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.

CD5-expressing CD8+ T-cell subsets differ between children with type 1 diabetes and controls.

Different lymphocyte subsets are involved in autoimmune pathogenesis of type 1 diabetes (T1D). Previous studies suggested a role of CD5-expressing T and B cells including rare unconventional lymphocytes with combined T- and B-cell features [dual expressing (DE) cells]. We performed algorithm-supported multiparameter flow cytometry and quantitative PCR to investigate immune cell subsets and DE cells in children with T1D (n = 20) and matched controls (n = 20). Comparisons of conventional immune cells detected increased proportions of CD3+ T cells in T1D patients, whereas CD19+ B-cell proportions were comparable to controls. Self-organizing maps for flow cytometry analyses (FlowSOM) showed highly similar CD5-expressing B-cell subsets and no differences for DE cells were detected between the study groups by flow cytometry or specific quantitative PCR. Notably, differences in CD8+ T cells were indicated by FlowSOM and similarity-based t-distributed stochastic neighbor embedding (tSNE) analyses. Study group comparisons confirmed significantly reduced CD8+ T-cell proportions with moderate or low CD5 expression in T1D patients. Finally, in vitro experiments showed stable CD5 expression differences of CD8+ T cells after T-cell activation, cytokine stimulation and culture. We observed differences of T-cell coreceptor CD5 expression in T1D patients with potential relevance for immune regulation of CD8+ T-cell activation.

Virtual auscultation course via video chat in times of COVID-19 improves cardiac auscultation skills compared to literature self-study in third-year medical students: a prospective randomized controlled cross-over study.

Background: Cardiac auscultation is a core clinical skill taught in medical school. Due to contact restrictions during the SARS-CoV-2 pandemic, interaction with patients was very limited. Therefore, a peer-to-peer virtual case-based auscultation course via video conference was established. Methods: A randomized controlled cross-over study was conducted to evaluate whether participation in a virtual auscultation course could improve heart auscultation skills in 3rd-year medical students. A total of sixty medical students were randomly assigned to either the experimental or control group after informed consent was obtained. Due to no-shows, 55 students participated. Depending on allocation, students attended three ninety-minute courses in intervals of one week in a different order: a virtual case-based auscultation course held via video chat, literature self-study, and an on-site course using a high-fidelity auscultation simulator (SAM II). The study's primary endpoint was the performance of the two groups at the simulator after participating in the virtual auscultation course or literature self-study. To evaluate their auscultation skills, students participated in five assessments using the same six pathologies: stenosis and regurgitation of the aortic and mitral valve, ventricular septal defect, and patent ductus arteriosus. Moreover, participants rated their satisfaction with each course and provided a self-assessment of competence. Results: Compared to literature self-study, participation in the virtual auscultation course led to a significantly improved description of heart murmurs at the auscultation simulator with regard to the presence in systole and diastole, low- and high-pitched sounds, and volume dynamics. There was no significant difference between the groups in diagnostic accuracy and identification of the point of maximal intensity. After the virtual course, students showed higher satisfaction rates and a higher increase in self-assessed competence compared to participants who engaged in literature self-study. Conclusions: For the first time, this study demonstrates that a case-based virtual auscultation course can improve aspects of cardiac auscultation skills on a simulator. This may facilitate the further acquisition of an essential clinical skill, even when contact restrictions will be lifted.

Undergraduate medical education amid COVID-19: a qualitative analysis of enablers and barriers to acquiring competencies in distant learning using focus groups.

Due to comprehensive social distancing measures related to the COVID-19 pandemic, medical faculties worldwide have made a virtue of necessity in resorting to online teaching. Medical faculties grapple with how to convey clinical competencies to students in this context. There is a need for research not only to map but also to explain the effect of these secondary measures on students' learning and mental wellbeing. During a period of ongoing comprehensive social distancing measures in Germany, we translated a competency-based curriculum including obstetrics, paediatrics, and human genetics to an e-learning course based on online patient and teacher encounters. In our qualitative study on students' and teachers' views, we identify potential enablers and drivers as well as barriers and challenges to undergraduate medical education under lockdown. In summer 2020, we conducted six focus group interviews to investigate medical students' and teachers' perspectives, experiences and attitudes. All focus groups were videotaped, transcribed verbatim and coded. To guide our deductive and inductive analysis, we applied the theoretical framework of Regmi and Jones. Content analysis was performed in a multi-perspective group. We identified five major themes contributing to a successful use of clinical competency-based e-learning under lockdown: Communication (with teachers, students, and patients), Mental wellbeing, Structure and self-organization, Technical issues, and Learning and commitment. We discuss enablers and potential barriers within all themes and their overlap and link them in an explanatory model. In our setting, students and teachers find e-learning holds strong potential and especially in times of COVID-19 it is greatly appreciated. We broaden the understanding of the impact of distant learning on acquiring competencies, on attitudes, and on mental wellbeing. Our model may serve for a thoughtful, necessary transition to future e-learning and hybrid programs for a competency-based medical education with ongoing social distancing measures.

Are psychiatric disorders associated with thyroid hormone therapy in adolescents and young adults with type 1 diabetes?

BACKGROUND: To evaluate the association between thyroid autoimmunity and psychiatric disorders (depression, anxiety, eating disorder, schizophrenia or attention-deficit/hyperactivity disorder) among adolescents and young adults with type 1 diabetes (11-25 years). METHODS: We compared 9368 type 1 diabetes patients with thyroid autoimmunity (3789 of them treated with levothyroxine) with 62 438 type 1 diabetes patients without any thyroid disease from a multicentre diabetes patient follow-up registry (DPV) in terms of psychiatric disorders. Thyroid autoimmunity was defined as documented diagnosis of Hashimoto thyroiditis or positive antibodies against thyroid peroxidase or thyroglobulin. Multivariable logistic regression models were used to calculate odds ratios for the respective psychiatric disorders in type 1 diabetes patients with thyroid autoimmunity (overall and stratified by levothyroxine therapy) compared to type 1 diabetes patients without thyroid diseases (reference). RESULTS: Of the 9368 patients with thyroid autoimmunity, 62% were female with a median (Q1-Q3) age of 16.3 (14.2-17.6) years. Thyroid autoimmunity (with or without levothyroxine therapy) revealed a slight, but significant higher chance for depression (odds ratio [OR], 1.35, 95% confidence interval [CI], 1.19, 1.52), eating disorder (OR, 1.25, CI, 1.03, 1.51), attention-deficit/hyperactivity disorder (OR, 1.22, CI, 1.07, 1.39) and schizophrenia (OR, 1.63, CI, 1.04, 2.56). In individuals with prescribed levothyroxine therapy because of thyroid dysfunction significantly higher odds for depression (OR, 1.63, CI, 1.34, 1.99), anxiety (OR, 1.60, CI, 1.18, 2.18), and attention-deficit/hyperactivity disorder (OR, 1.71, CI, 1.38, 2.12) were observed compared to reference. Thyroid autoimmunity without required levothyroxine therapy revealed no differences to the reference group. CONCLUSIONS: Patients on levothyroxine had significantly higher odds for psychiatric disorders, but thyroid autoimmunity in terms of high antibody levels only did not show higher odds for any psychiatric disorder.

Next Generation Sequencing Identifies the HLA-DQA1*03:03 Allele in the Type 1 Diabetes Risk-Associated HLA-DQ8 Serotype.

The highest genetic type 1 diabetes risk is conferred by HLA class II haplotypes defined by alleles at the HLA-DR and -DQ loci. The combination of HLA-DQA1*03:01 and DQB1*03:02 alleles (summarized as 'HLA-DQ8') is reported to be among the two most prevalent HLA class II haplotypes in Caucasian type 1 diabetes patients. This classification is based on conventional genotyping of exon 2 of the DQ gene locus and excludes exon 3. In this study, HLA genotyping on the type 1 diabetes susceptibility loci HLA-DRB1, DQA1 and DQB1 was performed using a high-resolution next generation sequencing method. In addition to the routinely examined exon 2, exon 3 was also sequenced. Samples from 229 children with type 1 diabetes were included and compared to a cohort of 9,786 controls. In addition to previously described HLA-DQ haplotypes in type 1 diabetes patients, we found that as well as HLA-DQA1*03:01,HLA-DQA1*03:03 also contributed to HLA-DQ8. HLA-DQA1*03:03 differs from HLA-DQA1*03:01 by one nucleotide substitution in exon 3 at position 160, leading to a single amino acid replacement. DRB1*04:05 was exclusively associated with DQA1*03:03 whereas the DRB1*04:01 haplotype comprised either DQA1*03:01 or DQA1*03:03. Significantly increased type 1 diabetes risk was confirmed for all these haplotypes with only minor differences between DQA1*03:01 and DQA1*03:03 alleles. This study identified the HLA-DQA1*03:03 allele as an addition to the already known type 1 diabetes risk haplotypes, and can contribute to more precise HLA genotyping approaches.

Virtual auscultation course for medical students via video chat in times of COVID-19.

Introduction: Auscultation skills are among the basic techniques to be learned in medical school. Such skills are achieved through supervised examination of patients often supported by simulator-based learning. The emergence of COVID-19 has disrupted and continues to hinder hands-on on-site medical training on a global scale. Project description: An effective virtual auscultation course was established in times of contact restrictions due to COVID-19 at the Medical Faculty of the Heinrich Heine University Düsseldorf. The interactive case-based webinar was designed to improve listening techniques, description and interpretation of auscultation findings in an off-site context. Clinical cases with pre-recorded auscultation sounds and additional case-based diagnostics were presented. The course focused on common heart murmurs including aortic and mitral valve stenosis and regurgitation as well as congenital heart defects (ventricular septal defect and patent ductus arteriosus). Results: The course was well received by the students and assessed as being useful and instructive. Assessment of learning effects, such as detection of pathological findings before and after training, is ongoing as part of a subsequent trial. Conclusion: Virtual interactive learning using a sound simulation lesson with clinical case presentations via video chat can well be used as a supplement to practical auscultation training. This learning format could also play a useful role in the curriculum of medical studies once contact restrictions are revoked.

Long-term plasticity of visually evoked potentials in humans is altered in major depression.

BACKGROUND: Long-term synaptic plasticity is a ubiquitous form of neuronal plasticity that regulates the strength of synaptic transmission in many brain areas. However, most data on long-term potentiation and long-term depression rely on research in animal brain slices. The role of synaptic plasticity in physiology and pathology of the functioning human brain remains obscure. Considering recent studies that provided evidence for a dysfunction of brain plasticity as the neurobiological basis of affective disorders, we assessed neural transmission and its plastic modulation in the visual pathway in healthy control subjects and patients with major depression. METHODS: Recordings of visually evoked potentials (VEPs) in humans. RESULTS: Prolonged visual presentation of checkerboard reversals resulted in a sustained amplitude modulation of early components of subsequent VEPs. After a 10-min block of visual stimulation (two checkerboard reversals per second), the C1 component was reduced, whereas P1 and N1 were both significantly increased for >30 min. Chronic application of the selective serotonin reuptake inhibitor sertraline in healthy control subjects augmented these effects, whereas the polarity of the modulation was inverted in patients with severe major depression. Moreover, early VEP amplitudes were decreased in depressed patients when compared with matched control subjects and increased in normal control subjects after chronic intake of an antidepressant. CONCLUSIONS: Our results demonstrate that stimulus-induced response plasticity of VEPs can be induced in the human brain and is sharing properties with hebbian forms of synaptic plasticity. Major depression and antidepressant treatment of healthy control subjects differentially modulate amplitude and plasticity of evoked potentials. This study provides direct evidence in humans for a central role of synaptic plasticity in the pathophysiology of depression.

Remission of congenital hyperinsulinism following conservative treatment: an exploratory study in patients with KATP channel mutations.

BACKGROUND: During conservative treatment, congenital hyperinsulinism (CHI) can resolve spontaneously. This study describes the hormonal and metabolic profiles in three patients with ABCC8/KCNJ11 mutations in clinical remission. METHODS: An age-adapted fasting and oral glucose tolerance test (OGTT) were performed. RESULTS: All patients (aged 6-9 years) tolerated age-adapted fasting durations (20, respectively 24 h), without reaching glucose concentrations ≤2.5 mmol/L, nor developing hypoglycemia-related symptoms. Nevertheless, insulin concentrations from all patients exceeded the 90th reference percentile at the end of the fasting test (range: 4.2-15.8 mU/L). During the OGTT, one patient (patient 2; BMI: 23.4 kg/m2; age: 7 years) reached a glucose concentration of 11.4 mmol/L after 2 h (concomitant insulin concentration: 148.3 mU/L). CONCLUSIONS: The insulin concentration profiles in CHI patients in apparent clinical remission range from almost complete normalization to persistent, yet attenuated, hypersecretion. The hyperglycemia, detected during the OGTT, must be further monitored.