Early life seizures and epileptic spasms in STXBP1-related disorders.

OBJECTIVE: Individuals with disease-causing variants in STXBP1 frequently have epilepsy onset in the first year of life with a variety of seizure types, including epileptic spasms. However, the impact of early onset seizures and antiseizure medication (ASM) on the risk of developing epileptic spasms and impact on their trajectory are poorly understood, limiting informed and anticipatory treatment, as well as trial design. METHODS: We retrospectively reconstructed seizure and medication histories in weekly intervals for individuals with STXBP1 developmental and epileptic encephalopathy (DEE) with epilepsy onset in the first year of life and quantitatively analyzed longitudinal seizure histories and medication response. RESULTS: We included 61 individuals with early onset seizures, 29 of whom had epileptic spasms. Individuals with neonatal seizures were likely to have continued seizures after the neonatal period (25/26). The risk of developing epileptic spasms was not increased in individuals with neonatal seizures or early infantile seizures (21/41 vs. 8/16, odds ratio [OR] = 1, 95% confidence interval [CI] = .3-3.9, p = 1). We did not find any ASM associated with the development of epileptic spasms following prior seizures. Individuals with prior seizures (n = 16/21, 76%) had a higher risk of developing refractory epileptic spasms (n = 5/8, 63%, OR = 1.9, 95% CI = .2-14.6, p = .6). Individuals with refractory epileptic spasms had a later onset of epileptic spasms (n = 20, median = 20 weeks) compared to individuals with nonrefractory epileptic spasms (n = 8, median = 13 weeks, p = .08). SIGNIFICANCE: We provide a comprehensive assessment of early onset seizures in STXBP1-DEE and show that the risk of epileptic spasms is not increased following a prior history of early life seizures, nor by certain ASMs. Our study provides baseline information for targeted treatment and prognostication in early life seizures in STXBP1-DEE.

Delineating clinical and developmental outcomes in STXBP1-related disorders.

STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end points, have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n = 39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n = 30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of end points revealed high variability during the first 5 years of life, with emerging stratification between clinical subgroups. An earlier epilepsy onset was associated with lower developmental abilities, most prominently when assessing gross motor development and expressive communication. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.

Growth hormone in pediatric chronic kidney disease: more than just height.

Recombinant human growth hormone therapy, which was introduced in the 1980s, is now routine for children with advanced chronic kidney disease (CKD) who are exhibiting growth impairment. Growth hormone usage remains variable across different centers, with some showing low uptake. Much of the focus on growth hormone supplementation has been on increasing height because of social and psychological effects of short stature. There are, however, numerous other changes that occur in CKD that have not received as much attention but are biologically important for pediatric growth and development. This article reviews the current knowledge about the multisystem effects of growth hormone therapy in pediatric patients with CKD and highlights areas where additional clinical research is needed. We also included clinical data on children and adults who had received growth hormone for other indications apart from CKD. Ultimately, having robust clinical studies which examine these effects will allow children and their families to make more informed decisions about this therapy.

Experiences and perceptions of multidisciplinary paediatric teams of blended tube feeding in children.

Background: Blended tube feeding (BTF) is the administration of pureed whole foods via gastric feeding tubes. There is some evidence to suggest that BTF may have clinical and psychosocial benefits when compared to commercial formula, but further investigation of how BTF is understood and recommended by health professionals is needed. This study aims to investigate awareness and knowledge of BTF among multi-disciplinary paediatric staff in Ireland. Methods: A cross-sectional observational study was conducted among paediatric staff in Children's Health Ireland (CHI). The 16-item anonymous online survey gathered information on awareness of BTF, willingness to recommend BTF, confidence in BTF knowledge, and self-assessed competence in managing BTF. Results: Of the 207 responses, doctors (n68), nurses (n66), and dietitians (n32) provided 80.3% of responses. Two-thirds (n136, 66%) of the total group were aware of BTF. Of these, 68.1% had cared for a child on BTF and 70% (n = 63/90) were willing to recommend BTF. Three in five (n = 39/63, 61.9%) stated they were somewhat confident in their BTF knowledge and one in five (n = 12/56, 21.4%) were not yet competent in managing children on BTF. The most common reasons for recommending BTF were parental desire (n17, 39.5%) and commercial formula intolerance (n15, 34.9%). The most common barrier to recommending BTF was family logistics (n18, 41.9%). The most valuable sources of information on BTF for two-thirds (68.3%) of participants were other healthcare professionals (HCPs) and patients/caregivers. Conclusion: Healthcare settings should provide evidence-based training to HCPs on BTF to optimise the treatment and safety of children under their care.

Youth-Onset Type 2 Diabetes: Burden of Complications and Socioeconomic Cost.

PURPOSE OF REVIEW: With the rise in prevalence of youth-onset type 2 diabetes (T2DM), it is imperative to understand the clinical burden of the disease and the socioeconomic burden this disease imposes. We review the most recent data on youth-onset T2DM, including its pathophysiology, complications, and treatment. We also review existing data to determine the socioeconomic burden of youth-onset T2DM. RECENT FINDINGS: The incidence of youth-onset T2DM is rising, and significantly accelerated following the COVID-19 pandemic. Youth with T2DM are more frequently from families of racial/ethnic minorities and lower socioeconomic status. Youth-onset T2DM has more rapid disease progression compared to adult-onset type 2 diabetes. It results in earlier and more severe microvascular and macrovascular complications compared to both adult-onset T2DM and youth-onset type 1 diabetes (T1DM). While there is a lack of data describing the socioeconomic cost of youth-onset T2DM, based on extrapolation from analyses of the burden of T2DM in adults and T1DM in youth, we propose that youth-onset T2DM has higher direct and indirect costs than adult-onset T2DM. Youth-onset T2DM presents a significant clinical and socioeconomic burden due to its aggressive presentation and earlier appearance of complications. Additional research is needed regarding the cost of illness in this population.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney.

BACKGROUND: Microscopic analysis of urine sediment is probably the most commonly used diagnostic procedure in nephrology. The urinary cells, however, have not yet undergone careful unbiased characterization. METHODS: Single-cell transcriptomic analysis was performed on 17 urine samples obtained from five subjects at two different occasions, using both spot and 24-hour urine collection. A pooled urine sample from multiple healthy individuals served as a reference control. In total 23,082 cells were analyzed. Urinary cells were compared with human kidney and human bladder datasets to understand similarities and differences among the observed cell types. RESULTS: Almost all kidney cell types can be identified in urine, such as podocyte, proximal tubule, loop of Henle, and collecting duct, in addition to macrophages, lymphocytes, and bladder cells. The urinary cell-type composition was subject specific and reasonably stable using different collection methods and over time. Urinary cells clustered with kidney and bladder cells, such as urinary podocytes with kidney podocytes, and principal cells of the kidney and urine, indicating their similarities in gene expression. CONCLUSIONS: A reference dataset for cells in human urine was generated. Single-cell transcriptomics enables detection and quantification of almost all types of cells in the kidney and urinary tract.

Precise endoballoon positioning for High-Risk sternal re-entry in an ascending aortic pseudoaneurysm with patent coronary grafts.

Redo cardiac surgery can present a unique set of challenges even to the experienced surgeon. Although outcomes have steadily improved in the modern era; if an intraoperative adverse event occurs, there is a 5% incidence of mortality and 19% incidence of myocardial infarction, stroke or death. Overall, the modern incidence of mortality at reoperation varies but be segregated into low and higher risk cohorts depending on the planning computed tomography imaging and risk to substernal structures on re-entry. Patients with ascending aortic or root pseudoaneurysms represent a particularly difficult subset of high-risk patients requiring reoperative cardiac surgery due to the danger of exsanguination and air embolization. The gold standard for management of such cases remains the use of deep hypothermic circulatory arrest (DHCA) to achieve safe re-entry in such cases however this can result in unpredictable DHCA duration depending on the degree of pericardial adhesions. We report a case of aortic pseudoaneurysm in a patient with patent coronary grafts managed using an endoballoon precisely positioned relative to the proximal anastomoses resulting in a safe surgical re-entry and shorter DHCA time.

The moderating role of sleep duration on momentary relations between negative affect and loss-of-control eating in children and adolescents.

OBJECTIVE: Loss-of-control (LOC) eating is associated with eating disorders and obesity, and thus it is imperative to understand its momentary risk factors in order to improve intervention efforts. Negative affect has been proposed as a momentary risk factor for LOC eating, but the evidence for its effects in children and adolescents is mixed. Short sleep duration (which is very common in youth), may be one variable that moderates the relation between negative affect and subsequent LOC eating. As such, we aimed to examine the moderating role of within-person sleep duration on the momentary relations between negative affect and subsequent LOC eating. METHOD: We recruited children (N = 30) with overweight/obesity ages 8-14, who completed a 2-week ecological momentary assessment protocol assessing negative affect and LOC eating several times per day, while also wearing a sleep actigraphy device and completing sleep diaries. RESULTS: Consistent with hypotheses, within-person sleep duration moderated the next-day momentary relation between within-person negative affect and LOC eating, such that shorter sleep duration strengthened the positive relation between negative affect and loss-of-control eating. CONCLUSIONS: Results suggest that, in children and adolescents, fluctuations in sleep duration may influence susceptibility to losing control over eating after experiencing negative affect. Future research should further investigate other metrics of sleep disturbance as they relate to emotion regulation and LOC eating. Such research will set the stage for augmenting paediatric interventions to better target maintenance factors for LOC eating.

Urinary podocyte-derived microparticles in youth with type 1 and type 2 diabetes.

AIMS/HYPOTHESIS: The release of podocyte-derived microparticles into the urine may reflect early kidney injury in diabetes. We measured the urinary excretion of podocyte-derived microparticles in youth with type 1 and type 2 diabetes, and related the values to blood pressure, renal function and blood glucose levels. METHODS: Cross-sectional, exploratory analysis of urine samples and clinical data from youth with type 1 (n = 53) and type 2 (n = 50) diabetes was carried out. Urinary podocyte-derived microparticle numbers, measured by flow cytometry, were assessed in relation to measures of blood glucose levels and renal function. RESULTS: Podocyte-derived microparticle excretion (MPE) normalised to urinary creatinine (MP/UCr) was higher in type 1 vs type 2 diabetes (median [IQR] MP/UCr: 7.88 [8.97] vs 1.84 [8.62]; p < 0.0001), despite the type 2 diabetes group having higher blood pressure (systolic blood pressure, median [range]: 124 [110-154] vs 114 [94-143] mmHg) and higher proportions of microalbuminuria (44.0% vs 13.2%), but shorter time since diabetes diagnosis (median [range]: 1.2 [0.0-7.0] vs 6.4 [2.0-13.9] years), than the type 1 diabetes cohort. MPE in youth with type 1 diabetes was associated with blood glucose (p = 0.01) and eGFR (p = 0.03) but not HbA1c, systolic or diastolic blood pressure or urine albumin/creatinine ratio. After adjustment for age at baseline, duration of diabetes, sex and BMI, the association with eGFR remained significant (p = 0.04). No associations were found between MPE and these clinical variables in youth with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Significant associations between podocyte MPE, blood glucose levels and eGFR were observed in youth with type 1 diabetes but not in those with type 2 diabetes, notwithstanding increased renal pathology in the type 2 diabetes cohort. These findings suggest that podocyte injury differs in the two diabetes cohorts. Graphical abstract.

A study of the immune infiltrate and patient outcomes in esophageal cancer.

OBJECTIVES: Cancer patient outcomes and selection for novel therapies are heavily influenced by the immune contexture of the tumor microenvironment. Esophageal cancer is associated with poor outcomes. In contrast to colorectal cancer, where the immunoscore is increasingly used in prognostic staging, little is known about the immune cell populations in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC), and their clinical significance. METHODS: Tissue microarrays were constructed from resected tumor tissue of 72 EAC patients and 23 SCC patients. Immunohistochemical staining of CD3, CD8, CD56, CD68, CD45RO, CD69, IFN-γ, IL-10, IL-4, IL-17, TGF-ß, FOXP3 and CD107a was performed. Positivity was examined in both the stromal and epithelial compartments. Statistical analysis was performed to identify differences in immune cell infiltration and functional phenotypes between cancer subtypes and tissue compartments. RESULTS: This study identified that esophageal tumors are enriched with CD45RO+ and CD8+ cells and such positivity is significantly higher in SCC compared with EAC. Furthermore, the expression of CD45RO positively correlates with that of CD8 within the tumors of both patient cohorts, suggesting a dominance of memory cytotoxic T cells. This is supported by strong positivity of degranulation marker CD107a in the stromal compartment of EAC and SCC tumors. Cytokine staining revealed a mixed pro- and anti-inflammatory profile within EAC tumors. CONCLUSIONS: Esophageal tumors are enriched with memory cytotoxic T cells. Applying these measurements to a larger cohort will ascertain the clinical utility of assessing specific lymphocyte infiltrates in EAC and SCC tumors with regards to future immunotherapy use, patient prognosis and outcomes.

Naturalistic, multimethod exploratory study of sleep duration and quality as predictors of dysregulated eating in youth with overweight and obesity.

Although poor sleep has been found to adversely impact eating and weight regulation in youth, past research is limited by retrospective reporting and/or non-naturalistic designs. We investigated the feasibility of combining three momentary, ecologically valid approaches to assessing sleep and eating behavior, and associations between these constructs, among youth (aged 8-14y) with overweight/obesity (n = 40). Participants completed 14 overlapping days of actigraphy assessment and smartphone-based ecological momentary assessment (EMA) of eating behavior, of which 3 days also included computerized, self-guided 24-h dietary recall. Feasibility of completing measures concurrently was evaluated by generating frequencies of compliance. Associations between sleep indices and next-day eating behavior were examined via generalized estimating equations. Of 29 participants who provided EMA and 24-h recall data that aligned with previous night actigraphy data, both EMA and sleep data were available on an average of 8.6 out of 14 possible days, and both 24-h recall and sleep data on an average of 2.7 out of 3 possible days. Each additional hour of sleep was associated with consuming fewer calories from solid fats, alcohol, and added sugars (b = 0.70; p = .04). Combining naturalistic, momentary assessments of sleep and eating behavior appears to be acceptable in youth. Larger experimental studies are needed to further understand associations between sleep parameters and eating behavior.

Epstein-Barr virus latent gene EBNA-1 genetic diversity among transplant patients compared with patients with infectious mononucleosis.

INTRODUCTION: As a step toward evaluating the association between Epstein-Barr virus genetic diversity and post-transplant lymphoproliferative disorder (PTLD), we conducted a preliminary study to compare the genetic diversity of the EBNA-1 gene among transplant patients and patients with infectious mononucleosis (IM). METHODS: We sequenced the EBNA-1 gene in blood samples from study subjects using Sanger methodology. The sequences were aligned with a reference strain and compared with publicly available sequences. RESULTS: We analyzed 33 study samples and 25 publicly available sequences along with the reference strain B95-8. The evaluable samples were from sixteen patients with IM (median age 14.0 years, range 2-24) and 17 transplant patients. There were six children without PTLD (median age 1.93 years, range 0.79-7.46) and 11 who developed PTLD (median age 5.67 years, range 0.96-17.45). A predominant EBNA-1 variant (P-thr) was identified across the study groups. Differences were observed between the samples from the IM patients compared with the transplant samples. CONCLUSION: The predominant EBNA-1 strain is in contrast to reports of the predominant strain in North America. The results suggest differences between the EBNA-1 strains among the study groups. Further studies will examine the relationship between EBNA-1 strains and PTLD occurrence and outcomes.

Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents.

BACKGROUND: Ganglioneuromas (GNs) usually demonstrate favorable histological and clinical features. Surgery is often performed due to clinical symptoms and/or theoretical concerns that GN may transform into neuroblastoma (NB); however, several studies have identified significant GN-surgical morbidities. OBJECTIVES: We compared the natural history, biological and clinical features of GN and ganglioneuroblastoma-intermixed (GNB-I) managed by surgery or observation to inform management and surveillance. PROCEDURES: This retrospective study includes patients (n = 67) with histological diagnosis of GN (50/67) and GNB-I (17/67) at the Hospital for Sick Children between 1990 and 2014. Clinical, pathological features, tumor dimensions, and management were recorded. RESULTS: Median age and maximal tumor diameter were 6 years (1.3-17.8) and 6.3 cm (1.4-16.9), respectively. Of the 67 patients, 46 (69%) had upfront surgery and 21 (31%) were observed. Of the 21 observed patients 4 later underwent resection. There were post-operative complications in 15 of the 50 (30%) surgical patients. The presence of imaging-defined risk factors correlated with complications (P = 0.005). Observed patients were older (median 8.4 vs. 5.3 years) and diagnosed more recently. Median growth was 0.3 cm/year and 6 of 21 had progressive disease (PD). At median follow-up of 2.2 years (0.2-14.3), all patients were alive and for those with evaluable imaging there were 27 complete and 10 partial responses, 19 stable and 6 PD. Pathology classification changed at resection for three cases, but no GN was reclassified to NB. CONCLUSIONS: GN and GNB-I have a slow growth rate and resection can be associated with significant morbidity. Watch and wait approaches should be considered for some GN and GNB-I.

Successful transcarotid transcatheter aortic valve replacement in a 34-kg patient with Schimke immuno-osseous dysplasia and severe biscuspid aortic stenosis.

We present the case of transcatheter aortic valve replacement in a 20-year-old woman with severe bicuspid aortic stenosis and Schmike immuno-osseous dysplasia who was unfit for surgical aortic valve replacement. Meticulous pre-procedural planning and a multidisciplinary team approach can enable successful transcatheter aortic valve replacement in complex patients with genetic syndromes.

pSTAT3 Levels Have Divergent Expression Patterns and Associations with Survival in Squamous Cell Carcinoma and Adenocarcinoma of the Oesophagus.

Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) (n = 38) tumours. The tissues were stained for pSTAT3 and IL-6R using immunohistochemistry. The OE33 (OAC) and OE21 (SCC) cell lines were treated with the STAT3 inhibitor, STATTIC. The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266⁻32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574⁻0.953). The IL-6R intensity levels were higher in the SCC tumours compared with the OAC tumours for the core and leading edge tumour tissue. The pSTAT3 levels correlated positively with the IL-6R levels in both the OAC and SCC. The treatment of OE21 and OE33 cells with the STAT3 inhibitor STATTIC in vitro resulted in decreased survival, proliferation, migration, and increased apoptosis. The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients. The inhibition of STAT3 in both of the tumour subtypes resulted in alterations in the survival, proliferation, migration, and apoptosis, suggesting a potential role for therapeutically targeting STAT3.

HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients.

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis, and incidence is increasing rapidly in the Western world. Measurement of immune markers has been shown to have prognostic significance in a growing number of cancers, but whether this is true for EAC has yet to be evaluated. This study aimed to characterize HLA-DR expression in the esophagus across the inflammation to cancer progression sequence and to assess the prognostic significance of HLA-DR expression in EAC. Tissue microarrays (TMA) were constructed from esophageal tissue taken from patients at different stages in the cancer progression sequence; normal, esophagitis, Barrett's esophagus (BE), low- and high-grade dysplasia (LGD, HGD) and EAC. HLA-DR expression in tissue epithelium and stroma was assessed by immunohistochemistry. HLA-DR expression increased early in the inflammation to cancer progression sequence; with higher expression detected in esophagitis and BE compared to normal tissue. Patients with low (<50%) HLA-DR expression in the EAC tumor epithelium had significantly worse survival outcomes, compared to those with high expression, in both the tumor core (hazard ratio, HR = 2.178, p = 0.024, n = 70) and leading edge (HR = 2.86, p = 0.013, n = 41). Multivariate analysis demonstrated that low HLA-DR expression in leading edge tumor epithelium was an independent predictor of poor survival, associated with a 2.8-fold increase in disease-associated death (p = 0.023). This study shows that HLA-DR is an independent prognostic marker in EAC tumor epithelium. This may have implications for patient stratification strategies as well as EAC tumor immunology.

Metabolic and glycemic sequelae of sleep disturbances in children and adults.

The prevalence of obesity in adults and children has increased greatly in the past three decades, as have metabolic sequelae, such as insulin resistance and type 2 diabetes mellitus (T2DM). Sleep disturbances are increasingly recognized as contributors to this widespread epidemic in adults, and data are emerging in children as well. The categories of sleep disturbances that contribute to obesity and its glycemic co-morbidities include the following: (1) alterations of sleep duration, chronic sleep restriction and excessive sleep; (2) alterations in sleep architecture; (3) sleep fragmentation; (4) circadian rhythm disorders and disruption (i.e., shift work); and (5) obstructive sleep apnea. This article reviews current evidence supporting the contributions that these sleep disorders play in the development of obesity, insulin resistance, and T2DM as well as possibly influences on glycemic control in type 1 diabetes, with a special focus on data in pediatric populations.

Transapical JenaValve in a patient with mechanical mitral valve prosthesis.

We report the first case of transcatheter aortic valve replacement implantation using JenaValve™ in a patient with mechanical mitral valve prosthesis. We believe that the design features of this valve may be particularly suited for use in this setting.