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The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function i n vitro and in vivo . It is unknown whether the "pro-differentiation effect" is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.
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Changes in physical growth, neurocognitive development, and pubertal maturation are some of the challenges to achieving blood glucose targets in children with type 1 diabetes mellitus. To optimize glycemic outcomes, a comprehensive approach is crucial to address psychosocial needs, expand the use of diabetes technology, and diminish health inequities.
Assuntos
Diabetes Mellitus Tipo 1 , Criança , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , GlicemiaRESUMO
Health disparities are a significant cause of concern globally and in the United States. Disparities have been additionally highlighted throughout the ongoing COVID-19 pandemic during which populations of color have been the most affected by the disease. Social determinants of health, race, ethnicity, and gender have all contributed to disparate outcomes and disparities spanning all age groups. Multiple socio-ecological factors contribute to disparities and different strategies have been proposed. The purpose of this paper is to provide an overview of disparities in pediatric treatment and outcomes, with a focus on children with endocrine disorders.
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COVID-19 , Pandemias , COVID-19/epidemiologia , COVID-19/terapia , Criança , Etnicidade , Hormônio do Crescimento , Humanos , Estados Unidos/epidemiologiaRESUMO
STUDY PURPOSE: Prior studies have identified paediatric attending physicians' screening and management patterns related to overweight/obesity, but less is known about resident physicians' behaviour. The objective was to understand paediatric resident physicians' knowledge, attitude and practice patterns of overweight/obesity screening and management. STUDY DESIGN: We performed a retrospective chart review of preventive visits conducted by residents between August and October 2019. Charts of patients 2-18 years with body mass index ≥85th percentile at the visit were reviewed (85th-<95th for age and sex defined as overweight, ≥95th defined as obese). A survey was distributed to residents assessing knowledge, attitudes and barriers towards obesity management. RESULTS: Of 1250 visits reviewed, 405 (32%) patients met the criteria for overweight or obesity. 39% were identified correctly by the provider, 53% were not identified and 8% were identified incorrectly. 89% of patients had diet history, 31% had physical activity and 43% had family history documented. Patients with obesity received physical activity documentation/counselling, portion size counselling, at least one referral, laboratory tests and a diagnosis more often than overweight patients. 84% of residents completed the survey. Although the majority of residents felt 'somewhat' or 'very' well prepared to counsel families about overweight/obesity, the majority thought their counselling on overweight/obesity was 'not at all' or 'slightly' effective. CONCLUSION: Despite residents feeling prepared and comfortable discussing overweight/obesity with patients, these diagnoses were often under-recognised or incorrectly made and appropriate counselling was lacking. Future work will focus on specific strategies to improve diagnosis, screening and management of overweight/obesity and include educational interventions and electronic medical record adaptations.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Sobrepeso , Índice de Massa Corporal , Criança , Humanos , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/terapia , Padrões de Prática Médica , Estudos RetrospectivosRESUMO
PURPOSE: This study aimed to evaluate the time interval to menarche after gonadotropin-releasing hormone agonist (GnRHa) treatment in females with central precocious puberty (CPP) and to identify factors contributing to timing of menarche. METHODS: We retrospectively reviewed medical records of 39 females with CPP who reached menarche after GnRHa treatment (leuprolide or histrelin). CPP diagnostic criteria were breast development at <8 years old, measurable pubertal luteinizing hormone and/or estradiol concentrations, and bone age advancement. Indications to treat were advanced bone age and psychosocial concerns. Descriptive summaries were reported as frequency and proportion for categorical variables and mean and standard deviation for continuous measures. Linear regression models were developed to evaluate the associations of clinical factors with the time interval to menarche. RESULTS: Mean age was 9.4±1.6 years at treatment onset, and treatment duration was 2.2±1.4 years. Menarche occurred at 12.6±1.1 years, which was 1.04±0.5 years after treatment discontinuation. This was negatively associated with Tanner stage of breast development and bone age at treatment onset and change in bone age during treatment. No association was seen between time interval to menarche and treatment duration, medication, or body mass index. CONCLUSION: We found the average time interval to menarche after GnRHa treatment in our population of female patients with CPP to be 1.04±0.5 years; this is in agreement with other reports. Tanner stage of breast development, bone age at treatment onset, and change in bone age were negatively associated with time interval to menarche. These data provide clinical correlates that assist providers during anticipatory guidance of patients with CPP after GnRHa treatment.
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PURPOSE: To identify the characteristics that predict successful telephone follow-up with parents of infants with severe bronchiolitis. METHODS: We analyzed data from a 17-center, prospective cohort study of infants (age <1 year) hospitalized with bronchiolitis during three consecutive fall/winter seasons. Participant contact information and clinical data were collected during the index hospitalization. Parents were called at 6-month intervals (based on the child's age) after discharge to assess respiratory problems. The primary outcome was age 12-month telephone interview status. Participants were classified as unreachable after 28 days of unsuccessful attempts. RESULTS: 798 of 916 children (87%) completed the age 12-month telephone interview. In unadjusted analyses, factors associated with successful follow-up included: private health insurance, annual household income $60,000 or more, and residing in the Northeast, Midwest, or West. Follow-up was less common among non-Hispanic blacks, Hispanics, and households with 3 or more children. In multivariable analyses, follow-up was more likely among parents of females, and, compared with the South, in the Northeast and Midwest (all P < .05). Compared with non-Hispanic whites, non-Hispanic blacks and Hispanics remained less likely to complete the interview as did households with 3 or more children (all P < .05). CONCLUSION: Sociodemographic and geographic factors predict successful telephone follow-up, even among parents of infants with severe illness.