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.

Elucidating glial responses to products of diabetes-associated systemic dyshomeostasis.

Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. DR has non-proliferative stages, characterized in part by retinal neuroinflammation and ischemia, and proliferative stages, characterized by retinal angiogenesis. Several systemic factors, including poor glycemic control, hypertension, and hyperlipidemia, increase the risk of DR progression to vision-threatening stages. Identification of cellular or molecular targets in early DR events could allow more prompt interventions pre-empting DR progression to vision-threatening stages. Glia mediate homeostasis and repair. They contribute to immune surveillance and defense, cytokine and growth factor production and secretion, ion and neurotransmitter balance, neuroprotection, and, potentially, regeneration. Therefore, it is likely that glia orchestrate events throughout the development and progression of retinopathy. Understanding glial responses to products of diabetes-associated systemic dyshomeostasis may reveal novel insights into the pathophysiology of DR and guide the development of novel therapies for this potentially blinding condition. In this article, first, we review normal glial functions and their putative roles in the development of DR. We then describe glial transcriptome alterations in response to systemic circulating factors that are upregulated in patients with diabetes and diabetes-related comorbidities; namely glucose in hyperglycemia, angiotensin II in hypertension, and the free fatty acid palmitic acid in hyperlipidemia. Finally, we discuss potential benefits and challenges associated with studying glia as targets of DR therapeutic interventions. In vitro stimulation of glia with glucose, angiotensin II and palmitic acid suggests that: 1) astrocytes may be more responsive than other glia to these products of systemic dyshomeostasis; 2) the effects of hyperglycemia on glia are likely to be largely osmotic; 3) fatty acid accumulation may compound DR pathophysiology by promoting predominantly proinflammatory and proangiogenic transcriptional alterations of macro and microglia; and 4) cell-targeted therapies may offer safer and more effective avenues for DR treatment as they may circumvent the complication of pleiotropism in retinal cell responses. Although several molecules previously implicated in DR pathophysiology are validated in this review, some less explored molecules emerge as potential therapeutic targets. Whereas much is known regarding glial cell activation, future studies characterizing the role of glia in DR and how their activation is regulated and sustained (independently or as part of retinal cell networks) may help elucidate mechanisms of DR pathogenesis and identify novel drug targets for this blinding disease.

Association of Socioeconomic, Demographic, and Health Care Access Disparities With Severe Visual Impairment in the US.

Importance: Approximately 13% of US adults are affected by visual disability, with disproportionately higher rates in groups impacted by certain social determinants of health (SDOH). Objective: To evaluate SDOH associated with severe visual impairment (SVI) to ultimately guide targeted interventions to improve ophthalmic health. Design, Setting, and Participants: This quality improvement study used cross-sectional data from a telephone survey from the Behavioral Risk Factor Surveillance System (BRFSS) that was conducted in the US from January 2019 to December 2020. Participants were noninstitutionalized adult civilians who were randomly selected and interviewed and self-identified as "blind or having serious difficulty seeing, even while wearing glasses." Exposures: Demographic and health care access factors. Main Outcomes and Measures: The main outcome was risk of SVI associated with various factors as measured by odds ratios (ORs) and 95% CIs. Descriptive and logistic regression analyses were performed using the Web Enabled Analysis Tool in the BRFFS. Results: During the study period, 820 226 people (53.07% female) participated in the BRFSS survey, of whom 42 412 (5.17%) self-identified as "blind or having serious difficulty seeing, even while wearing glasses." Compared with White, non-Hispanic individuals, risk of SVI was increased among American Indian/Alaska Native (OR, 1.63; 95% CI, 1.38-1.91), Black/African American (OR, 1.50; 95% CI, 1.39-1.62), Hispanic (OR, 1.65; 95% CI, 1.53-1.79), and multiracial (OR, 1.33; 95% CI, 1.15-1.53) individuals. Lower annual household income and educational level (eg, not completing high school) were associated with greater risk of SVI. Individuals who were out of work for 1 year or longer (OR, 1.78; 95% CI, 1.54-2.07) or who reported being unable to work (OR, 2.90; 95% CI, 2.66-3.16) had higher odds of SVI compared with the other variables studied. Mental health diagnoses and 14 or more days per month with poor mental health were associated with increased risk of SVI (OR, 1.87; 95% CI, 1.73-2.02). Health care access factors associated with increased visual impairment risk included lack of health care coverage and inability to afford to see a physician. Conclusions and Relevance: In this study, various SDOH were associated with SVI, including self-identification as being from a racial or ethnic minority group; low socioeconomic status and educational level; long-term unemployment and inability to work; divorced, separated, or widowed marital status; poor mental health; and lack of health care coverage. These disparities in care and barriers to health care access should guide targeted interventions.

Sphenofrontal intradiploic dermoid cyst with cutaneous dermal sinus tract.

We report the case of a 5-year-old boy who presented with a draining cutaneous pit temporal to the lateral canthus, with recurrent periorbital infections. MRI and CT revealed a sinus tract leading from the pit at the skin surface to a 5 mm lesion located in the sphenoid bone near the left sphenofrontal suture. Intraoperative facial nerve monitoring and a lacrimal probe inside the sinus tract were used to guide dissection to the cyst through a minimally invasive temporal approach, without need for neurosurgical intervention.

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.

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.

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.

CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis.

Multiple sclerosis is an inflammatory demyelinating disorder of the CNS. Recent studies have suggested diverse mechanisms as underlying demyelination, including a subset of lesions induced by an interaction between metabolic insult to oligodendrocytes and inflammatory mediators. For mice of susceptible strains, cuprizone feeding results in oligodendrocyte cell loss and demyelination of the corpus callosum. Remyelination ensues and has been extensively studied. Cuprizone-induced demyelination remains incompletely characterized. We found that mice lacking the type 2 CXC chemokine receptor (CXCR2) were relatively resistant to cuprizone-induced demyelination and that circulating CXCR2-positive neutrophils were important for cuprizone-induced demyelination. Our findings support a two-hit process of cuprizone-induced demyelination, supporting the idea that multiple sclerosis pathogenesis features extensive oligodendrocyte cell loss. These data suggest that cuprizone-induced demyelination is useful for modeling certain aspects of multiple sclerosis pathogenesis.

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.