Poorly controlled pediatric type 1 diabetes mellitus is a risk factor for metabolic dysfunction associated steatotic liver disease (MASLD): An observational study.

OBJECTIVES: Recent studies have suggested a link between type 1 diabetes mellitus (T1D) and metabolic dysfunction associated steatotic liver disease (MASLD) in children and adolescent, but longitudinal evidence is lacking. This study aimed to investigate the potential association between poorly controlled T1D and elevated alanine aminotransferase (ALT), serving as a proxy for MASLD in children and adolescents over time. METHODS: The study included 32,325 children aged 2-17 years with T1D from Germany, Austria, and Switzerland who had undergone at least one assessment of liver enzyme levels recorded in the Diabetes-Patienten- Verlaufsdokumentation registry. Multivariable logistic and Cox regression models were calculated to show possible associations between T1D and elevated ALT values (>26 U/L in males, >22 U/L in females) as a proxy for MASLD. RESULTS: Children with poorly controlled T1D (HbA1c > 11%) exhibited increased odds of elevated ALT values, after adjustment for age, sex, diabetes duration and overweight (odds ratio [OR] 2.54; 95% confidence interval [CI], 2.10-3.10; p < 0.01). This finding is substantiated by a longitudinal analysis, which reveals that inadequately controlled T1D was associated with a higher hazard ratio (HR) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 (HR: 1.54; 95% CI, 1.19-2.01; p < 0.01). CONCLUSION: In conclusion, the current study strongly links poorly controlled T1D in children and adolescents to MASLD irrespective of overweight. This association is not only present cross-sectionally but also increases over time. The study underscores the critical role of effective diabetes management in reducing the risk of MASLD in this population.

Dental Pulp Stem Cells for Salivary Gland Regeneration-Where Are We Today?

Xerostomia is the phenomenon of dry mouth and is mostly caused by hypofunction of the salivary glands. This hypofunction can be caused by tumors, head and neck irradiation, hormonal changes, inflammation or autoimmune disease such as Sjögren's syndrome. It is associated with a tremendous decrease in health-related quality of life due to impairment of articulation, ingestion and oral immune defenses. Current treatment concepts mainly consist of saliva substitutes and parasympathomimetic drugs, but the outcome of these therapies is deficient. Regenerative medicine is a promising approach for the treatment of compromised tissue. For this purpose, stem cells can be utilized due to their ability to differentiate into various cell types. Dental pulp stem cells are adult stem cells that can be easily harvested from extracted teeth. They can form tissues of all three germ layers and are therefore becoming more and more popular for tissue engineering. Another potential benefit of these cells is their immunomodulatory effect. They suppress proinflammatory pathways of lymphocytes and could therefore probably be used for the treatment of chronic inflammation and autoimmune disease. These attributes make dental pulp stem cells an interesting tool for the regeneration of salivary glands and the treatment of xerostomia. Nevertheless, clinical studies are still missing. This review will highlight the current strategies for using dental pulp stem cells in the regeneration of salivary gland tissue.

Elevated liver enzymes and comorbidities in type 2 diabetes: A multicentre analysis of 51 645 patients from the Diabetes Prospective Follow-up (DPV) database.

AIM: To assess the prevalence of elevated liver enzymes and associated diabetes-related comorbidities in type 2 diabetes (T2D). SUBJECTS AND METHODS: Between 2010 and 2019, 281 245 patients with T2D (aged 18-75 years) from 501 Diabetes Prospective Follow-up (DPV) centres were evaluated, resulting in analysis of 51 645 patients with complete data on demographics and liver enzymes. RESULTS: Elevated liver enzymes were found in 40.2% of all patients. However, only 8.6% of these patients had International Classification of Diseases-10 codes for nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis. Adjusted for age, sex, diabetes duration, body mass index and glycated haemoglobin, a higher prevalence of arterial hypertension (P < 0.0001), dyslipidaemia (P < 0.0001), peripheral artery disease (P = 0.0029), myocardial infarction (P = 0.0003), coronary artery disease (P = 0.0001), microalbuminuria (P < 0.0001) and chronic kidney disease (P < 0.0001) was seen in patients with elevated versus normal liver enzymes. The prevalence of elevated liver enzymes was lowest in patients receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors or a combination of SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists. CONCLUSION: Elevated liver enzymes are common in patients with T2D and clearly correlate with a higher prevalence of clinically relevant comorbidities. Assessing liver enzymes should be standard clinical routine in T2D due to a possible predictive role for comorbidities and complications.

Glycated hemoglobin at diagnosis of type 1 diabetes and at follow-up in children and adolescents during the COVID-19 pandemic in Germany.

BACKGROUND: This study investigated the diagnostic delay and the subsequent quality of care during the Covid-19 pandemic among children with new-onset type 1 diabetes. METHODS: We compared the HbA1c levels of 3111 children at diagnosis of type 1 diabetes and of 2825 children at a median follow-up of 4.7 months (interquartile range, 4.1-5.4) together with their daily insulin requirement during the Covid-19 pandemic with the two previous years via multivariable linear regression, using data from the German Diabetes Registry DPV. RESULTS: During the Covid-19 pandemic, HbA1c levels were higher at diagnosis of type 1 diabetes (mean estimated difference, 0.33% [95% confidence interval, 0.23-0.43], p < 0.001), but not at follow-up (mean estimated difference, 0.02% [-0.02-0.07]). Children with diabetes onset during the Covid-19 pandemic had a significantly higher daily insulin requirement after initiation of therapy (mean estimated difference, 0.08 U/kg [0.06-0.10], p < 0.001). Both the increase in HbA1c and daily insulin requirement were evident only after the first wave of the pandemic. CONCLUSIONS: This increase in HbA1c at diagnosis of type 1 diabetes during the Covid-19 pandemic may indicate a delay in seeking medical care due to the pandemic. However, this did not affect short-term glycemic control. The increased insulin requirement at follow-up could suggest a more rapid autoimmune progression during the pandemic.

Clinical presentation and long-term outcome of patients with KCNJ11/ABCC8 variants: Neonatal diabetes or MODY in the DPV registry from Germany and Austria.

OBJECTIVE: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. RESEARCH DESIGN AND METHODS: We analyzed patients in the Diabetes Prospective Follow-up (DPV) registry with diabetes and pathogenic variants in the ABCC8/KCNJ11 genes. For patients with available data at three specific time-points-classification as K+ -channel variant, 2-year follow-up and most recent visit-the longitudinal course was evaluated in addition to the cross-sectional examination. RESULTS: We identified 93 cases with ABCC8 (n = 54)/KCNJ11 (n = 39) variants, 63 of them with neonatal diabetes. For 22 patients, follow-up data were available. Of these, 19 were treated with insulin at diagnosis, and the majority of patients was switched to sulfonylurea thereafter. However, insulin was still administered in six patients at the most recent visit. Patients were in good metabolic control with a median (IQR) A1c level of 6.0% (5.5-6.7), that is, 42.1 (36.6-49.7) mmol/mol after 2 years and 6.7% (6.0-8.0), that is, 49.7 (42.1-63.9) mmol/mol at the most recent visit. Five patients were temporarily without medication for a median (IQR) time of 4.0 (3.5-4.4) years, while two other patients continue to be off medication at the last follow-up. CONCLUSIONS: ABCC8/KCNJ11 variants should be suspected in children diagnosed with diabetes below the age of 6 months, as a high percentage can be switched from insulin to oral antidiabetic drugs. Thirty patients with diabetes due to pathogenic variants of ABCC8 or KCNJ11 were diagnosed beyond the neonatal period. Patients maintain good metabolic control even after a diabetes duration of up to 11 years.

Cataract in children and adolescents with type 1 diabetes. Insights from the German/Austrian DPV registry.

OBJECTIVE: To study diabetic cataract in type 1 diabetes in a large pediatric cohort. METHODS: The 92,633 patients aged 0.5-21 years from German/Austrian multicenter diabetes registry (DPV) were analyzed. The 235 patients (0.25%) with diabetic cataract were found, 200 could be categorized: 67 with early cataract (3 months before diabetes onset - 12 months afterwards), 133 with late cataract (>12 months after diabetes onset). Regression models adjusted for age and gender were used to compare clinical parameters at diabetes onset. Regression models for patients with late cataract were implemented for the total documentation period and additionally adjusted for diabetes duration. RESULTS: Rate of cataract development shows a peak at diabetes onset and declines with longer diabetes duration. Patients with cataract showed strong female preponderance. Patients developing early cataract were older at diabetes onset (12.8 years [11.8/13.9] vs. 8.9 [8.9/9.0]; p < 0.001) and showed higher HbA1c than patients without cataract (9.0% [8.55/9.38] vs. 7.6% [7.60/7.61]; p < 0.001). They had lower height-SDS, (-0.22 [-0.48/0.04] vs. 0.25 [0.24/0.26]; p < 0.001), lower weight-SDS (-0.31 [-0.55/-0.08] vs. 0.21 [0.20/0.21]; p < 0.001) and lower BMI-SDS (-0.25 [-0.49/-0.02] vs. 0.12 [0.12/0.13); p = 0.002). Patients with late cataract showed higher HbA1c at diabetes onset (8.35% [8.08/8.62] vs. 8.04% [8.03/8.05]; p = 0.023) and higher mean HbA1c during total documentation period (8.00% [7.62/8.34] vs. 7.62% [7.61/7.63]; p = 0.048). CONCLUSIONS: Our data confirm known demographic and clinical characteristics of patients developing early cataract. Hyperglycemia-induced osmotic damage to lens fibers at diabetes onset might be the main pathomechanism. Long term glycemic control is associated with cataract development.

18F-FDG PET cannot predict expression of clinically relevant histopathological biomarkers in head and neck squamous cell carcinoma: a meta-analysis.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common cancer. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) is a widely used imaging modality in HNSCC. PURPOSE: To provide evident data about associations between 18F-FDG PET and histopathology in HNSCC. MATERIAL AND METHODS: The MEDLINE database was screened for associations between maximum standard uptake values (SUVmax) derived from 18F-FDG PET and histopathological features in HNSCC up to May 2020. Only papers containing correlation coefficients between SUVmax and histopathology were acquired. Overall, 23 publications were collected. RESULTS: The following correlations were calculated: KI 67: 12 studies (345 patients), pooled correlation coefficient (PCC): 0.23 (95% confidence interval [CI] 0.06-0.40); hypoxia-inducible factor-1α: eight studies (240 patients), PCC: 0.24 (95% CI 0.06-0.42); microvessel density: three studies (64 patients), PCC: 0.33 (95% CI 0.02-0.65); vascular endothelial growth factor: two studies (59 cases), PCC: 0.27 (95% CI 0.02-0.51); tumor suppressor protein p53: four studies (159 patients), PCC: 0.05 (95% CI -0.41 to 0.51); epidermal growth factor receptor: two studies (124 patients), PCC: 0.21 (95% CI 0.05-0.37); tumor cell count: three studies (67 patients), PCC: 0.18 (95% CI -0.06 to 0.42); tumor cell apoptosis: two studies (40 patients), PCC: 0.07 (95% CI = -0.85 to 0.99); B-cell lymphoma-2 protein: two studies (118 patients); PCC: 0.04 (95% CI -0.65 to 0.74); glucose-transporter 1: 10 studies (317 patients), PCC: 0.20 (95% CI 0.10-0.30). CONCLUSION: SUVmax derived from 18F-FDG PET cannot reflect relevant histopathological features in HNSCC.

Implant-to-nasal floor dimensions projected by panoramic radiographs in the maxillary incisor-canine region: implications for dental implant treatment.

To make a comparison of panoramic radiography (PAN) and cone-beam computed tomography (CBCT) determinations of implant-to-nasal floor dimensions (INFD) in the anterior maxillary region, and to assist in determining in which tooth regions additional radiation exposure involved in CBCT scans is justifiable. Data related to INFD by PAN (PAN-D) at implant-to-nasal floor sites (central incisor, lateral incisor, canine) were gathered using 141 implant sites from 119 adult patients. INFD was estimated employing the CBCT technique as a reference method. PAN analysis equations were created for estimation of INFD by CBCT (CBCT-D) specific to implant sites. For assessment of the agreement between the PAN and CBCT methodologies, the Bland-Altman approach was employed. There were robust and significant odds ratios that implants in the canine region would fall into the underestimation groups of > 0 mm (4.5:1) (p = 0.003), > 0.5 mm (6.2:1) (p < 0.001), and > 1 mm (5.4:1) (p = 0.002). The root mean squared error (RMSE) and pure error (PE) were highest for the canine region (RMSE = 1.973 mm, PE = 2.20 mm). This research offers evidence of site-specific underestimations of available horizontal bone dimensions for implants when PAN is employed to assess the availability of vertical bone dimensions. The data suggest that it may be necessary to exclude canine regions when making assessment of INFD through PAN. Use of CBCT may, therefore, be recommended for all implant size and angulation estimations in this region.

Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation.

BACKGROUND: Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy. METHODS: We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis. RESULTS: We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation. CONCLUSION: Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.

Association of the use of diabetes technology with HbA1c and BMI-SDS in an international cohort of children and adolescents with type 1 diabetes: The SWEET project experience.

OBJECTIVE: To examine the association between the use of diabetes technology (insulin pump [CSII], glucose sensor [CGM] or both) and metabolic control (HbA1c) as well as body adiposity (BMI-SDS) over-time in a cohort of children and adolescents with type 1 diabetes (T1D), that have never used these technologies before. SUBJECTS AND METHODS: Four thousand six hundred forty three T1D patients (2-18 years, T1D ≥1 year, without celiac disease, no CSII and/or CGM before 2016) participating in the SWEET prospective multicenter diabetes registry, were enrolled. Data were collected at two points (2016; 2019). Metabolic control was assessed by glycated hemoglobin (HbA1c) and body adiposity by BMI-SDS (WHO). Patients were categorized by treatment modality (multiple daily injections [MDI] or CSII) and the use or not of CGM. Linear regression models, adjusted for age, gender, duration of diabetes and region, were applied to assess differences in HbA1c and BMI-SDS among patient groups. RESULTS: The proportion of patients using MDI with CGM and CSII with CGM significantly increased from 2016 to 2019 (7.2%-25.7%, 7.8%-27.8% respectively; p < 0.001). Linear regression models showed a significantly lower HbA1c in groups that switched from MDI to CSII with or without CGM (p < 0.001), but a higher BMI-SDS (from MDI without CGM to CSII with CGM p < 0.05; from MDI without CGM to CSII without CGM p < 0.01). CONCLUSIONS: Switching from MDI to CSII is significantly associated with improvement in glycemic control but increased BMI-SDS over-time. Diabetes technology may improve glucose control in youths with T1D although further strategies to prevent excess fat accumulation are needed.