Activation of Piezo1 Inhibits Kidney Cystogenesis.

The disruption of calcium signaling associated with polycystin deficiency has been proposed as the primary event underlying the increased abnormally patterned epithelial cell growth characteristic of Polycystic Kidney Disease. Calcium can be regulated through mechanotransduction, and the mechanosensitive cation channel Piezo1 has been implicated in sensing of intrarenal pressure and in urinary osmoregulation. However, a possible role for PIEZO1 in kidney cystogenesis remains undefined. We hypothesized that cystogenesis in ADPKD reflects altered mechanotransduction, suggesting activation of mechanosensitive cation channels as a therapeutic strategy for ADPKD. Here, we show that Yoda-1 activation of PIEZO1 increases intracellular Ca 2+ and reduces forskolin-induced cAMP levels in mIMCD3 cells. Yoda-1 reduced forskolin-induced IMCD cyst surface area in vitro and in mouse metanephros ex vivo in a dose-dependent manner. Knockout of polycystin-2 dampened the efficacy of PIEZO1 activation in reducing both cAMP levels and cyst surface area in IMCD3 cells. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor affected cystogenesis in the Pkd1 RC/RC model of ADPKD. Our study suggests that polycystin-2 and PIEZO1 play a role in mechanotransduction during cystogenesis in vitro , and ex vivo , but that in vivo cyst expansion may require inactivation or repression of additional suppressors of cystogenesis and/or growth. Our study provides a preliminary proof of concept for PIEZO1 activation as a possible component of combination chemotherapy to retard or halt cystogenesis and/or cyst growth.

Increasing Continuous Glucose Monitoring Use for Non-Hispanic Black and Hispanic People With Type 1 Diabetes: Results From the T1D Exchange Quality Improvement Collaborative Equity Study.

Despite the benefits of continuous glucose monitoring (CGM), there is lower use of this technology among non-Hispanic Black and Hispanic people with type 1 diabetes compared with their non-Hispanic White counterparts. The T1D Exchange Quality Improvement Collaborative recruited five endocrinology centers to pilot an equity-focused quality improvement (QI) study to reduce racial inequities in CGM use. The centers used rapid QI cycles to test and expand interventions such as provider bias training, translation of CGM materials, provision of CGM education in multiple languages, screening for social determinants of health, and shared decision-making. After implementation of these interventions, median CGM use increased by 7% in non-Hispanic White, 12% in non-Hispanic Black, and 15% in Hispanic people with type 1 diabetes. The gap between non-Hispanic White and non-Hispanic Black patients decreased by 5%, and the gap between non-Hispanic White and Hispanic patients decreased by 8%.

Type 1 Diabetes Overview and Perioperative Management.

Type 1 diabetes (T1D) is an increasingly common condition. Although often more effective, treatment regimens for patients with T1D have become more variable and complex with newer insulin analogues and increasing use of diabetes technology. Both surgery and anesthesia are known to trigger a stress response that causes dramatic metabolic changes in the patient that tend to increase glucose variability. Close monitoring of glucose levels and clear algorithms for insulin administration can ameliorate these characteristic responses. As T1D treatment technology becomes more effective at maintaining glucose in target range, there should be more consideration of using this technology during hospitalization and surgery.

Implicit Racial-Ethnic and Insurance-Mediated Bias to Recommending Diabetes Technology: Insights from T1D Exchange Multicenter Pediatric and Adult Diabetes Provider Cohort.

Background: Despite documented benefits of diabetes technology in managing type 1 diabetes, inequities persist in the use of these devices. Provider bias may be a driver of inequities, but the evidence is limited. Therefore, we aimed to examine the role of race/ethnicity and insurance-mediated provider implicit bias in recommending diabetes technology. Method: We recruited 109 adult and pediatric diabetes providers across 7 U.S. endocrinology centers to complete an implicit bias assessment composed of a clinical vignette and ranking exercise. Providers were randomized to receive clinical vignettes with differing insurance and patient names as proxy for Racial-Ethnic identity. Bias was identified if providers: (1) recommended more technology for patients with an English name (Racial-Ethnic bias) or private insurance (insurance bias), or (2) Race/Ethnicity or insurance was ranked high (Racial-Ethnic and insurance bias, respectively) in recommending diabetes technology. Provider characteristics were analyzed using descriptive statistics and multivariate logistic regression. Result: Insurance-mediated implicit bias was common in our cohort (n = 66, 61%). Providers who were identified to have insurance-mediated bias had greater years in practice (5.3 ± 5.3 years vs. 9.3 ± 9 years, P = 0.006). Racial-Ethnic-mediated implicit bias was also observed in our study (n = 37, 34%). Compared with those without Racial-Ethnic bias, providers with Racial-Ethnic bias were more likely to state that they could recognize their own implicit bias (89% vs. 61%, P = 0.001). Conclusion: Provider implicit bias to recommend diabetes technology was observed based on insurance and Race/Ethnicity in our pediatric and adult diabetes provider cohort. These data raise the need to address provider implicit bias in diabetes care.

Increased anxiety symptoms in pediatric type 1 diabetes during the acute phase of COVID-19 lockdown.

OBJECTIVES: The prevalence of mental health issues has increased at an alarming rate during the COVID-19 pandemic. Furthermore, an exacerbated psychosocial burden in populations with chronic disease is observed. This cross-sectional study evaluated the psychosocial factors of pediatric type 1 diabetes (T1D) during the COVID-19 pandemic. METHODS: During April 2020, 15 min phone interviews were performed for pediatric T1D group (n=100) and healthy comparison group (n=93) to assess psychosocial functioning during the acute lockdown phase of the pandemic. The patient health questionnaire-4 was utilized to assess anxiety and depressive symptoms. An additional questionnaire to assess specific concerns related to T1D and COVID-19 was administered to the T1D group to explore potential causes for increased psychosocial burden. RESULTS: T1D was associated with a five-times higher risk of anxiety symptoms. Increased anxiety symptoms in T1D group appear to be, at least in part, due to fear of higher risk of severe COVID-19 infection and uncertainty regarding access to diabetes supplies. CONCLUSIONS: This study provides a snapshot of mental well-being in a diverse population of patients with T1D in the acute phase of a crisis and underscores the need for timely, accurate medical information and distribution of medical resources for pediatric T1D population.

Facilitators and Barriers to Smart Insulin Pen Use: A Mixed-Method Study of Multidisciplinary Stakeholders From Diabetes Teams in the United States.

This study sought to identify barriers and facilitators to successful smart insulin pen (SIP) use and gauge prescribing practices and integration into clinical practice by assessing provider and care team perspectives at participating endocrinology clinics within the T1D Exchange Quality Improvement Collaborative. The identified provider-related, patient-related, and clinic- and operational-level barriers and facilitators varied based on clinic knowledge, capacity, and resources. High-impact barriers included insurance coverage and prescribing processes; high-impact facilitators included improved diabetes clinic visit quality and use of SIPs as an alternative to insulin pump therapy. Findings indicated the need for provider and care team education and training on proper SIP features, use, and prescribing.

Quality Improvement in Diabetes Care: A Review of Initiatives and Outcomes in the T1D Exchange Quality Improvement Collaborative.

Despite immense strides in therapeutic advances, clinical outcomes continue to be less than ideal for people with type 1 diabetes. This discrepancy has prompted an outpouring of quality improvement (QI) initiatives to address the medical, psychosocial, and health equity challenges that complicate ideal type 1 diabetes care and outcomes. This article reviews a framework for QI in diabetes care that guided the development of the T1D Exchange Quality Improvement Collaborative to improve care delivery and health outcomes in type 1 diabetes. Evaluation of the methodology, outcomes, and knowledge gained from these initiatives will highlight the importance of continued QI initiatives in diabetes care.

Islet expression of type I interferon response sensors is associated with immune infiltration and viral infection in type 1 diabetes.

Previous results indicate the presence of an interferon (IFN) signature in type 1 diabetes (T1D), capable of inducing chronic inflammation and compromising b cell function. Here, we determined the expression of the IFN response markers MxA, PKR, and HLA-I in the islets of autoantibody-positive and T1D donors. We found that these markers can be coexpressed in the same islet, are more abundant in insulin-containing islets, are highly expressed in islets with insulitis, and their expression levels are correlated with the presence of the enteroviral protein VP1. The expression of these markers was associated with down-regulation of multiple genes in the insulin secretion pathway. The coexistence of an IFN response and a microbial stress response is likely to prime islets for immune destruction. This study highlights the importance of therapeutic interventions aimed at eliminating potentially persistent infections and diminishing inflammation in individuals with T1D.

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome.

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with 2 other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1X753/L1002P and BubR1H/X753 mice died prematurely, BubR1H/L1002P mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.

Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice.

BACKGROUND & AIMS: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell-cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. METHODS: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onward. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and nontransgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation. RESULTS: Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of nonperpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress. CONCLUSIONS: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress; all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells.

Delayed Puberty.

Delayed puberty is defined as the absence of physical signs of puberty 2 to 2.5 standard deviations above the mean age and affects approximately 2% of adolescents. Causes of delayed puberty are broadly divided into two categories: hypergonadotropic hypogonadism and hypogonadotropic hypogonadism. One exception to this classification system is constitutional delay of growth and puberty, the most common cause of delayed puberty. For the general pediatrician, knowledge of the different causes and initial steps to evaluation is crucial when a patient with delayed puberty presents. [Pediatr Ann. 2018;47(1):e16-e22.].