Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.

Monitoring of blood glucose after pediatric kidney transplantation: a longitudinal cohort study.

BACKGROUND: Glucose metabolism after kidney transplantation (KT) is highly dynamic with the first post-transplantation year being the most critical period for new-onset diabetes after transplantation (NODAT) occurrence. The present study aimed to analyze dynamics of glucose metabolism and report incidence/risk factors of abnormal glycemic state during the first year after KT in children. METHODS: Twenty-one consecutive freshly transplanted pediatric kidney transplant recipients (KTRs) were assessed for fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) weekly for 4 weeks, then every 3 months for 1 year. RESULTS: Interpretation of OGTT test showed normal glucose tolerance (NGT) in 6 patients (28.6%) while 15 (71.4%) experienced impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) at any time point of monitoring. Seven patients had NODAT, for which three needed insulin therapy. Hyperglycemia onset was 7.8 ± 13.12 weeks (median (range) = 1 (0-24) week) after KT. Percent of patients with abnormal OGTT was significantly more than that of IFG (38.1% vs. 71.4%, p = 0.029). Patients with abnormal glycemic state had significantly elevated trough tacrolimus levels at 6 months (p = 0.03). Glucose readings did not correlate with steroid doses nor rejection episodes while positively correlating with tacrolimus doses at 3 months (p = 0.02, CC = 0.73) and 6 months (p = 0.01, CC = 0.63), and negatively correlating with simultaneous GFR at 9 months (p = 0.04, CC = - 0.57). CONCLUSIONS: Up to two thirds of pediatric KTRs (71.4%) experienced abnormal glycemic state at some point with peak incidence within the first week up to 6 months after KT. OGTT was a better tool for monitoring of glucose metabolism than FPG. Abnormal glycemic state was induced by tacrolimus and adversely affected graft function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-term outcomes of percutaneous closure of ventricular septal defects in children using different devices: A single centre experience from Egypt.

BACKGROUND: The feasibility of percutaneous closure ventricular septal defects (VSD) in children has been previously proven. However, data on long-term outcomes are limited. We aim to evaluate the long-term outcome of our experience with percutaneous closure of VSD using various occluders. METHODS: Retrospective institutional analysis of children who underwent transcatheter closure of perimembranous and muscular VSDs between September 2012 and February 2020. Patient demographics, procedural, and long-term follow-up data were comprehensively analyzed. Patients who lost to follow-up within two years post-procedure were excluded. RESULTS: We identified 75 patients (54.7% males) with a median of 66 months (IQR, 46-96). The closure success rate at one year was 95.7%. Complete heart block was detected in two patients early post-procedure and resolved with steroids. The VSDs were perimembranous (52%), muscular (33.33%), and residual (14.67%). Implanted devices were Pfm Nit-Occlud LeˆVSD Coil (42.7%), HyperionTM VSD Muscular Occluder (28%), Amplatzer VSD muscular occluder (10.7%), Amplatzer Duct Occluder (14.7%), Occlutech Muscular VSD Occluder (2.7%), and Amplatzer Duct Occluder II (1.3%). No new arrhythmia or valve regurgitation was detected after two years post-procedure. Persisted complications on long-term follow-up included: residual shunting in 3(4%), mild tricuspid regurgitation in 2(2.7%), and aortic regurgitation in 2(2.7%), with one immediate post-catheterization mild aortic regurgitation worsened during follow-up, requiring surgical repair of VSD three years after device implantation. No deaths were reported. CONCLUSION: Long-term outcomes of pediatric transcatheter VSD closure using different devices are satisfactory. Post-procedural adverse events are limited, but long-term surveillance is necessary to monitor their progression.

Contrast-enhanced mammography versus breast MRI in the assessment of multifocal and multicentric breast cancer: a retrospective study.

BACKGROUND: Breast cancer multifocality and multicentricity diagnosis influences the surgeon's choice between applying breast conservative therapy or performing mastectomy. PURPOSE: To assess the role of contrast enhanced mammography (CEM) and breast magnetic resonance imaging (MRI) in the assessment of preoperative breast cancer multifocality and multicentricity and to assess their accuracy, agreement and impact on the surgical management. MATERIAL AND METHODS: The study retrospectively included cases over a 5-year period. After analysis and interpretation of suspicious breast lesions, a comparative evaluation of CEM and MRI was conducted with the assessment of diagnostic indices, including sensitivity, specificity and diagnostic accuracy. The kappa (κ) measure of agreement between both modalities was measured. The postoperative specimen pathology was the reference standard. RESULTS: One hundred and twenty-two female cases with 126 breast lesions were evaluated. Specimen pathology, MRI and CEM showed a single neoplastic lesion in 67.5%, 35% and 48.5% of cases, respectively, and multiple neoplastic lesions in 32.5%, 65% and 51.6% of cases, respectively. The sensitivity, specificity and accuracy of MRI were 95.12%, 49.41%,and 64.29%, and the CEM values were 85.37%, 64.71% and 71.43%, respectively. The κ value was 0.592 with an intermediate agreement between both modalities. When comparing between both modalities, enhancing foci showed a statistically significant difference, although there were no statistically significant difference in terms of high breast density or molecular subtype. CONCLUSION: In terms of breast cancer multifocality and multicentricity evaluation, MRI showed a higher sensitivity, while CEM showed a higher specificity, and there was moderate agreement between the two modalities.

An in vitro study measuring marginal gaps of inlay restorations fabricated from different CAD-CAM materials after thermocycling.

BACKGROUND: Many monolithic machined materials have been introduced and provided a suitable mechanical and physical properties for inlay restorations. However, there is shortage in the studies evaluating the marginal adaptation using these materials. PURPOSE: This study aimed to compare the effect of fabricating inlay restorations from 3 different CAD-CAM materials on marginal gaps before and after thermocycling. MATERIALS AND METHODS: Sixty human premolars were randomly divided into 3 groups (n = 20) according to the material used: (e.max CAD, Ivoclar AG, Schaan, Liechtenstein), (HC, Shofu, Koyoto, Japan) and (Brilliant Crios, Coltene, Altstätten, Switzerland) (n = 20). A scanning electron microscope (SEM) (JSM- 6510 lv, JEOL, Tokyo, JAPAN) was used to for measuring the marginal gaps after cementation of inlay restorations. The magnification was adapted to 250x. Marginal gaps were revaluated with SEM after thermocycling. The temperatures of baths were 5 and 55 °C was applied for a total of 5000 cycles. All data were statistically analyzed by using ANCOVA to demonstrate if there were any statistically significant differences between the gap measures after thermocycling of the three independent (unrelated) groups. A Bonferroni adjustmen was used to perform post hoc analysis (α = 0.05). RESULTS: Post-intervention marginal gap was statistically significantly lower in group EX (110.8 µm) which was statistically significant compared with group SF (112.5 µm) (mean difference=-1.768, P = .007) and group BR (113 µm) (mean difference=-2.272, P = .001), however, in. comparing SF and BR groups, there was no significant difference (mean difference=-0.5, P = .770). CONCLUSIONS: Thermocycling affected the marginal gaps of composite based restoration and resin-modified ceramics widely. However, it had a very small effect on glass ceramics marginal adaptation. CLINICAL IMPLICATIONS: The marginal gaps of CAD-CAM inlays varied according to material used (ceramic based, combination, or resin based). Thermocycling has a minor effect on the marginal adaptation of lithium disilicate glass-ceramic inlays, where it affected the margin of resin-modified ceramic and composite based inlays greatly. Using lithium disilicate glass-ceramic might improve the clinical longevity of inlay restored teeth.

Liraglutide in Children and Adolescents with Type 2 Diabetes.

BACKGROUND: Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with metformin monotherapy. Whether liraglutide added to metformin (with or without basal insulin treatment) is safe and effective in youth with type 2 diabetes is unknown. METHODS: Patients who were 10 to less than 17 years of age were randomly assigned, in a 1:1 ratio, to receive subcutaneous liraglutide (up to 1.8 mg per day) or placebo for a 26-week double-blind period, followed by a 26-week open-label extension period. Inclusion criteria were a body-mass index greater than the 85th percentile and a glycated hemoglobin level between 7.0 and 11.0% if the patients were being treated with diet and exercise alone or between 6.5 and 11.0% if they were being treated with metformin (with or without insulin). All the patients received metformin during the trial. The primary end point was the change from baseline in the glycated hemoglobin level after 26 weeks. Secondary end points included the change in fasting plasma glucose level. Safety was assessed throughout the course of the trial. RESULTS: Of 135 patients who underwent randomization, 134 received at least one dose of liraglutide (66 patients) or placebo (68 patients). Demographic characteristics were similar in the two groups (mean age, 14.6 years). At the 26-week analysis of the primary efficacy end point, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of -1.06 percentage points (P<0.001); the difference increased to -1.30 percentage points by 52 weeks. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The number of patients who reported adverse events was similar in the two groups (56 [84.8%] with liraglutide and 55 [80.9%] with placebo), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide. CONCLUSIONS: In children and adolescents with type 2 diabetes, liraglutide, at a dose of up to 1.8 mg per day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks. This efficacy came at the cost of an increased frequency of gastrointestinal adverse events. (Funded by Novo Nordisk; Ellipse ClinicalTrials.gov number, NCT01541215.).

Urinary C-peptide and urinary C-peptide creatinine ratio as markers for insulin resistance in obese children and adolescents.

BACKGROUND: Obesity is associated with insulin resistance (IR). Identifying high-risk obese children affected with IR is crucial to apply preventive management. We aimed to assess the diagnostic value of urinary C-peptide (UCP) and urinary C-peptide creatinine ratio (UCPCR) to diagnose IR in obese children. METHODS: This prospective cross-sectional study was performed on 60 children with obesity as the study group. Sixty healthy children of matched age and sex with normal body mass index (BMI) served as the control group. Hemostasis model for the assessment of IR (HOMA-IR), glycated hemoglobin (HbA1c), fasting blood glucose and insulin, UCP, and UCPCR were assessed in all included children. RESULTS: UCP and UCPCR were significantly higher in children with obesity (2.075 ± 0.783) ng/ml, (0.200 ± 0.021) nmol/mmol compared to the control group (1.012 ± 0.465) ng/ml, (0.148 ± 0.016) nmol/mmol, respectively. Both UCP and UCPCR were positively correlated with each other and with HOMA-IR, HbA1c, acanthosis nigricans, waist circumference, and BMI. At cutoff ≥2.45, the sensitivity of UCP to diagnose IR in obese children was 71.4%. At cutoff ≥0.20, the sensitivity of UCPCR to diagnose IR in obese children was 87.6%. CONCLUSIONS: UCP and UCPCR are promising surrogate markers of IR in children and adolescents with obesity. However, UCPCR is a better marker than UCP. IMPACT: Obesity is associated with IR. Identifying high-risk obese children affected with IR is crucial to apply preventive management. We aimed to assess the diagnostic value of UCP and UCPCR to detect IR in obese children. To the best of our knowledge, we are the first to use UCP and UCPCR to assess IR in obese children. We found that UCP and UCPCR are practical, easy, dependable noninvasive markers to assess IR in children with obesity and could potentially be useful in epidemiological studies and clinical practice.

Cardiac implications of multisystem inflammatory syndrome associated with COVID-19 in children under the age of 5 years.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is responsible for significant lung disease in adults. Despite mild manifestations in most children, multisystem inflammatory syndrome (MIS-C) associated with COVID-19 is well described in older children with cardiac manifestations. However, MIS-C-related cardiac manifestations are not as well described in younger children. METHODS: The study is a retrospective analysis of MIS-C patients under the age of 5 years admitted between May and November 2020 to a single centre. Included cases fulfilled the case definition of MIS-C according to Royal College of Pediatrics and Child Health criteria with laboratory, electrocardiogram, or echocardiographic evidence of cardiac disease. Collected data included patients' demographics, laboratory results, echocardiographic findings, management, and outcomes. RESULTS: Out of 16 MIS-C cases under 5 years of age, 10 (62.5%) had cardiac manifestations with a median age of 12 months, 9 (90%) were previously healthy. Cardiac manifestations included coronary arterial aneurysms or ectasia in five (50%) cases, two (20%) with isolated myopericarditis, coronary ectasia with myocarditis in two (20%), and supraventricular tachycardia in one (10%). Intravenous immunoglobulins were given in all cases with coronary involvement or myocarditis. The median duration of hospitalisation was 7 (6-14) days; two (20%) cases with cardiac disease were mechanically ventilated and mortality in MIS-C cases below 5 years was 12.5%. Normalisation of systolic function occurred in half of the affected cases within 1 week and reached 100% by 30 days of follow-up. CONCLUSIONS: MIS-C associated with SARS-CoV-2 has a high possibility of serious associated cardiac manifestations in children under the age of 5 years with mortality and/or long-term morbidities such as coronary aneurysms even in previously healthy children.

The RSNA International COVID-19 Open Radiology Database (RICORD).

The coronavirus disease 2019 (COVID-19) pandemic is a global health care emergency. Although reverse-transcription polymerase chain reaction testing is the reference standard method to identify patients with COVID-19 infection, chest radiography and CT play a vital role in the detection and management of these patients. Prediction models for COVID-19 imaging are rapidly being developed to support medical decision making. However, inadequate availability of a diverse annotated data set has limited the performance and generalizability of existing models. To address this unmet need, the RSNA and Society of Thoracic Radiology collaborated to develop the RSNA International COVID-19 Open Radiology Database (RICORD). This database is the first multi-institutional, multinational, expert-annotated COVID-19 imaging data set. It is made freely available to the machine learning community as a research and educational resource for COVID-19 chest imaging. Pixel-level volumetric segmentation with clinical annotations was performed by thoracic radiology subspecialists for all COVID-19-positive thoracic CT scans. The labeling schema was coordinated with other international consensus panels and COVID-19 data annotation efforts, the European Society of Medical Imaging Informatics, the American College of Radiology, and the American Association of Physicists in Medicine. Study-level COVID-19 classification labels for chest radiographs were annotated by three radiologists, with majority vote adjudication by board-certified radiologists. RICORD consists of 240 thoracic CT scans and 1000 chest radiographs contributed from four international sites. It is anticipated that RICORD will ideally lead to prediction models that can demonstrate sustained performance across populations and health care systems.

A novel POU1F1 pathogenic variant: Two familial case reports with phenotype expansion.

Up: A schematic-diagram of POU1F1-gene. Down right: an electrophoretogram of the detected novel pathogenic-variant in comparison with wild-type POU1F1 exon-6 sequence. Down left: Family pedigree of the two-siblings reported.

Evaluation of carotid artery access in comparison with femoral artery access in neonatal percutaneous stenting of ductus arteriosus.

BACKGROUND: Patent ductus arteriosus stenting in duct-dependent pulmonary circulation is a challenging procedure. Percutaneous carotid artery access for ductal stenting has proven to be feasible; however, comparison with femoral artery access in terms of procedure details and complications either immediate or late is scarce. Therefore, we evaluated carotid artery access in comparison with femoral artery for stenting of patent ductus arteriosus. METHODS: Forty neonates were reviewed, 20 were stented via carotid artery access, and 20 via the traditional femoral artery access. Comparison variables were neonatal demographics at the procedure, angiographic ductal anatomy, procedure details, and immediate complications. Follow-up Doppler ultrasound on access site was performed to document late complications. RESULTS: Median age of included cases was 10.5 (3-28) days with complex ductal anatomy more frequently accessed via carotid artery than femoral. Immediate access-related complications were significantly higher with femoral than carotid artery access; 9 (45%) versus 3 (15%) respectively, p = 0.038. With carotid access, we had only one case with small pseudoaneurysm and acute hemiparesis 3 days after the procedure. Delayed local complications were more common with femoral access (15%) than carotid access (5%), mild stenosis in one case, and severe in another with femoral access; while with transcarotid arterial access, only one case had mild narrowing. CONCLUSION: Percutaneous carotid artery access in neonates is a more convenient approach for patent ductus arteriosus stenting especially with complex ductal anatomy. Moreover, local complications are limited and vascular patency is better preserved, in comparison with trans-femoral arterial access. However, the potential for neurological adverse events should not be overlooked.

Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients.

LPS-responsive beige-like anchor (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM (#614700). LRBA deficiency patients suffer from variable manifestations including recurrent infections, immune dysregulation, autoimmunity, cytopenias, and enteropathy. This study describes different clinical phenotypes and immunological characteristics of 18 LRBA deficiency patients diagnosed from Egypt. T and B lymphocyte subpopulations, LRBA, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression were evaluated in resting and stimulated T cells using flow cytometry. Next-generation sequencing was used to identify mutations in the LRBA gene. LRBA deficiency patients had significantly lower B cells and increased percentage of memory T cells. CTLA4 levels were lower in LRBA-deficient T regulatory cells in comparison to healthy donors at resting conditions and significantly increased upon stimulation of T cells. We identified 11 novel mutations in LRBA gene ranging from large deletions to point mutations. Finally, we were able to differentiate LRBA-deficient patients from healthy control and common variable immunodeficiency patients using a simple flow cytometry test performed on whole blood and without need to prior stimulation. LRBA deficiency has heterogeneous phenotypes with poor phenotype-genotype correlation since the same mutation may manifest differently even within the same family. Low LRBA expression, low numbers of B cells, increased numbers of memory T cells, and defective CTLA4 expression (which increase to normal level upon T cell stimulation) are useful laboratory tests to establish the diagnosis of LRBA deficiency. Screening of the siblings of affected patients is very important as patients may be asymptomatic at the beginning of the disease course.

Rapid progression of type 2 diabetes and related complications in children and young people-A literature review.

Type 2 diabetes (T2D) is suggested to progress faster in children and young people vs type 1 diabetes (T1D) in the same age group and T2D in adults. We reviewed the evidence base for this. A literature search was performed of PubMed-indexed publications between 2000 and 2018, for the terms "pediatric" and "T2D." Results were combined and filtered for those relating to "progression." Searches of abstract books from Latin American and Asian congresses were performed to include these populations. Pediatric populations were defined as <25 completed years of age. Of the articles and congress abstracts found, 30 were deemed relevant. Dividing the studies into categories based on how T2D progresses, we found the following: (a) yearly beta-cell function deterioration was shown to be 20% to 35% in children with T2D compared with 7% to 11% in adults with T2D, despite similar disease durations; (b) retinopathy progression was likely dependent on diabetes duration rather than diabetes type; however, nephropathy, neuropathy and probably hypertension progressed faster in youth-onset T2D vs T1D. Nephropathy progression was similar to adults with T2D, allowing for disease duration. Youth with T2D had a worse cardiovascular (CV) risk profile than youth with T1D, and a faster progression to CV death. (c) Progression to treatment failure was faster in youth-onset T2D vs adult-onset T2D. Substantial evidence exists for faster progression of T2D in pediatric patients vs T1D or adult-onset T2D. New treatments targeting the pathology are needed urgently to address this issue.

Changes of cardiac functions after hemodialysis session in pediatric patients with end-stage renal disease: conventional echocardiography and two-dimensional speckle tracking study.

BACKGROUND: Although acute effects of hemodialysis (HD) on cardiac functions in end-stage renal disease (ESRD) have been studied frequently in adults, limited data are available in pediatric age. Therefore, this work elucidates the acute impact of HD on cardiac functions using conventional echocardiography and two-dimensional (2D) speckle tracking in ESRD pediatric patients. METHODS: Between June 2018 and April 2019, 40 ESRD pediatric subjects on chronic HD were prospectively recruited. All patients were subjected to history taking and baseline laboratory tests. Anthropometric measures, heart rate, blood pressure, and bioimpedance were assessed before and after HD session. Moreover, conventional echocardiography including M.mode and Doppler parameters for valves, as well as left ventricle (LV) 2D speckle tracking were performed pre- and post-dialysis session. RESULTS: The included patients mean age was 12.9 ± 2.9 years, and males were 24 (60%). Significant reductions in body weight and blood pressure were noted after sessions. Post-dialysis LV and left atrial diameters, as well as left atrium to aortic diameter ratio, were lower. Nevertheless, conventional echocardiography-derived LV ejection fraction (EF), and fractional shortening were not significantly changed. Doppler-derived E/A ratio of mitral and tricuspid valves were lower post-dialysis. Global longitudinal strain (GLS) for LV was significantly reduced after dialysis (- 20.31 ± 3.58%, - 17.17 ± 3.40% vs, P < 0.0001), and global circumferential strain (GCS) was lower post-dialysis in comparison to pre-dialysis (- 21.37 ± 6.46% vs - 17.74 ± 6.16%, P < 0.0001). The speckle tracking-derived EF was significantly lower post-dialysis (57.58 ± 6.94 vs 53.64 ± 10.72, P = 0.018). All myocardial segments longitudinal and circumferential strains decreased significantly after dialysis. CONCLUSIONS: Post-hemodialysis significant decline in left ventricular EF as well as global and segmental strains can be detected in ESRD pediatric patients using 2D speckle tracking, despite the nonsignificant changes in systolic functions derived from conventional echocardiography. This is considered additional evidence of HD deleterious effect on myocardial functions, particularly in the pediatric age.

Recommendations for improving clinical trial design to facilitate the study of youth-onset type 2 diabetes.

BACKGROUND: The prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs are approved for youth-onset type 2 diabetes and many patients are not meeting glycemic targets. Clearly, there is an urgent need to complete clinical trials in youths with type 2 diabetes to increase the therapeutic choice for these patients. However, factors such as limited patient numbers, unwillingness of patients to participate in trials, failure to meet strict inclusion and exclusion criteria, and poor clinic attendance have limited the size and number of trials in this complicated patient demographic. RECOMMENDATIONS: This is a narrative opinion piece on the design of clinical trials in youth-onset type 2 diabetes prepared by researchers who undertake this type of study in different countries. The review addresses possible ways to enhance trial designs in youth-onset type 2 diabetes to meet regulatory requirements, while minimizing the barriers to patients' participation. The definition of adolescence, recruitment of sufficient patient numbers, increasing flexibility in selection criteria, improving convenience of trial visits, requirements of a control group, possible endpoints, and trial compliance are all considered. The authors recommend allowing extrapolation from adult data, using multiple interventional arms within future trials, broadening inclusion criteria, and focusing on endpoints beyond glucose control, among others, in order to improve the successful completion of more trials in this population. CONCLUSIONS: Improvements in trial design will enable better recruitment and retention and thereby more evidence for treatment outcomes for youth-onset type 2 diabetes.

Country-Specific Prevalence and Incidence of Youth-Onset Type 2 Diabetes: A Narrative Literature Review.

BACKGROUND: With increased awareness of type 2 diabetes (T2D) in children and adolescents, an overview of country-specific differences in epidemiology data is needed to develop a global picture of the disease development. SUMMARY: This study examined country-specific prevalence and incidence data of youth-onset T2D published between 2008 and 2019, and searched for national guidelines to expand the understanding of country-specific similarities and differences. Of the 1,190 articles and 17 congress abstracts identified, 58 were included in this review. Our search found the highest reported prevalence rates of youth-onset T2D in China (520 cases/100,000 people) and the USA (212 cases/100,000) and lowest in Denmark (0.6 cases/100,000) and Ireland (1.2 cases/100,000). However, the highest incidence rates were reported in Taiwan (63 cases/100,000) and the UK (33.2 cases/100,000), with the lowest in Fiji (0.43 cases/100,000) and Austria (0.6 cases/100,000). These differences in epidemiology data may be partly explained by variations in the diagnostic criteria used within studies, screening recommendations within national guidelines and race/ethnicity within countries. Key Messages: Our study suggests that published country-specific epidemiology data for youth-onset T2D are varied and scant, and often with reporting inconsistencies. Finding optimal diagnostic criteria and screening strategies for this disease should be of high interest to every country. TRIAL REGISTRATION: Not applicable.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11ß-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11ß-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11ß-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11ß-hydroxylase deficiency CAH.

Lipid Biomarkers as Predictors of Diastolic Dysfunction in Diabetes with Poor Glycemic Control.

Uncontrolled type-1 diabetes (T1DM) can lead to dyslipidaemia and albuminuria, which may promote cardiovascular injuries. However, some lipidemic factors could be useful in predicting cardiac dysfunction. Seventy-eight adolescents under insulin treatment due to a 6-year history of T1DM and were retrospectively examined. Glycemia, lipidemia, and albuminuria were measured in addition to development of cardiovascular abnormalities Both girls and boys showed higher HbA1c and fasting blood glucose and 27.1% females and 33.3% males exhibited microalbuminuria though their plasma levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL) and high-density lipoproteins (HDL lipoproteins were in the normal range. They exhibited a preserved systolic function, but 50% of females and 66.6% of males had developed diastolic failures. Interestingly, girls with diastolic dysfunction showed significantly lower concentrations of HDL and higher TC/HDL and TG/HDL ratios. In fact, low HDL levels (OR 0.93; 95% CI 0.88-0.99; p = 0.029) and high TC/HDL (OR 2.55; 95% CI 1.9-5.45; p = 0.016) and TG/HDL (OR 2.74; 95% CI 1.12-6.71; p = 0.028) ratios associated with the development of diastolic complications. The cut-off values for HDL, TC/HDL, and TG/HDL were 49 mg/dL, 3.0 and 1.85, respectively. HDL and TC/HDL and TG/HDL ratios may be useful for predicting diastolic dysfunction in girls with uncontrolled T1DM.

Thymoquinone attenuates diabetes-induced hepatic damage in rat via regulation of oxidative/nitrosative stress, apoptosis, and inflammatory cascade with molecular docking approach.

Diabetes mellitus (DM) is a complex metabolic condition that causes organ dysfunction. The current experiment sought to determine the effect of thymoquinone (TQ) on hyperglycemia, hyperlipidemia, oxidative/nitrosative stress, inflammation, and apoptosis in diabetic rats prompted by streptozotocin (STZ) (55 mg/kg body weight i/p). The animals were allocated into control, TQ (50 mg/kg B.W. orally administered for 4 succeeding weeks), Diabetic, and Diabetic + TQ groups. This study confirmed that TQ preserves the levels of insulin, fasting blood glucose, HOMA ß-cell indices, HbA1c %, body weight, and lipid profile substantially relative to the DC group. Furthermore, hepatic antioxidant (CAT, GSH, and T-SOD) values were reduced. Conversely, the enzymatic activity of liver functions (AST, ALT, ALP, cytochrome P450, and hepatic glucose-6-phosphatase), lipid peroxidation (MDA), pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6), nitric oxide (NO) and inflammatory marker (CRP) enhanced with STZ administration, which is substantially restored after TQ treatment. Relative to the diabetic rats, TQ reestablished the hepatic architectural changes and collagen fibers. Additionally, TQ downregulated the intensity of the immunohistochemical staining of pro-apoptotic marker (caspase-3), p53, and tumor necrosis factor-alpha (TNF-α) proteins in hepatic tissues. Furthermore, TQ displayed abilities to interact and inhibit the binding site of caspase-3, interleukin-6 receptor, interleukin-1 receptor type 1, TNF receptor superfamily member 1A, and TNF receptor superfamily member 1B in rats following the molecular docking modeling. All these data re-establish the liver functions, antioxidant enzymes, anti-inflammatory markers, and anti-apoptotic proteins impacts of TQ in STZ-induced DM rats. Founded on these outcomes, the experiment proposes that TQ is a novel natural supplement with various clinical applications, including managing DM, which in turn is recommended to play a pivotal role in preventing the progression of diabetes mellitus.

Effect of sonic oscillation on penetration and marginal adaptation of filled-resin-based fissure sealants.

OBJECTIVES: To evaluate the effect of sonic oscillation on penetration depth and marginal adaptation of resin-based fissure sealants. METHOD AND MATERIALS: Thirty-six extracted human third molars were randomized into three groups: in the HF group, teeth were sealed with a filled-resin-based sealant (Helioseal F); in the Sonic-HF group, teeth were sealed with Helioseal F and subjected to sonic oscillation (Compothixo Device, 140 Hz vibration frequency and ± 150 µm amplitude) before curing; in the CO group, teeth were sealed with an unfilled-resin-based sealant (Clinpro). All teeth were thermocycled for 1,500 cycles at 5°C and 55°C, then sectioned buccolingually into four sections (mesial, two middle, and distal). Sections were evaluated under SEM for marginal adaptation and scored. For penetration depth, three independent measurements from each tooth were recorded under SEM, and data were subjected to statistical analysis. RESULTS: The group subjected to sonic oscillation (Sonic HF) resulted in significantly superior penetration depth and marginal adaptation compared with the HF group, but with no significant difference compared with the CO group. CONCLUSIONS: Sonic activation of resin-based sealant increased penetration depth into fissures and marginal adaptation to the enamel wall without decreasing filler load or compromising sealant mechanical properties.