Next-generation phenotyping: introducing phecodeX for enhanced discovery research in medical phenomics.

MOTIVATION: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure. RESULTS: Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology-and is a more robust representation of the medical phenome for global use in discovery research. AVAILABILITY AND IMPLEMENTATION: phecodeX is available at https://github.com/PheWAS/phecodeX.

Bioelectric impact of pathological angiogenesis on vascular function.

Pathological angiogenesis, as seen in many inflammatory, immune, malignant, and ischemic disorders, remains an immense health burden despite new molecular therapies. It is likely that further therapeutic progress requires a better understanding of neovascular pathophysiology. Surprisingly, even though transmembrane voltage is well known to regulate vascular function, no previous bioelectric analysis of pathological angiogenesis has been reported. Using the perforated-patch technique to measure vascular voltages in human retinal neovascular specimens and rodent models of retinal neovascularization, we discovered that pathological neovessels generate extraordinarily high voltage. Electrophysiological experiments demonstrated that voltage from aberrantly located preretinal neovascular complexes is transmitted into the intraretinal vascular network. With extensive neovascularization, this voltage input is substantial and boosts the membrane potential of intraretinal blood vessels to a suprahyperpolarized level. Coincident with this suprahyperpolarization, the vasomotor response to hypoxia is fundamentally altered. Instead of the compensatory dilation observed in the normal retina, arterioles constrict in response to an oxygen deficiency. This anomalous vasoconstriction, which would potentiate hypoxia, raises the possibility that the bioelectric impact of neovascularization on vascular function is a previously unappreciated pathophysiological mechanism to sustain hypoxia-driven angiogenesis.

Factors Affecting Visits to the Emergency Department for Urgent and Nonurgent Ocular Conditions.

PURPOSE: To determine the frequency of emergency department (ED) visits for nonurgent and urgent ocular conditions and risk factors associated with ED use for nonurgent and urgent ocular problems. DESIGN: Retrospective, longitudinal cohort analysis. PARTICIPANTS: All enrollees aged 21 years or older in a United States managed care network during 2001-2014. METHODS: We identified all enrollees visiting an ED for ocular conditions identified by International Classification of Diseases, billing codes. Diagnosis is well-described as urgent, nonurgent, or other. We assessed the frequency of ED visits for urgent and nonurgent ocular conditions and how they changed over time. Next, we performed multivariable Cox regression modeling to determine factors associated with visiting an ED for urgent or nonurgent ocular conditions. MAIN OUTCOME MEASURES: Hazard ratios (HRs) with 95% confidence intervals (CIs) of visiting an ED for urgent or nonurgent ocular conditions. RESULTS: Of the 11 160 833 enrollees eligible for this study, 376 680 (3.4%) had 1 or more ED visit for an eye-related problem over a mean ± standard deviation of 5.4±3.3 years' follow-up. Among these enrolled, 86 473 (23.0%) had 1 or more ED visits with a nonurgent ocular condition and 25 289 (6.7%) had at least 1 ED visit with an urgent ocular condition. Use of the ED for nonurgent ocular problems was associated with younger age (P < 0.0001 for all comparisons), black race or Latino ethnicity (P < 0.0001 for both), male sex (P < 0.0001), lower income (P < 0.0001 for all comparisons), and those who frequently sought treatment at an ED for nonophthalmologic medical problems in a given year (P < 0.0001). Enrollees with established eye care professionals had a 10% reduced hazard of visiting the ED for nonurgent ocular conditions (adjusted HR, 0.90; 95% CI, 0.88-0.92; P < 0.0001). CONCLUSIONS: Nearly one-quarter of enrollees who visited the ED for an ocular problem received a diagnosis of a nonurgent condition. Better educating and incentivizing patients to seek care for nonurgent ocular diseases in an office-based setting could yield considerable cost savings without adversely affecting health outcomes and could allow EDs to better serve patients with more severe conditions.

Fibroblasts expressing the thyrotropin receptor overarch thyroid and orbit in Graves' disease.

CONTEXT: Graves' disease (GD) is a systemic autoimmune syndrome comprising manifestations in thyroid and orbital connective tissue. The link between these two tissues in GD eludes our understanding. Patients with GD have increased frequency of circulating monocyte lineage cells known as fibrocytes. These fibrocytes infiltrate orbital connective tissues in thyroid-associated ophthalmopathy and express functional TSH receptor (TSHR). OBJECTIVE: The aim of the study was to identify and characterize CD34(+) fibrocytes in thyroid tissue. DESIGN/SETTING/PARTICIPANTS: Patients undergoing surgical thyroidectomy at two academic medical centers were recruited to the study. MAIN OUTCOME MEASURES: We performed immunohistochemistry, flow cytometry, real-time PCR, cytokine-specific ELISA, and cell differentiation. RESULTS: CD34(+)ColI(+)CXCR4(+)TSHR(+) cells can be identified in situ in thyroid tissue from donors with GD, Hashimoto's thyroiditis, or in normal-appearing tissue. Thyroid fibroblasts cultivated from these glands express a CD34(-)ColI(+)CXCR4(+)TSHR(+) phenotype. TSHR levels are higher than those in orbital fibroblasts. When treated with TSH, thyroid fibroblasts generate IL-6 and IL-8. The induction of IL-6 can be blocked by dexamethasone, a chemical inhibitor of Akt/Pkb, and by knocking down Akt with a specific small interfering RNA. When treated with TGF-ß or rosiglitazone, thyroid fibroblasts differentiate into myofibrocytes or adipocytes, respectively. CONCLUSIONS: ColI(+)CXCR4(+)TSHR(+) thyroid fibroblasts resemble orbital fibroblasts and circulating fibrocytes. CD34(+) fibrocytes appear to infiltrate both tissues in GD. Thyroid fibroblasts lose CD34 display in culture, unlike orbital fibroblasts and circulating fibrocytes. Fibrocytes and their fibroblast derivatives may participate in the pathogenesis of thyroid autoimmunity after TSHR activation. They could represent a therapeutic target for these diseases.

Alterations in the oligodendrocyte lineage, myelin, and white matter in adult mice lacking the chemokine receptor CXCR2.

Oligodendrocyte precursor cell (OPC) proliferation and migration are critical for the development of myelin in the central nervous system (CNS). Previous studies showed that localized expression of the chemokine CXCL1 signals through the receptor CXCR2 to inhibit the migration and enhance the proliferation of spinal cord OPCs during development. Here, we report structural and functional alterations in the adult CNS of Cxcr2-/- mice. In Cxcr2-/- adult mice, we observed regional alterations in the density of oligodendrocyte lineage cells in Cxcr2-/- adult mice, with decreases in the cortex and anterior commissure but increases in the corpus callosum and spinal cord. An increase in the density and arborization of spinal cord NG2 positive cells was also observed in Cxcr2-/- adult mice. Compared with wild-type (WT) littermates, Cxcr2-/- mice exhibited a significant decrease in spinal cord white matter area, reduced thickness of myelin sheaths, and a slowing in the rate of central conduction of spinally elicited evoked potentials without significant changes in axonal caliber or number. Biochemical analyses showed decreased levels of myelin basic protein (MBP), proteolipid protein (PLP), and glial fibrillary acidic protein (GFAP). In vitro studies showed reduced numbers of differentiated oligodendrocytes in Cxcr2-/- spinal cord cultures. Together, these findings indicate that the chemokine receptor CXCR2 is important for the development and maintenance of the oligodendrocyte lineage, myelination, and white matter in the vertebrate CNS.