation to clinical risk factors.