Dexamethasone Intracanalicular Insert for Clinically Significant Aqueous-Deficient Dry Eye: A Randomized Controlled Trial.

PURPOSE: To evaluate a commercially available dexamethasone intracanalicular insert to treat dry eye. DESIGN: Single-center, double-masked randomized controlled trial. PARTICIPANTS: Patients with clinically significant aqueous-deficient dry eye (combined ocular surface staining score, ≥ 3 [0-12]; corneal fluorescein staining score, ≥ 2 [0-6]; and Schirmer's wetting, < 10 mm at 5 minutes in both eyes) with symptoms (dryness, eye discomfort, or visual fatigue, ≥ 30 [0-100]) despite treatment with at least 1 prescription drop and deemed candidates for topical steroid therapy. METHODS: Seventy-five adult patients were enrolled. A 1:1 randomization sequence was used to determine which eye of each patient would receive the treatment (dexamethasone 0.4-mg intracanalicular insert with 30-day elution time) or sham (collagen plug). The fellow eye received the opposite treatment. Patients were masked to treatment assignment. Follow-up visits (at weeks 2, 4, and 6) were performed by a masked investigator. MAIN OUTCOME MEASURES: Dry eye parameters and patient symptoms were used for efficacy, and intraocular pressure (IOP) was used for safety assessment. RESULTS: The severity of dry eye was comparable between the treatment arms (fellow eyes) at baseline. Eyes that received the dexamethasone insert showed significantly less corneal staining at week 4 (mean difference [MD], -0.55; 95% confidence interval [CI], -0.91 to -0.19) and conjunctival staining at week 4 (MD, -0.68; 95% CI, -1.05 to -0.30) and week 6 (MD, -0.34; 95% CI, -0.65 to -0.02). Schirmer's wetting was comparable between the two treatment arms. Although the patients reported less dryness in eyes that received the insert at week 4 (MD, -5.5; 95% CI, -11.4 to 0.4), no statistically significant differences were found in any patient-reported symptoms. At week 4, dexamethasone-treated eyes were more likely to show an IOP increase (by 5-10 mmHg; 9 eyes vs. 1 eye; relative risk, 9.00; 95% CI, 1.14-71.0). All cases of increased IOP were managed with short-term topical ß-blockers and subsided. CONCLUSIONS: The dexamethasone intracanalicular insert may be considered a dropless dual treatment for clinically significant aqueous-deficient dry eye when topical steroid treatment is deemed appropriate. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Utilizing visual symptoms to distinguish dry eye from glaucoma, cataract, and suspect glaucoma patients: a cross-sectional study.

BACKGROUND: The diagnosis of dry eye and other common ophthalmological conditions can be supported using patient reported symptoms, which is increasingly useful in contexts such as telemedicine. We aim to ascertain visual symptoms that differentiate dry eye from cataract, glaucoma, or glaucoma suspects. METHODS: Adults with dry eye, glaucoma, cataract, and suspected glaucoma (controls) completed a questionnaire to rate the frequency and severity of 28 visual symptoms. Univariate, followed by multivariable logistic regression with backward stepwise selection (p < 0.05), determined the individual symptoms and set of symptoms best distinguishing dry eye from each of the other conditions. RESULTS: Mean age of 353 patients (94 glaucoma suspect controls, 79 glaucoma, 84 cataract, and 96 dry eye) was 64.1 years (SD = 14.1); 67% were female and 68% White. Dry eye patients reported more frequent light sensitivity (OR = 15.0, 95% CI = 6.3-35.7) and spots in vision (OR = 2.8, 95% CI = 1.2-6.3) compared to glaucoma suspect controls. Compared to glaucoma patients, dry eye patients experienced more frequent light sensitivity (OR = 9.2, 95% CI = 2.0-41.7), but less frequent poor peripheral vision (OR = 0.2, 95% CI = 0.06-0.7), difference in vision between eyes (OR = 0.09, 95% CI = 0.01-0.7), and missing patches of vision (OR = 0.06, 95% CI = 0.009-0.3). Compared to cataract patients, dry eye patients reported more frequent spots in vision (OR = 4.5, 95% CI = 1.5-13.4) and vision variability across the week (OR = 4.7, 95% CI = 1.2-17.7) and were less likely to report worsening vision (OR = 0.1, 95% CI = 0.03-0.4) and blindness (OR = 0.1, 95% CI = 0.02-0.8). CONCLUSION: Visual symptoms may serve as a complementary tool to distinguish dry eye from various ocular conditions, though the symptoms that best distinguish dry eye differ across comparisons. Differentiating how patients visually perceive common eye diseases may be used in a variety of clinical settings to rule out specific conditions.

Preclinical Proof-of-Concept of a Minimally Invasive Direct Cardiac Compression Device for Pediatric Heart Support.

PURPOSE: For pediatric patients, extracorporeal membrane oxygenation (ECMO) remains the predominant mechanical circulatory support (MCS) modality for heart failure (HF) although survival to discharge rates remain between 50 and 60% for these patients. The device-blood interface and disruption of physiologic hemodynamics are significant contributors to poor outcomes. METHODS: In this study, we evaluate the preclinical feasibility of a minimally invasive, non-blood-contacting pediatric DCC prototype for temporary MCS. Proof-of-concept is demonstrated in vivo in an animal model of HF. Hemodynamic pressures and flows were examined. RESULTS: Minimally invasive deployment on the beating heart was successful without cardiopulmonary bypass or anticoagulation. During HF, device operation resulted in an immediate 43% increase in cardiac output while maintaining pulsatile hemodynamics. Compared to the pre-HF baseline, the device recovered up to 95% of ventricular stroke volume. At the conclusion of the study, the device was easily removed from the beating heart. CONCLUSIONS: This preclinical proof-of-concept study demonstrated the feasibility of a DCC device on a pediatric scale that is minimally invasive and non-blood contacting, with promising hemodynamic support and durability for the initial intended duration of use. The ability of DCC to maintain pulsatile MCS without blood contact represents an opportunity to mitigate the mortality and morbidity observed in non-pulsatile, blood-contacting MCS.

Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (µDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 1013 vector genomes per kilogram (vg/kg), 1 × 1014 vg/kg, and 2 × 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-µDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day -7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; µDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.

Racial and Ethnic Disparities in Dry Eye Diagnosis and Care.

PURPOSE: To investigate health disparities in racial and ethnic minorities with dry eye. METHODS: Medical records were reviewed for demographics, socioeconomic factors, treatments, and objective dry eye parameters. Race/ethnicity was self-reported as delineated by the U.S. Census. The reference group comprised of randomly selected White patients, with number equal to the largest minority group. RESULTS: The study included 465 patients (157 Black, 157 White, 85 Asian, and 66 Hispanic). Compared to White (3.2%) patients, larger proportion of minorities used Medicaid or lacked health insurance (Black 8.3%, P = .054; Asian 10.6%, P = .019; Hispanic 18.2%, P < .001). Black and Hispanic patients had lower estimated median household income than Whites (White $98,472, Black $75,554, P < .001; Asian $105,503, P = .088; Hispanic $86,839, P = .030). Prior to presentation, fewer minority patients received prescription treatments or procedures (White 61.8%; Black 30.6%, P < .001; Asian 43.5%, P = .006; Hispanic 43.9%, P = .014). Although at baseline visit minorities had worse mean conjunctival (White, 1.7; Black 2.2, P = .136, Asian 2.4, P = .022; Hispanic 2.6, P = .005) and corneal staining scores (White, 1.6; Black 2.5, P < .001; Asian 2.3, P = .003; Hispanic 2.4, P = .001), no differences were noted at final visit. CONCLUSION: Minorities presented with worse objective dry eye parameters, and less prior dry eye care. Income and health care access may not fully explain the observed undertreatment at presentation. Differential management by eye care providers and patient attitudes warrant further investigation.

Short-term treatment of golden retriever muscular dystrophy (GRMD) dogs with rAAVrh74.MHCK7.GALGT2 induces muscle glycosylation and utrophin expression but has no significant effect on muscle strength.

We have examined the effects of intravenous (IV) delivery of rAAVrh74.MHCK7.GALGT2 in the golden retriever muscular dystrophy (GRMD) model of Duchenne Muscular Dystrophy (DMD). After baseline testing, GRMD dogs were treated at 3 months of age and reassessed at 6 months. This 3-6 month age range is a period of rapid disease progression, thus offering a relatively short window to establish treatment efficacy. Measures analyzed included muscle AAV transduction, GALGT2 transgene expression, GALGT2-induced glycosylation, muscle pathology, and muscle function. A total of five dogs were treated, 4 at 2x1014vg/kg and one at 6x1014vgkg. The 2x1014vg/kg dose led to transduction of regions of the heart with 1-3 vector genomes (vg) per nucleus, while most skeletal muscles were transduced with 0.25-0.5vg/nucleus. GALGT2-induced glycosylation paralleled levels of myofiber vg transduction, with about 90% of cardiomyocytes having increased glycosylation versus 20-35% of all myofibers across the skeletal muscles tested. Conclusions from phenotypic testing were limited by the small number of dogs. Treated dogs had less pronounced fibrosis and overall lesion severity when compared to control groups, but surprisingly no significant changes in limb muscle function measures. GALGT2-treated skeletal muscle and heart had elevated levels of utrophin protein expression and GALGT2-induced expression of glycosylated α dystroglycan, providing further evidence of a treatment effect. Serum chemistry, hematology, and cardiac function measures were largely unchanged by treatment. Cumulatively, these data show that short-term intravenous treatment of GRMD dogs with rAAVrh74.MHCK7.GALGT2 at high doses can induce muscle glycosylation and utrophin expression and may be safe over a short 3-month interval, but that such treatments had only modest effects on muscle pathology and did not significantly improve muscle strength.

Natural History of Histopathologic Changes in Cardiomyopathy of Golden Retriever Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked inherited myopathy that causes progressive skeletal and cardiac muscle disease. Heart lesions were described in the earliest DMD reports, and cardiomyopathy is now the leading cause of death. However, diagnostics and treatment for cardiomyopathy have lagged behind those for appendicular and respiratory skeletal muscle disease. Most animal model studies have been done in the mdx mouse, which has a relatively mild form of cardiomyopathy. Dogs with the genetically homologous condition, Golden Retriever muscular dystrophy (GRMD), develop progressive cardiomyopathy analogous to that seen in DMD. Previous descriptive studies of GRMD cardiomyopathy have mostly been limited to selective sampling of the hearts from young dogs. METHODS AND RESULTS: We systematically assessed cardiac lesions in 31 GRMD and carrier dogs aged 3 to 76 months and a separate cohort of 2-10-year-old normal hounds. Both semi-quantitative lesion scoring and quantitation of the cross-sectional area of fibrosis distinguished dogs with GRMD disease from normal dogs. The carriers generally had intermediate involvement but had even greater fibrosis than GRMD dogs. Fatty infiltration was the most prominent feature in some older GRMD dogs. Vascular hypertrophy was increased in GRMD dogs and correlated positively with lesion severity. Purkinje fiber vacuolation was also increased but did not correlate with lesion severity. Histopathologic changes correlated with late gadolinium enhancement on cardiac MRI. CONCLUSION: These features are generally compatible with those of DMD and further validate GRMD as a useful model to study cardiomyopathy pathogenesis and treatment. Additionally, the nature of some degenerative lesions suggests that functional hypoxia or non-thrombotic ischemia may contribute to disease progression.

Natural History of Cardiomyopathy in Adult Dogs With Golden Retriever Muscular Dystrophy.

Background Duchenne muscular dystrophy (DMD) is an X-linked disease that causes progressive muscle weakness. Affected boys typically die from respiratory or cardiac failure. Golden retriever muscular dystrophy (GRMD) is genetically homologous with DMD and causes analogous skeletal and cardiac muscle disease. Previous studies have detailed features of GRMD cardiomyopathy in mostly young dogs. Cardiac disease is not well characterized in adult GRMD dogs, and cardiac magnetic resonance (CMR) imaging studies have not been completed. Methods and Results We evaluated echocardiography and CMR in 24 adult GRMD dogs at different ages. Left ventricular systolic and diastolic functions, wall thickness, and myocardial strain were assessed with echocardiography. Features evaluated with CMR included left ventricular function, chamber size, myocardial mass, and late gadolinium enhancement. Our results largely paralleled those of DMD cardiomyopathy. Ejection fraction and fractional shortening correlated well with age, with systolic dysfunction occurring at ≈30 to 45 months. Circumferential strain was more sensitive than ejection fraction in early disease detection. Evidence of left ventricular chamber dilatation provided proof of dilated cardiomyopathy. Late gadolinium enhancement imaging showed DMD-like left ventricular lateral wall lesions and earlier involvement of the anterior septum. Multiple functional indexes were graded objectively and added, with and without late gadolinium enhancement, to give cardiac and cardiomyopathy scores of disease severity. Consistent with DMD, there was parallel skeletal muscle involvement, as tibiotarsal joint flexion torque declined in tandem with cardiac function. Conclusions This study established parallels of progressive cardiomyopathy between dystrophic dogs and boys, further validating GRMD as a model of DMD cardiac disease.

Glucose Metabolism as a Pre-clinical Biomarker for the Golden Retriever Model of Duchenne Muscular Dystrophy.

PURPOSE: Metabolic dysfunction in Duchenne muscular dystrophy (DMD) is characterized by reduced glycolytic and oxidative enzymes, decreased and abnormal mitochondria, decreased ATP, and increased oxidative stress. We analyzed glucose metabolism as a potential disease biomarker in the genetically homologous golden retriever muscular dystrophy (GRMD) dog with molecular, biochemical, and in vivo imaging. PROCEDURES: Pelvic limb skeletal muscle and left ventricle tissue from the heart were analyzed by mRNA profiling, qPCR, western blotting, and immunofluorescence microscopy for the primary glucose transporter (GLUT4). Physiologic glucose handling was measured by fasting glucose tolerance test (GTT), insulin levels, and skeletal and cardiac positron emission tomography/X-ray computed tomography (PET/CT) using the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). RESULTS: MRNA profiles showed decreased GLUT4 in the cranial sartorius (CS), vastus lateralis (VL), and long digital extensor (LDE) of GRMD vs. normal dogs. QPCR confirmed GLUT4 downregulation but increased hexokinase-1. GLUT4 protein levels were not different in the CS, VL, or left ventricle but increased in the LDE of GRMD vs. normal. Microscopy revealed diffuse membrane expression of GLUT4 in GRMD skeletal but not cardiac muscle. GTT showed higher basal glucose and insulin in GRMD but rapid tissue glucose uptake at 5 min post-dextrose injection in GRMD vs. normal/carrier dogs. PET/ CT with [18F]FDG and simultaneous insulin stimulation showed a significant increase (p = 0.03) in mean standard uptake values (SUV) in GRMD skeletal muscle but not pelvic fat at 5 min post-[18F]FDG /insulin injection. Conversely, mean cardiac SUV was lower in GRMD than carrier/normal (p < 0.01). CONCLUSIONS: Altered glucose metabolism in skeletal and cardiac muscle of GRMD dogs can be monitored with molecular, biochemical, and in vivo imaging studies and potentially utilized as a biomarker for disease progression and therapeutic response.

Suspected acute myocardial infarction in a dystrophin-deficient dog.

Golden retriever muscular dystrophy (GRMD) is a model for the genetically homologous human disease, Duchenne muscular dystrophy (DMD). Unlike the mildly affected mdx mouse, GRMD recapitulates the severe DMD phenotype. In addition to skeletal muscle involvement, DMD boys develop cardiomyopathy. While the cardiomyopathy of DMD is typically slowly progressive, rare early episodes of acute cardiac decompensation, compatible with myocardial infarction, have been described. We report here a 7-month-old GRMD dog with an apparent analogous episode of myocardial infarction. The dog presented with acute signs of cardiac disease, including tachyarrhythmia, supraventricular premature complexes, and femoral pulse deficits. Serum cardiac biomarkers, cardiac-specific troponin I (cTnI) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), were markedly increased. Echocardiography showed areas of hyperechoic myocardial enhancement, typical of GRMD cardiomyopathy. Left ventricular dyskinesis and elevated cTnI were suggestive of acute myocardial damage/infarction. Over a 3-year period, progression to a severe dilated phenotype was observed.

Minimally invasive functional approach for cholesteatoma surgery.

OBJECTIVES/HYPOTHESIS: Report the efficacy of a functional minimally invasive approach for cholesteatoma surgery. STUDY DESIGN: Retrospective review of surgical cases performed between 1996 and 2008. METHODS: One hundred sixty-nine patient charts were reviewed in which ears with primary cholesteatomas that extended beyond the mesotympanum were operated on with a plan for canal wall up (CWU) mastoidectomy. The surgical approach consisted of progressive exposure from transcanal to postauricular tympanoplasty to CWU mastoidectomy, as needed, to identify and lyse the fibrous attachments that bind the capsule to the surrounding mucosa. Endoscopic guidance was employed as appropriate to minimize exposure needs. Any planned second-stage operations were attempted with a transcanal approach if appropriate and with endoscopic assistance. RESULTS: One hundred eighty-four ears of 169 patients were included. The median age was 32 years (range, 1-79 years). The mean follow-up was 3.2 years (range, 1-11 years). Eighty-three (45%) were planned for a second-look operation, and three (2%) required unplanned second operations. The overall recurrence rate was 24/184 (13%), and the unexpected residual rate was 5/184 (3%). The residual rate with endoscopy (5/119, 4%,) or without endoscopy (1/65, 2%), were not significantly different. Hearing results in 156 ears improved significantly, from a preoperative pure-tone average (PTA) of 41 dB to a postoperative PTA average of 29 dB (P < .0001). CONCLUSIONS: A functional minimally invasive approach to cholesteatoma surgery provided equivalent residual rates but higher recurrence rates compared to published canal wall down mastoidectomy. Endoscopic techniques were helpful in providing adequate views while minimizing exposure.

Multicenter ICU Surveillance Study for Nosocomial Infection in Korea / 병원감염관리

Purpose: The purpose of this study is to determine the risk adjusted nosocomial infection (NI) rate and distribution of Nls and their causative pathogens in adult lCU. Methods: Prospective surveillance was performed at 12 lCU's of 5 acute care hospitals in Seoul and Kyonggi Do during a 3-months period from May to July 2002. The case finding was done by direct reviews of medical charts regularly for all patients by ICPs using CDC definitions. Results: Total NI rate was 10.18/1,000 patient-days in Medical-surgical ICU (MSICU) and 12.35/1,000 patient-days in Neurosurgucal ICU(NCI). Risk adjusted infection rate was 3.44 in indwelling catheter associated UTI 2.12 in central line associated BSI. 3.51/1,000 device-days in ventilator associated pneumonia in MSICU. There were 3.72, 2.26, 6.06/1,000 device-days in NCU. The infection rate by leu type showed no significant difference. The distribution of Nls were PNEU (28.99%). UTI (28.99%), BSI (18,84%), SSI(4.35%) in MSICU, and UTI(48.0%), PNEU(24.0%), BSI (14.0%), SSI(6.I) in NCU. The most commonly isolated organisms were Candida spp (38.6%), Enterococcus spp. (13.4%) in UTI, Staphylococcus aureus(36.2%), p. aeruginosa(18.8%) in PNEU and Coagulase negative staphylococcus(44.1%). S. aureus (14.7%) in BSL, S. aureus (19.8%) was the most common organism from overall nosocomial infections in the ICU, and 96.3% of S. aureus were MRSA. Conclusion: Distribution of site-specific nosocomial infection and isolated organisms were similar to the results of KOSNIC (Korea society for nosocomial infection control) surveillance in 1996. However, the total infection rate and a risk adjusted infection rate at MSJCU is lower than 1996's. This decrease is considered to be a result of efforts to prevention and control nosocomial infections.