Aims/hypothesis 6q24 transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes presenting in the neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. Methods One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. Results 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. Conclusions/interpretation This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.

Imprinting disorders are associated with mutations and epimutations affecting imprinted genes, that is those whose expression is restricted by parent of origin. Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi-locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management.

OBJECTIVETransient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.RESEARCH DESIGN AND METHODSThe 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.RESULTSThe key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.CONCLUSIONSThere is yet no clear genotype–epigenotype–phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.

The COVID-19 pandemic has undoubtedly affected education at all levels, including medical and dental education. Our study aimed to assess the effectiveness of the blended learning in conservative dentistry with endodontics. The students had theoretical classes in a remote form (using the e-learning portal and Teams communicator) and practical classes with the participation of patients in the appropriate sanitary regime. The author’s survey was conducted among fourth-year dental students. The online questionnaire consisted of 5 parts: self-evaluation, evaluation of theoretical e-learning classes, evaluation of practical clinical classes, evaluation of safety, and evaluation of performed blended learning. The majority of respondents declared that their learning effectiveness increased during the pandemic. Most surveyed students preferred remote learning in asynchronous form (e-learning portals) to synchronous form (virtual meetings in real-time). All respondents described the provided personal protective equipment as sufficient or even as excessive. Our students were very satisfied with the proposed blended-learning model and would like to continue it even after the pandemic has ended. Among the advantages, they particularly mentioned the increase in efficiency and the individualised pace of learning, while the disadvantage was the limitation of social contacts. The appropriate use of modern technology can effectively revolutionise dental education.

In many cases, X-linked conditions are transmitted through families "silently" until the first affected individual is diagnosed. Grandmothers are often then tested to help determine the risk to other family members. To date, psychosocial research on carriers of X-linked conditions has focused primarily on mothers and sisters of affected males. In the wider social science literature, studies on grandparents of children with disabilities have centered on their role within the family and relationship with the grandchild. We therefore know little about the impact of carrier testing for a genetic condition on grandparents. This qualitative study aims to contribute towards filling that gap. This study included thirteen grandmothers in families with Fragile X or Duchenne muscular dystrophy; ten had living affected grandsons and three had daughters who chose not to continue with affected male pregnancies after prenatal diagnosis. All thirteen took part in semi-structured interviews and provided a rich and varied data source for conducting thematic analysis. Most of the grandmothers expressed recurring feelings of guilt and a strong sense of responsibility for what had occurred in the family. Other themes included feelings of shock after receiving their test result, changes in family relationships and searching to make sense of the inheritance within the context of the family's experience. This study provides evidence that X-linked carrier testing can have a profound and lasting impact on grandmothers. Although genetic counseling for X-linked conditions is often focused on the potential reproductive implications for carriers, these findings suggest that grandmothers should also be offered genetic counseling when tests are carried out, because of the likely psychosocial impact of a positive test result.

Aims/hypothesis Transient neonatal diabetes (TND) is associated with overexpression of genes within a critical region on 6q24. This study aims to refine the boundaries of this region to reduce the number of potential candidate genes for 6q24 TND. Methods Fifteen patients with transient neonatal diabetes and submicroscopic chromosome 6 duplications were investigated. The duplications were confirmed by microsatellite analysis and subsequently mapped using tiled chromosome 6 array Comparative Genomic Hybridisation (aCGH) and MLPA. Duplication boundaries were compared to identify the minimal shared region of duplication.These data were then used with available clinical data to identify associations between size of 6q24 duplication and severity of TND phenotype. Results Alignment of the minimal region of duplication to the human genome reduced the minimal TND critical region, formerly estimated at 440 kb, to 160-173 kb, revealing PLAGL1 (pleiomorphic adenoma gene-like 1) and HYMAI (imprinted in hydatidiform mole) to be the only genes wholly included therein. Additionally, the complete paternal duplication of a region containing the theoretical protein FAM164B was associated with the severe growth restriction observed in 6q24 duplication patients. Conclusions/interpretation This study has significantly reduced the critical region associated with 6q24 TND. It has eliminated several previous TND candidate genes, leaving the overlapping imprinted genes PLAGL1 and HYMAI as the only remaining complete candidate genes for 6q24 TND. Moreover, these data provide the first evidence that an additional region, encompassing the theoretical protein FAM164B, may have a critical role in the growth restriction phenotype observed in many 6q24 TND patients.

The study aimed to determine if oral hygiene influences not only oral health but also potentially metabolic disorders such as overweight or obesity. Participants were 94 patients: 40 with increased body mass and 54 with normal body mass. The methods included dental examination, a questionnaire concerning hygienic habits and an assessment of selected salivary inflammatory markers. The new parameter named “cleaning index” (describing the interaction between average time of tooth brushing in minutes and its frequency per day) significantly correlated with Body Mass Index (RSpearman = 0.300). The multivariate regression model incorporating cleaning index, approximal plaque index, receptor 1 for tumor necrosis factor-alpha (TNFα-R1) and interleukin-15 (IL-15) had a high power to predict overweight or obesity (AUC = 0.894). Patients with poor oral hygiene (approximal plaque index >40%) were more than eight times more likely to suffer from obesity than patients with good oral hygiene. Cleaning index higher than 4 decreased the odds by about 85%. Oral hygiene habits, adjusted by salivary concentrations of selected inflammatory markers may allow predicting effectively overweight or obesity risk. Early proper dental prophylaxis and treatment could lead to the better prevention of metabolic disorders.

well as their severe consequences like cardiovascular disease, diabetes, metabolic disorders, carcinogenesis, and severe asthma. 1-5 New molecular technologies within the last decade have focused on analyses of salivary proteome and transcriptome. Saliva has been studied as an alternative biological fluid in the noninvasive diagnostics of several systemic diseases, such as endocrine, cardiovascular, autoimmune, or infectious diseases. 6,7 Saliva is generally composed of water (about 99%), proteins (eg, enzymes and immunoglobulins), and electrolytes (eg, sodium and calcium). All these substances are delivered to saliva mainly by salivary glands, gingival crevices, and upper respiratory mucosa. The majority of blood components pass to saliva via intracellular mechanisms, such as passive or active transport or ultrafiltration between cell junctions, by analogy to INTROduCTION Adipose tissue plays an important role in storage of excessive nutrients and regulating energy balance. Due to limited ability of adipocytes for fat deposition, overnutrition generates the production of oxygen free radicals resulting in oxidative stress and, consequently, inflammation. In obesity, low-grade inflammatory status is primarily caused by the activity of adipocytes and immune cells secreting various proinflammatory molecules, such as tumor necrosis factor-α receptors 1 (TNF-α-R1) and 2 (TNF-α-R2), pentraxin 3 (PTX3), interleukin 15 (IL-15), monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule 1 (sICAM-1), or soluble CD40 ligand (sCD40L). All these signaling molecules are responsible for such processes as chronic systemic inflammation, adipogenesis, atherosclerosis, or insulin resistance, as