Risk Factors for Missed Appointments at a Multisite Academic Urban Urogynecology Practice.

IMPORTANCE: Missed appointments lead to decreased clinical productivity and poor health outcomes. OBJECTIVES: The objectives of this study were to describe sociodemographic and clinical characteristics of patients who miss urogynecology appointments and identify risk factors for missed appointments. STUDY DESIGN: We conducted an institutional review board-approved case-control study of women 18 years or older scheduled for a urogynecology appointment at 1 of 4 sites associated with an urban academic tertiary care center over 4 months. Patients were included in the missed appointment group if they canceled their appointments the same day or did not show up for them. For comparison, we included a control group consisting of patients immediately preceding or following the ones who missed their appointments with the same visit type. Logistic regression was used to identify risk factors for missed appointments. RESULTS: Four hundred twenty-six women were included: 213 in the missed appointment group and 213 in the control group. Women who missed appointments were younger (60 years [interquartile range (IQR), 47-72 years] vs 69 years [IQR, 59-78 years], P < 0.0001). More women in the missed appointment group were Hispanic (24.4% vs 13.1%) and non-Hispanic Black (7.5% vs 3.8%, P = 0.009), had Medicaid (17.4% vs 6.57%, P = 0.0006), missed previous appointments (24.9% vs 11.7% P = 0.0005), waited longer for appointments (39 days [IQR, 23.5-55.5 days] vs 30.5 days [IQR, 12.8-47.0 days], P = 0.002), and made appointments for urinary incontinence (44.1% vs 26.8%, P = 0.0002). On multivariate logistic regression, women with Medicaid had significantly higher odds of missing appointments (adjusted OR, 2.11 [1.04-4.48], P = 0.044). CONCLUSIONS: Women with Medicaid were more likely to miss urogynecology appointments. Further research is needed to address barriers this group faces when accessing care.

Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development.

The stepwise progression of common endoderm progenitors into differentiated liver and pancreas organs is regulated by a dynamic array of signals that are not well understood. The nuclear receptor subfamily 5, group A, member 2 gene nr5a2, also known as Liver receptor homolog-1 (Lrh-1) is expressed in several tissues including the developing liver and pancreas. Here, we interrogate the role of Nr5a2 at multiple developmental stages using genetic and chemical approaches and uncover novel pleiotropic requirements during zebrafish liver and pancreas development. Zygotic loss of nr5a2 in a targeted genetic null mutant disrupted the development of the exocrine pancreas and liver, while leaving the endocrine pancreas intact. Loss of nr5a2 abrogated exocrine pancreas markers such as trypsin, while pancreas progenitors marked by ptf1a or pdx1 remained unaffected, suggesting a role for Nr5a2 in regulating pancreatic acinar cell differentiation. In the developing liver, Nr5a2 regulates hepatic progenitor outgrowth and differentiation, as nr5a2 mutants exhibited reduced hepatoblast markers hnf4α and prox1 as well as differentiated hepatocyte marker fabp10a. Through the first in vivo use of Nr5a2 chemical antagonist Cpd3, the iterative requirement for Nr5a2 for exocrine pancreas and liver differentiation was temporally elucidated: chemical inhibition of Nr5a2 function during hepatopancreas progenitor specification was sufficient to disrupt exocrine pancreas formation and enhance the size of the embryonic liver, suggesting that Nr5a2 regulates hepatic vs. pancreatic progenitor fate choice. Chemical inhibition of Nr5a2 at a later time during pancreas and liver differentiation was sufficient to block the formation of mature acinar cells and hepatocytes. These findings define critical iterative and pleiotropic roles for Nr5a2 at distinct stages of pancreas and liver organogenesis, and provide novel perspectives for interpreting the role of Nr5a2 in disease.

Hypoxia as a therapy for mitochondrial disease.

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.

Cannabinoid receptor signaling regulates liver development and metabolism.

Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.