Disease-modifying rdHSV-CA8* non-opioid analgesic gene therapy treats chronic osteoarthritis pain by activating Kv7 voltage-gated potassium channels.

Chronic pain is common in our population, and most of these patients are inadequately treated, making the development of safer analgesics a high priority. Knee osteoarthritis (OA) is a primary cause of chronic pain and disability worldwide, and lower extremity OA is a major contributor to loss of quality-adjusted life-years. In this study we tested the hypothesis that a novel JDNI8 replication-defective herpes simplex-1 viral vector (rdHSV) incorporating a modified carbonic anhydrase-8 transgene (CA8*) produces analgesia and treats monoiodoacetate-induced (MIA) chronic knee pain due to OA. We observed transduction of lumbar DRG sensory neurons with these viral constructs (vHCA8*) (~40% of advillin-positive cells and ~ 50% of TrkA-positive cells colocalized with V5-positive cells) using the intra-articular (IA) knee joint (KJ) route of administration. vHCA8* inhibited chronic mechanical OA knee pain induced by MIA was dose- and time-dependent. Mechanical thresholds returned to Baseline by D17 after IA KJ vHCA8* treatment, and exceeded Baseline (analgesia) through D65, whereas negative controls failed to reach Baseline responses. Weight-bearing and automated voluntary wheel running were improved by vHCA8*, but not negative controls. Kv7 voltage-gated potassium channel-specific inhibitor XE-991 reversed vHCA8*-induced analgesia. Using IHC, IA KJ of vHCA8* activated DRG Kv7 channels via dephosphorylation, but negative controls failed to impact Kv7 channels. XE-991 stimulated Kv7.2-7.5 and Kv7.3 phosphorylation using western blotting of differentiated SH-SY5Y cells, which was inhibited by vHCA8* but not by negative controls. The observed prolonged dose-dependent therapeutic effects of IA KJ administration of vHCA8* on MIA-induced chronic KJ pain due to OA is consistent with the specific activation of Kv7 channels in small DRG sensory neurons. Together, these data demonstrate for the first-time local IA KJ administration of vHCA8* produces opioid-independent analgesia in this MIA-induced OA chronic pain model, supporting further therapeutic development.

rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels.

Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.

Hematic Pseudocyst Masquerading as Orbital Cellulitis and Sinusitis.

Hematic pseudocysts are fibrous, nonepithelial lined capsules containing blood byproducts that typically present remotely following orbital fracture hardware implantation. Trauma, implant migration, and tissue erosion are believed to cause hemorrhage to pool within the capsular space. Risk factors include inadequate posterior fracture reduction and use of nonporous material which prevents fibrovascular ingrowth and stabilization. Mass effect from these lesions may cause patients to present with pain, lid swelling, hyperglobus, proptosis, lid retraction, motility restriction, or blurry vision. Pseudocysts associated with fracture hardware have been misdiagnosed as tumors or in one prior case as an infection. Herein we report a unique case of hematic pseudocyst masquerading as orbital cellulitis with maxillary sinusitis. A 59-year-old man presented with periorbital pain, hyperglobus, proptosis, and ptosis 2 years after repair of an orbital floor fracture. CT demonstrated a soft tissue collection adjacent to an implant as well as maxillary sinus opacification. He did not improve with antibiotics, at which point surgery revealed a pseudocyst and its contents were removed. This report describes a unique presentation of orbital pseudocyst and summarizes the literature on this entity.

Vascular Endothelial Growth Factor Receptor Expression in Orbital Cavernous Malformations and Lymphatic Malformations.

PURPOSE: To investigate the presence of vascular endothelial growth factor receptors (VEGFR) in orbital cavernous malformations and lymphatic malformations to further understand the feasibility of anti-VEGF treatment. METHODS: This study was a single-center retrospective chart review performed at the Bascom Palmer Eye Institute of patients who underwent surgical excision of orbital cavernous malformations and lymphangiomas from 2000 - 2017. Immunohistochemical staining of these lesions for VEGFR1 and VEGFR2 expression was performed. RESULTS: A total of 25 patients were identified with cavernous malformations (n=15) and lymphatic malformations (n=10). Ten specimens (7 cavernous malformations, 3 lymphatic malformations) underwent further immunohistochemical analysis. Six of 7 cavernous malformations and one of 3 lymphatic malformations stained positive for VEGFR1 and VEGFR2. CONCLUSIONS: Both cavernous malformations and lymphatic malformations appear to express VEGFR with varying frequency. Additional studies are needed to better characterize the pathogenesis of these lesions, nature of VEGFR expression, and potential efficacy of anti-VEGF treatment.

Bilateral iPhone Gorilla Glass Intraocular Foreign Bodies in a Pediatric Patient.

A 13-year old male presented with bilateral intraocular foreign bodies (IOFBs) after a bullet struck his iPhone. The right eye vision was 20/50 and examination disclosed a limbal entry wound at 6:00, dense traumatic cataract, and vitreous hemorrhage. The left eye was 20/40 and an entry wound located roughly 4mm posterior to the limbus was noted. Fundoscopy revealed multiple refractile particles with pre-retinal and vitreous hemorrhage. CT scan demonstrated hyperdensities in the vitreous cavity bilaterally. Globe closure, cataract removal, vitrectomy, and endolaser were undertaken in the right eye, while only globe closure was performed in the left eye. On latest follow-up, the patient had 20/20 corrected vision without inflammation bilaterally. This case highlights challenges associated with the management of IOFBs of unknown material in a pediatric patient. A conservative approach led to full visual recovery, despite retained intraocular smartphone Gorilla glass.

Ocular Adnexal MALT Lymphoma in Association With Rosai-Dorfman Disease in a Child.

A 12-year-old boy presented with persistent proptosis and periorbital swelling after a school altercation. MRI revealed a mass in the right superonasal orbit extending along the orbital roof to the frontal bone and right frontal sinus, and intracranially to the dura of the right frontal lobe. Immunohistochemistry revealed CD20- and CD43-positive B cells consistent with a low-grade B-cell lymphoma. The patient was diagnosed with stage I ocular adnexal MALT lymphoma and treated with radiation therapy, followed by systemic chemotherapy. However, an enhancing orbital and intracranial mass remained on follow-up imaging, leading to a repeat biopsy, which was consistent with a diagnosis of Rosai-Dorfman disease. This is the first reported pediatric case of ocular adnexal MALT lymphoma with subsequent development of Rosai-Dorfman disease.

Bilateral Leukemic Infiltration of the Lacrimal Sac in a Child.

An 8-year-old boy with a history of refractory acute lymphoblastic leukemia presented with left-sided periorbital erythema and painless enlargement of the lacrimal sac. MRI revealed a soft tissue mass on the floor of the left orbit, extending into the nasolacrimal sac and duct. Lacrimal sac biopsy was consistent with B-lymphoblastic leukemia. The patient was treated with chemotherapy and radiation with satisfactory remission of local disease. However, similar symptoms emerged shortly after on the contralateral side, and repeat MRI was concerning for new leukemic infiltration of the right lacrimal sac. Bone marrow biopsy revealed concurrent medullary relapse. Systemic chemotherapy was adjusted and radiation therapy of the right orbit was initiated. This is the first reported pediatric case of bilateral leukemic involvement of the lacrimal sac.

Pain sensitivity and autonomic nervous system parameters as predictors of dry eye symptoms after LASIK.

PURPOSE: Differences in pain processing and autonomic function among patients have been implicated in the development of chronic pain after surgery. This study was designed to evaluate whether pain and autonomic metrics predict severity of chronic dry eye (DE) symptoms after LASIK, as there is increasing evidence that DE symptoms may be manifestations of persistent post-operative ocular pain. METHODS: Secondary analysis of prospective randomized clinical trial. Patients were treated with either pregabalin or placebo. As no significant differences in DE symptoms were detected by treatment allocation at six months, all participants were grouped together for the present analyses. Subjects were evaluated pre-LASIK with regard to evoked pain sensitivity (utilizing quantitative sensory testing), autonomic metrics and DE and ocular pain symptoms (via validated questionnaires). Measures of DE and ocular pain were assessed post-LASIK, and the Dry Eye Questionnaire 5 (DEQ5) score 6-months after surgery was the primary outcome of interest. RESULTS: 43 individuals were randomized to pregabalin (n = 21) or placebo (n = 22). 42 completed the 6-month visit. Several baseline autonomic metrics correlated with 6-month post-operative DEQ5 scores, including lower systolic (r -0.37, p = 0.02) and diastolic blood pressure (r -0.32, p = 0.04). Ocular pain at 6 months was also negatively correlated with blood pressure (r -0.31, p = 0.047). The presence of painful aftersensations was a significant predictor of chronic DE symptoms at 6 months (mean DEQ5 scores: 8.0 ± 1.9 versus 5.0 ± 5.0, p = 0.009). CONCLUSIONS: Heightened parasympathetic tone and prolonged pain sensitivity measured prior to surgery predicted greater DE symptom severity 6 months after LASIK. TRIAL REGISTRATION: NCT02701764.

Periorbital botulinum toxin A improves photophobia and sensations of dryness in patients without migraine: Case series of four patients.

PURPOSE: Individuals receiving botulinum toxin A (BoNT-A) injections in the head and neck for migraine treatment have reported decreases in photophobia and sensations of dryness, independent of ocular surface parameters. We hypothesized that patients without migraine but with similar ocular neuropathic-like symptoms would also experience symptomatic improvement with periocular BoNT-A injections, independent of ocular surface changes. OBSERVATIONS: We identified four individuals without a history of migraine but with neuropathic ocular pain (symptoms of dryness, burning, and photophobia that were out of proportion to ocular surface findings and unresponsive to ongoing dry eye (DE) therapies). Individuals underwent 1 session of periocular BoNT-A injections. Validated questionnaires (Visual Light Sensitivity Questionnaire-8, Dry Eye Questionnaire-5) assessed photophobia and DE symptoms pre- and 1-month post-injections. All four reported improvements in frequency and severity of photophobia and eye discomfort following BoNT-A injections. Tear film parameters (phenol red thread test, tear break-up time, corneal staining, and Schirmer test) and eyelid (palpebral fissure height and levator palpebrae superioris function) and eyebrow (position) anatomy were also evaluated before and after injections. Despite a unanimous improvement in symptoms, there were no consistent changes in ocular surface parameters with BoNT-A injections across individuals. CONCLUSIONS: Periocular BoNT-A shows promise in reducing photophobia and sensations of dryness in individuals with neuropathic-like DE symptoms without a history of migraine, independent of tear film, eyelid, or eyebrow parameters.

Ablative Fractional Laser Resurfacing With Laser-Assisted Delivery of 5-Fluorouracil for the Treatment of Cicatricial Ectropion and Periocular Scarring.

PURPOSE: Cicatricial ectropion and periocular scarring can cause significant functional and cosmetic deficits. Surgical treatments can be associated with recicatrization, donor site morbidity, and textural and pigmentary abnormalities. This case series reports on efficacy and safety of a novel nonsurgical approach to treating cicatricial ectropion using ablative fractional laser resurfacing and laser-assisted delivery of 5-fluorouracil. METHODS: A retrospective review was conducted of all patients at a single institution who received ≥3 rounds of ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil. Six patients with cicatricial ectropion and periocular scarring secondary to reconstructive surgery, traumatic lacerations, and facial burns were included. Aesthetic and functional improvement were evaluated via fluorescein staining, tear breakup time, external photography, questionnaires gauging dry eye symptoms, and scar appearance. RESULTS: All patients showed functional improvement based on fluorescein staining (mean improvement 6.0 ± 1.4; p = 0.0007) and other indicators of dry eye. All 4 patients with lagophthalmos improved and 2 showed complete resolution. All patients demonstrated significant cosmetic improvement based on a validated scar assessment questionnaire (mean improvement 37.5 ± 18.9; p = 0.004), and 5 of 6 patients reported improved satisfaction with scar appearance (mean improvement 19.3 ± 12.8; p = 0.014). There were no adverse effects reported. CONCLUSIONS: Ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil appears to be a safe and effective modality for treating the functional and aesthetic abnormalities associated with periocular scarring, yielding results that are difficult to attain through surgery alone. Optimal management of cicatricial ectropion and periocular scarring often requires multimodality treatment, and ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil may be considered as part of a comprehensive approach to managing periocular scars.

Evidence that Dry Eye Represents a Chronic Overlapping Pain Condition.

Abstract: Recent data suggest that corneal somatosensory dysfunction may be the underlying cause of severe dry eye symptoms in the absence of ocular surface pathology seen in a subset of patients diagnosed with "dry eye syndrome." This subset of patients tends to demonstrate a unique constellation of symptoms that are persistent, more severe, and generally respond poorly to current dry eye therapies targeting inadequate or dysfunctional tears. A growing body of literature suggests that symptoms in these patients may be better characterized as neuropathic ocular pain rather than dry eye. In these patients, dry eye symptoms are often associated with numerous comorbid pain conditions and evidence of central pain processing abnormalities, where eye pain is just one of multiple overlapping peripheral manifestations. In this review, we discuss the concept and potential mechanisms of chronic overlapping pain conditions as well as evidence for considering neuropathic ocular pain as one of these overlapping pain conditions.

Community Mitigation Guidelines to Prevent Pandemic Influenza - United States, 2017.

When a novel influenza A virus with pandemic potential emerges, nonpharmaceutical interventions (NPIs) often are the most readily available interventions to help slow transmission of the virus in communities, which is especially important before a pandemic vaccine becomes widely available. NPIs, also known as community mitigation measures, are actions that persons and communities can take to help slow the spread of respiratory virus infections, including seasonal and pandemic influenza viruses.These guidelines replace the 2007 Interim Pre-pandemic Planning Guidance: Community Strategy for Pandemic Influenza Mitigation in the United States - Early, Targeted, Layered Use of Nonpharmaceutical Interventions (https://stacks.cdc.gov/view/cdc/11425). Several elements remain unchanged from the 2007 guidance, which described recommended NPIs and the supporting rationale and key concepts for the use of these interventions during influenza pandemics. NPIs can be phased in, or layered, on the basis of pandemic severity and local transmission patterns over time. Categories of NPIs include personal protective measures for everyday use (e.g., voluntary home isolation of ill persons, respiratory etiquette, and hand hygiene); personal protective measures reserved for influenza pandemics (e.g., voluntary home quarantine of exposed household members and use of face masks in community settings when ill); community measures aimed at increasing social distancing (e.g., school closures and dismissals, social distancing in workplaces, and postponing or cancelling mass gatherings); and environmental measures (e.g., routine cleaning of frequently touched surfaces).Several new elements have been incorporated into the 2017 guidelines. First, to support updated recommendations on the use of NPIs, the latest scientific evidence available since the influenza A (H1N1)pdm09 pandemic has been added. Second, a summary of lessons learned from the 2009 H1N1 pandemic response is presented to underscore the importance of broad and flexible prepandemic planning. Third, a new section on community engagement has been included to highlight that the timely and effective use of NPIs depends on community acceptance and active participation. Fourth, to provide new or updated pandemic assessment and planning tools, the novel influenza virus pandemic intervals tool, the Influenza Risk Assessment Tool, the Pandemic Severity Assessment Framework, and a set of prepandemic planning scenarios are described. Finally, to facilitate implementation of the updated guidelines and to assist states and localities with prepandemic planning and decision-making, this report links to six supplemental prepandemic NPI planning guides for different community settings that are available online (https://www.cdc.gov/nonpharmaceutical-interventions).

Neuropathic Ocular Pain due to Dry Eye is Associated with Multiple Comorbid Chronic Pain Syndromes.

UNLABELLED: Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS. We recruited a cohort of 154 DE patients from the Miami Veterans Affairs Hospital and defined high and low CPS groups using cluster analysis. In addition to worse nonocular pain complaints and higher post-traumatic stress disorder and depression scores (P < .01), we found that the high CPS group reported more severe neuropathic type DE symptoms compared with the low CPS group, including worse ocular pain assessed via 3 different pain scales (P < .05), with similar objective corneal DE signs. To our knowledge, this was the first study to show that DE patients who manifest a greater number of comorbid CPS reported more severe DE symptoms and features of NOP. These findings provided further evidence that NOP might represent a central pain disorder, and that shared mechanistic factors might underlie vulnerability to some forms of DE and other comorbid CPS. PERSPECTIVE: DE patients reported more frequent CPS (high CPS group) and reported worse DE symptoms and ocular and nonocular pain scores. The high CPS group reported symptoms of NOP that share causal genetic factors with comorbid CPS. These results imply that an NOP evaluation and treatment should be considered for DE patients.

Ocular Inflammation in the Setting of Concomitant Systemic Autoimmune Conditions in an Older Male Population.

PURPOSE: This retrospective cross-sectional study was designed to investigate the frequency and types of inflammatory ocular manifestations of specific systemic autoimmune diseases in a South Florida Veterans Affairs Hospital population. METHODS: Demographic and medical diagnosis information was extracted from the Veterans Administration database for 1225 patients. These patients were seen in Miami and Broward Veterans Affairs hospitals between April 18, 2008, and April 17, 2013, and were diagnosed with at least 1 of the following: systemic lupus erythematosus, sarcoid, rheumatoid arthritis, polymyalgia rheumatica, Takayasu arteritis, giant cell arteritis, Kawasaki disease, polyarteritis nodosa, Buerger disease, Henoch-Schonlein purpura, Behcet syndrome, granulomatosis with polyangiitis, other polyarteritis nodosa-associated vasculitides, or arteritis not otherwise specified. RESULTS: Of 1225 patients, 618 were seen in the VA eye clinic and 25 were diagnosed with concomitant inflammatory ocular conditions. Uveitis was the most common, and included 8 cases of anterior, 1 anterior-intermediate, 1 intermediate, 2 panuveitis, and 3 unspecified. Other manifestations included 7 cases of keratitis and 2 each of scleritis, episcleritis, and acute ischemic optic neuropathy. The overall frequency of inflammatory ocular disease was 2%. The diseases associated with the highest frequency of ocular involvement were granulomatosis with polyangiitis (1/8), sarcoid (9/198), giant cell arteritis (2/68), and rheumatoid arthritis (11/576). Of these 25 patients, 9 were diagnosed with eye disease before systemic disease. CONCLUSIONS: In this population, ocular manifestations were rarely the presenting feature of systemic disease, but autoimmune disorders are an important underlying cause of inflammatory eye disease that should be considered on first evaluation, even in this "nontraditional," predominantly male, autoimmune disease population.

Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders.

Laser in-situ keratomileusis (LASIK) is a commonly performed surgical procedure used to correct refractive error. LASIK surgery involves cutting a corneal flap and ablating the stroma underneath, with known damage to corneal nerves. Despite this, the epidemiology of persistent pain and other long-term outcomes after LASIK surgery are not well understood. Available data suggest that approximately 20-55% of patients report persistent eye symptoms (generally regarded as at least 6 months post-operation) after LASIK surgery. While it was initially believed that these symptoms were caused by ocular surface dryness, and referred to as "dry eye," it is now increasingly understood that corneal nerve damage produced by LASIK surgery resembles the pathologic neuroplasticity associated with other forms of persistent post-operative pain. In susceptible patients, these neuropathological changes, including peripheral sensitization, central sensitization, and altered descending modulation, may underlie certain persistent dry eye symptoms after LASIK surgery. This review will focus on the known epidemiology of symptoms after LASIK and discuss mechanisms of persistent post-op pain due to nerve injury that may be relevant to these patients. Potential preventative and treatment options based on approaches used for other forms of persistent post-op pain and their application to LASIK patients are also discussed. Finally, the concept of genetic susceptibility to post-LASIK ocular surface pain is presented.

Challenges of infectious diseases in the USA.

In the USA, infectious diseases continue to exact a substantial toll on health and health-care resources. Endemic diseases such as chronic hepatitis, HIV, and other sexually transmitted infections affect millions of individuals and widen health disparities. Additional concerns include health-care-associated and foodborne infections--both of which have been targets of broad prevention efforts, with success in some areas, yet major challenges remain. Although substantial progress in reduction of the burden of vaccine-preventable diseases has been made, continued cases and outbreaks of these diseases persist, driven by various contributing factors. Worldwide, emerging and reemerging infections continue to challenge prevention and control strategies while the growing problem of antimicrobial resistance needs urgent action. An important priority for control of infectious disease is to ensure that scientific and technological advances in molecular diagnostics and bioinformatics are well integrated into public health. Broad and diverse partnerships across governments, health care, academia, and industry, and with the public, are essential to effectively reduce the burden of infectious diseases.

Surveillance systems to track progress toward global polio eradication - worldwide, 2012-2013.

In 2012, the World Health Assembly of the World Health Organization (WHO) declared completion of polio eradication a programmatic emergency. Polio cases are detected through surveillance of acute flaccid paralysis (AFP) cases and subsequent testing of stool specimens for polioviruses (PVs) at WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN). AFP surveillance is supplemented by environmental surveillance, testing sewage samples from selected sites for PVs. Virologic surveillance, including genomic sequencing to identify isolates by genotype and measure divergence between isolates, guides Global Polio Eradication Initiative (GPEI) activities by confirming the presence of PV, tracking chains of PV transmission, and highlighting gaps in AFP surveillance quality. This report provides AFP surveillance quality indicators at national and subnational levels during 2012-2013 for countries that experienced PV cases during 2009-2013 in the WHO African Region (AFR) and Eastern Mediterranean Region (EMR), the remaining polio-endemic regions. It also summarizes the results of environmental surveillance and reviews indicators assessing the timeliness of reporting of PV isolation and of virus strain characterization globally. Regional-level performance indicators for timely reporting of PV isolation were met in five of six WHO regions in 2012 and 2013. Of 30 AFR and EMR countries that experienced cases of PV (wild poliovirus [WPV], circulating vaccine-derived poliovirus [cVDPV], or both) during 2009-2013, national performance indicator targets for AFP surveillance and collection of adequate specimens were met in 27 (90%) countries in 2012 and 22 (73%) in 2013. In 17 (57%) countries, ≥80% of the population lived in subnational areas meeting both AFP performance indicators in 2012, decreasing to 13 (43%) in 2013. To achieve polio eradication and certify interruption of PV transmission, intensive efforts to strengthen and maintain AFP surveillance are needed at subnational levels, including in field investigation and prompt collection of specimens, particularly in countries with current or recent active PV transmission.