Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants.

PURPOSE: The American College of Medical Genetics and Genomics and the Association for Molecular Pathology have outlined a schema that allows for systematic classification of variant pathogenicity. Although gnomAD is generally accepted as a reliable source of population frequency data and ClinGen has provided guidance on the utility of specific bioinformatic predictors, there is no consensus source for identifying publications relevant to a variant. Multiple tools are available to aid in the identification of relevant variant literature, including manually curated databases and literature search engines. We set out to determine the utility of 4 literature mining tools used for ascertainment to inform the discussion of the use of these tools. METHODS: Four literature mining tools including the Human Gene Mutation Database, Mastermind, ClinVar, and LitVar 2.0 were used to identify relevant variant literature for 50 RYR1 variants. Sensitivity and precision were determined for each tool. RESULTS: Sensitivity among the 4 tools ranged from 0.332 to 0.687. Precision ranged from 0.389 to 0.906. No single tool retrieved all relevant publications. CONCLUSION: At the current time, the use of multiple tools is necessary to completely identify the literature relevant to curate a variant.

Evidence for Menopause as a Sex-Specific Risk Factor for Glaucoma.

Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive loss of visual function and retinal ganglion cells (RGC). Current epidemiological, clinical, and basic science evidence suggest that estrogen plays a role in the aging of the optic nerve. Menopause, a major biological life event affecting all women, coincides with a decrease in circulating sex hormones, such as estrogen. While 59% of the glaucomatous population are females, sex is not considered a risk factor for developing glaucoma. In this review, we explore whether menopause is a sex-specific risk factor for glaucoma. First, we investigate how menopause is defined as a sex-specific risk factor for other pathologies, including cardiovascular disease, osteoarthritis, and bone health. Next, we discuss clinical evidence that highlights the potential role of menopause in glaucoma. We also highlight preclinical studies that demonstrate larger vision and RGC loss following surgical menopause and how estrogen is protective in models of RGC injury. Lastly, we explore how surgical menopause and estrogen signaling are related to risk factors associated with developing glaucoma (e.g., intraocular pressure, aqueous outflow resistance, and ocular biomechanics). We hypothesize that menopause potentially sets the stage to develop glaucoma and therefore is a sex-specific risk factor for this disease.

Dependence of visual and cognitive outcomes on animal holder configuration in a rodent model of blast overpressure exposure.

Blast-induced traumatic brain injury is the signature injury of modern military conflicts. To more fully understand the effects of blast exposure, we placed rats in different holder configurations, exposed them to blast overpressure, and assessed the degree of eye and brain injury. Anesthetized Long-Evans rats received blast exposures directed at the head (63 kPa, 195 dB-SPL) in either an "open holder" (head and neck exposed; n = 7), or an "enclosed holder" (window for blast exposure to eye; n = 15) and were compared to non-blast exposed (control) rats (n = 22). Outcomes included optomotor response (OMR), electroretinography (ERG), and spectral domain optical coherence tomography (SD-OCT) at 2, 4, and 6 months post-blast, and cognitive function (Y-maze) at 3 months. Spatial frequency and contrast sensitivity were reduced in ipsilateral blast-exposed eyes in both holders (p < 0.01), while contralateral eyes showed greater deficits with the enclosed holder (p < 0.05). Thinner retinas (p < 0.001) and reduced ERG a- and b- wave amplitudes (p < 0.05) were observed for both ipsilateral and contralateral eyes with the enclosed, but not the open, holder. Rats in the open holder showed cognitive deficits compared to rats in the enclosed holder (p < 0.05). Overall, the animal holder configuration used in blast exposure studies can significantly affect outcomes. Enclosed holders may cause secondary damage to the contralateral eye by concussive injury or blast wave reflection off the holder wall. Open holders may damage the brain via rapid head movement (contrecoup injury). These results highlight additional factors to be considered when evaluating patients with blast exposure or developing models of blast injury.

Initiation of L-DOPA Treatment After Detection of Diabetes-Induced Retinal Dysfunction Reverses Retinopathy and Provides Neuroprotection in Rats.

Purpose: L-DOPA treatment initiated at the start of hyperglycemia preserves retinal and visual function in diabetic rats. Here, we investigated a more clinically relevant treatment strategy in which retinal and visual dysfunction designated the beginning of the therapeutic window for L-DOPA treatment. Methods: Spatial frequency thresholds using optomotor response and oscillatory potential (OP) delays using electroretinograms were compared at baseline, 3, 6, and 10 weeks after streptozotocin (STZ) between diabetic and control rats. L-DOPA/carbidopa treatment (DOPA) or vehicle was delivered orally 5 days per week beginning at 3 weeks after STZ, when significant retinal and visual deficits were measured. At 10 weeks after STZ, retinas were collected to measure L-DOPA, dopamine, and 3,4-dihydroxyphenylacetic acid (DOPAC) levels using high-performance liquid chromatography. Results: Spatial frequency thresholds decreased at 6 weeks in diabetic vehicle rats (28%), whereas diabetic DOPA rats had stable thresholds (<1%) that maintained to 10 weeks, creating significantly higher thresholds compared with diabetic vehicle rats (P < 0.0001). OP2 implicit times in response to dim, rod-driven stimuli were decreased in diabetic compared with control rats (3 weeks, P < 0.0001; 10 weeks, P < 0.01). With L-DOPA treatment, OP2 implicit times recovered in diabetic rats to be indistinguishable from control rats by 10 weeks after STZ. Rats treated with L-DOPA showed significantly increased retinal L-DOPA (P < 0.001) and dopamine levels (P < 0.05). Conclusions: L-DOPA treatment started after the detection of retinal and visual dysfunction showed protective effects in diabetic rats. Translational Relevance: Early retinal functional deficits induced by diabetes can be used to identify an earlier therapeutic window for L-DOPA treatment which protects from further vision loss and restores retinal function.

Impacts of high fat diet on ocular outcomes in rodent models of visual disease.

High fat diets (HFD) have been utilized in rodent models of visual disease for over 50 years to model the effects of lipids, metabolic dysfunction, and diet-induced obesity on vision and ocular health. HFD treatment can recapitulate the pathologies of some of the leading causes of blindness, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rodent models of visual disease. However, there are many important factors to consider when using and interpreting these models. To synthesize our current understanding of the importance of lipid signaling, metabolism, and inflammation in HFD-driven visual disease processes, we systematically review the use of HFD in mouse and rat models of visual disease. The resulting literature is grouped into three clusters: models that solely focus on HFD treatment, models of diabetes that utilize both HFD and streptozotocin (STZ), and models of AMD that utilize both HFD and genetic models and/or other exposures. Our findings show that HFD profoundly affects vision, retinal function, many different ocular tissues, and multiple cell types through a variety of mechanisms. We delineate how HFD affects the cornea, lens, uvea, vitreous humor, retina, retinal pigmented epithelium (RPE), and Bruch's membrane (BM). Furthermore, we highlight how HFD impairs several retinal cell types, including glia (microglia), retinal ganglion cells, bipolar cells, photoreceptors, and vascular support cells (endothelial cells and pericytes). However, there are a number of gaps, limitations, and biases in the current literature. We highlight these gaps and discuss experimental design to help guide future studies. Very little is known about how HFD impacts the lens, ciliary bodies, and specific neuronal populations, such as rods, cones, bipolar cells, amacrine cells, and retinal ganglion cells. Additionally, sex bias is an important limitation in the current literature, with few HFD studies utilizing female rodents. Future studies should use ingredient-matched control diets (IMCD), include both sexes in experiments to evaluate sex-specific outcomes, conduct longitudinal metabolic and visual measurements, and capture acute outcomes. In conclusion, HFD is a systemic exposure with profound systemic effects, and rodent models are invaluable in understanding the impacts on visual and ocular disease.

Ovariectomy worsens visual function after mild optic nerve crush in rodents.

Glaucoma is the leading cause of irreversible blindness worldwide, and women represent roughly 60% of the affected population. Early menopause and estrogen signaling defects are risk factors for glaucoma. Recently, we found that surgical menopause exacerbated visual dysfunction in an ocular hypertension model of glaucoma. Here, we investigated if surgical menopause exacerbated visual dysfunction in a model of direct retinal ganglion cell (RGC) damage via optic nerve crush (ONC). Female Long Evans rats (n = 12) underwent ovariectomy (OVX) to induce surgical menopause or Sham surgery. Eight weeks post-surgery, baseline visual function was assessed via optomotor response. Afterwards, rats underwent monocular ONC. Visual function was assessed at 4, 8, and 12 weeks post-ONC. At 12 weeks, retinal function via electroretinography and retinal nerve fiber layer (RNFL) thickness via optical coherence tomography were measured. Visual acuity was reduced after ONC (p < 0.001), with surgical menopausal animals having 31.7% lower visual acuity than Sham animals at 12 weeks (p = 0.01). RNFL thinning (p < 0.0001) and decreased RGC function (p = 0.0016) occurred at 12 weeks in ONC groups. Surgical menopause worsens visual acuity after direct RGC damage using an ONC model. This demonstrates that surgical menopause plays a role in visual function after injury.

Behavioral Assessment of Visual Function via Optomotor Response and Cognitive Function via Y-Maze in Diabetic Rats.

The optomotor response and the Y-maze are behavioral tests useful for assessing visual and cognitive function, respectively. The optomotor response is a valuable tool to track changes in spatial frequency (SF) and contrast sensitivity (CS) thresholds over time in a number of retinal disease models, including diabetic retinopathy. Similarly, the Y-maze can be used to monitor spatial cognition (as measured by spontaneous alternation) and exploratory behavior (as measured by a number of entries) in a number of disease models that affect the central nervous system. Advantages of the optomotor response and the Y-maze include sensitivity, speed of testing, the use of innate responses (training is not needed), and the ability to be performed on awake (non-anesthetized) animals. Here, protocols are described for both the optomotor response and the Y-maze and examples of their use shown in models of Type I and Type II diabetes. Methods include preparation of rodents and equipment, performance of the optomotor response and the Y-maze, and post-test data analysis.

Intersession Remediation to Minimize Attrition in a Three-Year Pharmacy Program.

Objective. To describe an intersession remediation process in an accelerated three-year Doctor of Pharmacy (PharmD) program and to determine if the remediation process reduced attrition rates, including program withdrawals, progression to advanced pharmacy practice experiences (APPEs), and on-time graduation rates. Methods. Attrition was defined as dismissal, withdrawal, leave of absence, and/or change in graduation date. Progression data from students who matriculated between 2008 to 2016, with data available through spring 2017, were analyzed for number of course failures and successful intersession remediation. Other factors such as pharmacy year (first or second year), course subject, and course repeats were evaluated to characterize successful remediation attempts and identify elements that foster student success. Results. Of the 812 matriculated students across the time period analyzed, 18% (n=146) failed at least one didactic course (defined as course average <69.5%). Overall, 74.7% (n=109) of the students who failed a course remediated, with 75.2% (n=82) of those able to remediate being successful, remaining on-time for graduation. If students who remediated were instead required to repeat coursework, the college attrition rate would have averaged over 10 percentage points higher for the time period analyzed than the actual rate of 13.4%. Conclusion. Our study demonstrated that the majority of students who qualified for remediation were successful and graduated on time. Further studies in this area are needed to fully elucidate the effect of remediation processes on learning and retention of knowledge and skills.

Description of a pharmacist-led clinical video telehealth group clinic for opioid overdose prevention and naloxone education.

To achieve the nationwide goal of reducing opioid-related deaths, a clinical pharmacy specialist-led clinical video telehealth (CVT) clinic was created at a Veterans Affairs medical center (VAMC) to deliver opioid overdose prevention and naloxone education to at-risk patients. The purpose of this innovative practice was to improve access to this potentially life-saving intervention to patients across urban and rural areas. This study is a single-center, descriptive analysis of adult patients across 2 VAMC campuses and 4 community-based outpatient clinics from July 11, 2016, through December 31, 2016. The purpose of this innovative practice was to increase access to overdose education and naloxone distribution (OEND) to at-risk patients across urban and rural areas. Patient-specific factors were also examined among those receiving naloxone through the CVT clinic compared to other prescribers. During the first 6 months from the initiation of the clinic, 1 pharmacist prescribed 21% of the health care system's naloxone. These patients identified by the pharmacist-led CVT clinic were more likely to be considered high-risk due to concomitant use of opioids and benzodiazepines. In conclusion, the pharmacist-led CVT group clinic has been an efficient strategy to extend OEND services to high-risk patients beyond central, urban areas.

Evaluation of perceptions and knowledge of mental illness in the United States through crowdsourcing.

INTRODUCTION: Crowdsourcing is a method of data collection with possible benefits in assessing perceptions of mental illness in a large US population. METHODS: The objective was to describe perceptions and trends of stigma surrounding mental illness in the United States using crowdsourcing. An online survey was conducted evaluating adults in the United States recruited via the online resource Amazon Mechanical Turk. Questions evaluated demographics and perceptions of mental illness. Survey data were adjusted for demographic variables and compared via logistic regression. RESULTS: Respondents (n = 1422) were predominately 18 to 30 years of age (n = 743; 52.3%) and white (n = 1101; 77.4%). Over half reported an individual close to them had mental illness (n = 932; 65.5%), and more than one quarter (n = 397; 27.9%) reported having a current or previous mental illness. Non-whites were less likely to agree that: medications are effective (odds ratio [OR] 0.63); they would be comfortable around a coworker with mental illness (OR 0.66); and mental illness is inheritable (OR 0.74). They are also more likely to agree that mental illness is preventable (OR 1.49). Individuals reporting mental illness were more likely to agree that medications (OR 1.34; 95% confidence interval 1.03 to 1.74) and talk therapy (OR 1.46; 95% confidence interval 1.12 to 1.90) are effective. Those reporting some or no college were more likely to agree that the United States has good access to mental health treatment. DISCUSSION: Crowdsourcing may be an effective way to obtain information regarding demographics, stigma, and mental illness. Personal experiences with mental illness, ethnicity, and educational level appear to continue to impact perceptions of mental illness.

A case report of guardian-consent forced paliperidone palmitate for behavioral disturbance due to traumatic brain injury.

Psychosis after traumatic brain injury (TBI) occurs in up to 10% of cases. Although guideline consensus is lacking regarding drugs of choice for this condition, current literature points to the use of atypical antipsychotics. This case describes a 58-year-old male with major neurocognitive disorder due to TBI with behavioral disturbance that was successfully treated with paliperidone palmitate. In addition to the off-label use of paliperidone, this case also explores the use of forced medication as the initial injection was given per guardian consent. After completion of a literature review, this appears to be the first case report describing the use of a long-acting antipsychotic for the treatment of TBI-related psychosis. This case suggests that paliperidone palmitate may be efficacious for psychosis following TBI; however, further study is warranted.