The N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan Improves Glucose Homeostasis and Preserves Pancreatic Islets in NOD Mice.

For treatment of type 1 diabetes mellitus, a combination of immune-based interventions and medication to promote beta-cell survival and proliferation has been proposed. Dextromethorphan (DXM) is an N-methyl-D-aspartate receptor antagonist with a good safety profile, and to date, preclinical and clinical evidence for blood glucose-lowering and islet-cell-protective effects of DXM have only been provided for animals and individuals with type 2 diabetes mellitus. Here, we assessed the potential anti-diabetic effects of DXM in the non-obese diabetic mouse model of type 1 diabetes. More specifically, we showed that DXM treatment led to five-fold higher numbers of pancreatic islets and more than two-fold larger alpha- and beta-cell areas compared to untreated mice. Further, DXM treatment improved glucose homeostasis and reduced diabetes incidence by 50%. Our data highlight DXM as a novel candidate for adjunct treatment of preclinical or recent-onset type 1 diabetes.

Motivational interviewing from the paediatricians' perspective: assessments after a 2-day training for physicians caring for adolescents with chronic medical conditions (CMCs).

BACKGROUND: Counselling adolescents with chronic medical conditions (CMCs) can be challenging regarding suitable interviewing skills and clinicians' attitudes toward the patient. Successful communication can be a key element of treatment. Motivational Interviewing (MI) is broadly applicable in managing behavioural problems and diseases by increasing patient motivation for lifestyle changes. However, data concerning the applicability, feasibility and implementation of MI sessions in everyday practice are missing from the physicians' point of view. METHOD: The present study was conducted as a mixed methods design. Twenty paediatricians were randomized to a 2-day MI course followed by MI consultations. Data were collected through a questionnaire one year after MI training. Factors for effective training and possible barriers to successful use of MI were examined. RESULTS: Completed questionnaires were returned by 19 of 20 paediatricians. The paediatricians' experiences with MI demonstrate that MI is regarded as a valuable tool when working with adolescents with CMCs. 95% of all respondents reported that they found MI education necessary for their clinical work and were using it also outside the COACH-MI study context. 73.7% percent saw potential to strengthen the connection to their patients by using MI. The doctors were already using more MI conversation techniques after a 2-day MI course. Obstacles were seen in the short training, the lack of time and missing undisturbed environment (interruptions by telephone, staff, etc.) during clinical flow. CONCLUSIONS: MI techniques are not yet a regular part of medical training. However, a 2-day MI course was rated effective and provided a lasting impact by physicians caring for children and adolescents with chronic medical conditions (CMCs), although booster sessions should be offered regularly. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00014043) on 26/04/2018.

Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants.

The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.

Delayed-Onset Transient Hyperinsulinism in Infants with Very Low and Extremely Low Birth Weights: A Cohort Study.

We describe 16 infants born preterm with birth weights <1500 g and transient hyperinsulinism. The onset of hyperinsulinism was delayed and often coincident with clinical stabilization. We hypothesize that postnatal stress caused by prematurity and associated problems may contribute to development of delayed-onset transient hyperinsulinism.

Strengthening the Resilience of Children and Adolescents during a Pandemic: A Scoping Review on Eligible Interventions.

BACKGROUND: The COVID-19 pandemic dramatically affects children's and adolescents' mental health. The accumulation of stress factors and a lack of social support complicate a healthy development. Since the beginning of the pandemic, there has been almost a doubling of mental health problems in children and adolescents. Promoting resilience is a possible approach to reduce the incidence of mental health problems despite these adverse circumstances. OBJECTIVES: This literature search aims at identifying and evaluating interventions to promote resilience mechanisms, with a special focus on feasibility in a crisis situation. MATERIALS AND METHODS: This scoping review is based on a systematic literature search including the databases Cochrane Library, PubMed, Psyc-Info, Psyndex and Google Scholar (2006-2020). Of 1733 identified articles 75 were included. RESULTS: Out of 72 identified intervention studies 28% were feasible under pandemic conditions. The most effective resilience trainings seem to be individualized interventions using cognitive behavioral therapy elements. However, many approaches primarily show short-term success. DISCUSSION: Few evidence-based programs are feasible online or under pandemic restrictions. Most of them show short-term effects and focus on parents and individuals. Multiple programs are ready for use, but still lack proof of efficacy. The development and improvement of (digital) resilience interventions should be an essential part of preventive health care, especially for risk groups. HINTERGRUND: Die COVID-19-Pandemie beeinflusst die mentale Gesundheit von Kindern und Jugendlichen auf dramatische Weise. Durch eine Akkumulation von Belastungsfaktoren und das Wegfallen sozialer Unterstützung ist eine regelrechte Entwicklung erschwert. Seit Beginn der Pandemie kam es nahezu zu einer Verdopplung der psychischen Auffälligkeiten. Die Förderung der Resilienz kann ein Ansatz sein, das Auftreten von psychischen Auffälligkeiten trotz dieser widrigen Umstände zu vermindern. ZIEL DER ARBEIT: Ziel dieser Literaturrecherche ist die Identifikation und Bewertung von Interventionen zur Förderung von Resilienzmechanismen, mit Fokus auf die Durchführbarkeit unter Krisenbedingungen. MATERIAL UND METHODEN: Dieses Scoping Review basiert auf einer systematischen Literaturrecherche der Datenbanken Cochrane Library, PubMed, Psyc-Info, Psyndex sowie Google Scholar (2006-2021). Von der insgesamt 1733 Artikel umfassenden Suche wurden 75 Artikel eingeschlossen. ERGEBNISSE: Von 72 identifizierten Interventionsstudien sind 28% unter Pandemiebedingungen durchführbar. Die wirksamsten Resilienztrainings scheinen individualisierte Interventionen mit Elementen der kognitiven Verhaltenstherapie zu sein. Viele Ansätze zeigen jedoch in erster Linie kurzfristige Erfolge. DISKUSSION: Nur wenige evidenzbasierte Programme sind online oder unter Pandemiebedingungen verfügbar. Die meisten von ihnen zeigen kurzfristige Effekte und konzentrieren sich auf Eltern und Einzelpersonen. Zahlreiche Programme sind nutzbar, allerdings fehlt häufig ein Evidenznachweis. Die Entwicklung und Verbesserung von (digitalen) Resilienzmaßnahmen sollte ein wesentlicher Bestandteil der präventiven Gesundheitsversorgung sein, insbesondere für Risikogruppen.

Interleukin-7 and soluble Interleukin-7 receptor levels in type 1 diabetes - Impact of IL7RA polymorphisms, HLA risk genotypes and clinical features.

High soluble IL-7 receptor (sIL-7R) serum levels and associated single nucleotide polymorphisms in the IL7RA gene were found in autoimmune diseases including type 1 diabetes. Further determinants on sIL-7R and IL-7 availability as well as changes during type 1 diabetes disease course remain elusive. Here we performed multiparameter analysis to identify influential genetic and disease-associated factors on sIL-7R and IL-7 serum levels during type 1 diabetes disease course (239 children) and in healthy controls (101 children). We found higher sIL-7R serum concentrations at type 1 diabetes onset and decreasing levels during therapy whereas IL-7 was only higher in long term patients as compared to controls. Multiple linear regression analyses revealed several factors, including IL7RA SNP rs6897932 and HLA risk haplotypes, influencing sIL-7R levels but not IL-7, which was solely associated with the sIL-7R. This study revealed unexpected complexity in the regulation of the sIL-7R but not for IL-7.

Interleukin-7-dependent nonclassical monocytes and CD40 expression are affected in children with type 1 diabetes.

The important role of IL-7 in the generation of self-reactive T-cells in autoimmune diseases is well established. Recent studies on autoimmunity-associated genetic polymorphisms indicated that differential IL-7 receptor (IL-7R) expression of monocytes may play a role in the underlying pathogenesis. The relevance of IL-7-mediated monocyte functions in type 1 diabetes remains elusive. In the present study, we characterized monocyte phenotype and IL-7-mediated effects in children with type 1 diabetes and healthy controls with multicolor flow cytometry and t-distributed Stochastic Neighbor-Embedded (t-SNE)-analyses. IL-7R expression of monocytes rapidly increased in vitro and was boosted through LPS. In the presence of IL-7, we detected lower monocyte IL-7R expression in type 1 diabetes patients as compared to healthy controls. This difference was most evident for the subset of nonclassical monocytes, which increased after IL-7 stimulation. t-SNE analyses revealed IL-7-dependent differences in monocyte subset distribution and expression of activation and maturation markers (i.e., HLA-DR, CD80, CD86, CD40). Notably, monocyte CD40 expression increased considerably by IL-7 and CD40/IL-7R co-expression differed between patients and controls. This study shows the unique effects of IL-7 on monocyte phenotype and functions. Lower IL-7R expression on IL-7-induced CD40high monocytes and impaired IL-7 response characterize monocytes from patients with type 1 diabetes.

Reliability and Observer Dependence of Signs of Neonatal Hypoglycemia.

OBJECTIVES: To evaluate, using video documentation, the sensitivity, specificity, and interobserver reliability of visualizable signs of neonatal hypoglycemia at different glucose concentrations in neonates. STUDY DESIGN: In a prospective cohort study of 145 neonates with and without risk factors for hypoglycemia, 430 videos were recorded before blood glucose measurements and analyzed by 10 blinded investigators of different professions. The primary outcome measures were sensitivity and specificity for clinical detection of hypoglycemia. RESULTS: The overall sensitivity to detect low blood glucose (<55 mg/dL [<3.1 mmol/L]) based on signs was 30%, and the specificity was 82%. Significantly more investigators suspected hypoglycemia while viewing videos of infants with blood glucose levels of 46-54 mg/dL (2.6-3.0 mmol/L) and 30-45 mg/dL (1.7-2.5 mmol/L) compared with ≥55 mg/dL (≥3.1 mmol/L) (29 ± 3% and 31 ± 4% vs 18 ± 1%; P = .001; P = .007). After 48 hours of life, significantly more investigators suspected hypoglycemia in videos of infants with blood glucose levels of ≤45 mg/dL (≤2.5 mmol/L) compared with blood glucose levels of >45 mg/dL (>2.5 mmol/L) (28.9 ± 8.1% vs 10.9 ± 1.8%; P = .007). For blood glucose levels 30-45 mg/dL (1.7-2.5 mmol/L), sensitivity varied widely between investigators, ranging from 5% to 62%. Three hypoglycemic episodes <30 mg/dL (<1.7 mmol/L) were only partially recognized. CONCLUSIONS: Clinical observation of signs is neither sensitive nor specific to detect neonatal hypoglycemia, and there are large interobserver differences. Thus, guidelines on neonatal hypoglycemia should reconsider whether distinguishing between asymptomatic and symptomatic hypoglycemia provides useful information for the management of neonatal hypoglycemia, because it may pose a risk for systematic under-recognition and undertreatment, leading to an increased risk for neurodevelopmental impairment. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00021500 www.drks.de/drks_web/setLocale_EN.do.

Clinical characteristics and cardiovascular risk profile in children and adolescents with latent autoimmune diabetes: Results from the German/Austrian prospective diabetes follow-up registry.

AIMS: To characterize children and adolescents with latent autoimmune diabetes of the young (LADY), and to assess the utility of classifying individuals as LADYs regarding their cardiovascular (CV) risk factors. METHODS: Data from 25,520 individuals (age at diagnosis <18 years) of the Prospective Diabetes Follow-up Registry Diabetes-Patienten Verlaufsdokumentation (DPV) were analyzed. LADY was defined as positivity of ≥one islet autoantibody (iAb+) and an insulin-free interval of ≥6 months upon diabetes diagnosis. LADYs were compared to iAb+ individuals immediately requiring insulin ("immunologically confirmed" type 1 diabetes, T1DM), iAb-/Ins- individuals ("classical" T2DM) and to those clinically defined as T2DM (iAbs not measured). RESULTS: Clinical characteristics of LADYs (n = 299) fell in between those with T1DM (n = 24,932) and T2DM (iAb-/Ins-, n = 152) or suspected T2DM (iAB not measured, n = 137). Stratifying LADYs according to their clinical diagnosis however revealed two distinct populations, highly resembling either T1DM or T2DM. Particularly, CV risk profile, precisely prevalence rates of arterial hypertension and dyslipidemia, was significantly higher in LADYs clinically classified as T2DM compared to LADYs classified as T1DM, and did not differ from those with "classical" T2DM. CONCLUSIONS: In terms of CV risk, classifying children and adolescents with diabetes as LADYs provides no additional benefit. Instead, clinical diagnosis seems to better assign individuals to appropriate risk groups for increased CV risk profiles.

Anxiety, depression, and quality of life in parents of children with congenital hyperinsulinism.

This study aimed to assess mental health, family burden, and quality of life (PQoL) in parents of children with persistent congenital hyperinsulinism (CHI). Forty-eight individual CHI parents (75% female) completed self-reported questionnaires and screening tools for anxiety (GAD-7), depression (PHQ-8), PQoL (ULQIE), and family burden (FaBeL). Additional data on sociodemographics, social support, and child- and disease-related data were recorded. 29.8% of parents showed major depressive symptoms and 38.3% had a probable general anxiety disorder, including 20.8% who had both. The family burden was moderate and assessment of PQoL yielded average scores. Neurological impairment in an affected child (p = .002 and p < .001, respectively) and lower working hours (p = .001 and p = .012, respectively) were the strongest predictors of worse GAD-7 and PHQ-8 scores. Furthermore, lower working hours (p = .012) and comorbidities in the affected child (p = .007) were significantly associated with lower PQoL. Mothers had worse GAD-7 scores (p = .006) and lower PQoL (p = .035) than fathers. Indication of sleep disturbance was associated with worse PHQ-8 scores (p = .003), higher family burden (p = .039), and reduced PQoL (p = .003). A higher number of caretakers besides parents was associated with decreased family burden (p = .019), improved PQoL (p < .001), and lower scores for anxiety (p = .016) and depressive (p = .021) symptoms.    Conclusion: Symptoms of depression and anxiety are alarmingly prevalent in parents of children with CHI. Psychological screening of parents should be initiated to ensure early identification of psychological strains and psychosocial support should be offered as needed. A good support network and regular work activities can improve parental mental health and well-being. What is Known: • Psychosocial strains and reduced quality of life are common in parents of chronically ill children. What is New: • In this first study evaluating mental health, family burden, and quality of life in parents of children with congenital hyperinsulinism (CHI), symptoms of depression and anxiety were alarmingly prevalent. • Parents of children with CHI should receive regular psychological screening and psychosocial support should be offered as needed. A good support network and regular work activities can improve parental mental health and well-being.