First-in-Human Robot-Assisted Subretinal Drug Delivery Under Local Anesthesia.

PURPOSE: To report the results of a first-in-human study using a robotic device to assist subretinal drug delivery in patients undergoing vitreoretinal surgery for macular hemorrhage. DESIGN: Double-armed, randomized controlled surgical trial (ClinicalTrials.gov identifier: NCT03052881). METHODS: The study was performed at the Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. In total, 12 participants were recruited-6 in the robot-assisted and 6 in the control manual surgery arm according to the prespecified inclusion and exclusion criteria. All subjects presented with acute loss of vision owing to a subfoveal hemorrhage secondary to neovascular age-related macular degeneration. After standard vitrectomy, intraoperative optical coherence tomography-guided subretinal injection of tissue plasminogen activator (TPA) was performed by either robot-assisted or conventional manual technique under local anesthesia. The robotic part of the procedure involved advancement of a cannula through the retina and stabilizing it during foot-controlled injection of up to 100 µL of TPA solution. We assessed surgical success, duration of surgery, adverse events, and tolerability of surgery under local anesthesia. RESULTS: The procedure was well tolerated by all participants and safely performed in all cases. Total duration of surgery, time taken to complete the injection, and retinal microtrauma were similar between the groups and not clinically significant. Subretinal hemorrhage was successfully displaced at 1 month postintervention, except for 1 control subject, and the median gain in visual acuity was similar in both arms. CONCLUSIONS: This first-in-human study demonstrates the feasibility and safety of high-precision robot-assisted subretinal drug delivery as part of the surgical management of submacular hemorrhage, simulating its potential future application in gene or cell therapy.

Pragmatic Use of Catheter-Directed Thrombolysis in Venous Thromboembolism and a Comparative Evaluation With Traditional Therapies in Submassive Pulmonary Embolism.

BACKGROUND: Catheter-directed thrombolysis (CDT) is a novel treatment for venous thromboembolism (VTE). Limited data describe pragmatic use of CDT and compare CDT to other VTE therapies. OBJECTIVE: Assess the use of CDT and comparatively evaluate CDT, anticoagulation, and systemic thrombolysis in submassive pulmonary embolism (PE). METHODS: Retrospective, single-center, chart audit. Part 1 described all patients who received CDT for VTE. Part 2 matched patients with submassive PE who received CDT, heparin, or systemic thrombolysis and assessed length of stay (LOS), bleeding, all cause in-hospital mortality, and escalation of care. RESULTS: For part 1, 70 CDT patients were identified; 42 with DVT and 28 with PE. ICU LOS was longer (2.5 ± 2.9 vs. 4.9 ± 8.4 days, p = 0.07), escalation of care more frequent (0% vs. 35.7%, p < 0.0001), and hospital mortality greater (2.4% vs. 21.4%, p = 0.014) in the PE group. For part 2, 21 CDT patients were matched to 21 heparin and 21 systemic thrombolysis patients. All CDT and tPA patients were admitted to the ICU versus only 6 (28.6%, p < 0.001) heparin patients. ICU LOS was significantly longer in the CDT group versus systemic tPA and systemic anticoagulation (80.7 ± 64.1 vs. 48.2 ± 27.7 vs. 24.9 ± 59.1 hours; p = 0.0048). More IVC filters and thrombectomies were performed in the CDT group. CONCLUSIONS: CDT is frequently used for both DVT and PE and requires ICU admission. Escalation of care is common when CDT is used for PE. For submassive PE, CDT is associated with prolonged ICU LOS compared to heparin or systemic thrombolysis. Resource utilization with CDT requires further evaluation.

Transcorneal Electrical Stimulation for the Treatment of Retinitis Pigmentosa: A Multicenter Safety Study of the OkuStim® System (TESOLA-Study).

BACKGROUND: Transcorneal electrical stimulation (TES) has been suggested as a possible treatment for retinitis pigmentosa (RP). OBJECTIVE: To expand the safety assessment of repeated applications of an electrical current from a DTL-like electrode in patients with RP. METHODS: This single-arm open label interventional safety trial included a total of 105 RP patients from 11 European centers, who received weekly TES for 6 months on 1 eye followed by observation for another 6 months without stimulation. The primary outcome measure was safety, indicated by the frequency and severity of adverse events. Secondary measures included intraocular pressure and central retinal thickness. Visual field and visual acuity were examined using the methods available at each site. RESULTS: Dry eye sensation was the most common adverse event recorded (37.5%). Serious adverse events secondary to TES were not observed. Most adverse events were mild and all resolved without sequelae. The secondary outcome measures revealed no significant or clinically relevant changes. CONCLUSION: The present results confirm the excellent safety profile of TES. Transient dry eye symptoms were the most common adverse event.

Filtration of Short-Wavelength Light Provides Therapeutic Benefit in Retinitis Pigmentosa Caused by a Common Rhodopsin Mutation.

Purpose: The role of light exposure in accelerating retinitis pigmentosa (RP) remains controversial. Faster degeneration has however been observed in the inferior than superior retina in several forms ("sector" RP), including those caused by the rhodopsin P23H mutation, suggesting a modifying role of incident light exposure in such cases. Rearing of equivalent animal models in complete darkness has been shown to slow the degeneration. Here we investigate the use of red filters as a potential treatment strategy, with the hypothesis that minimizing retinal exposure to light <600 nm to which rods are maximally sensitive may provide therapeutic benefit. Methods: Knockin mice heterozygous for the P23H dominant rhodopsin mutation (RhoP23H/+) housed in red-tinted plastic cages were divided at weaning into either untinted or red-tinted cages. Subsequently, photoreceptor layer (PRL) thickness was measured by spectral-domain ocular coherence tomography, retinal function quantified by ERG, and cone morphology determined by immunohistochemical analysis (IHC) of retinal flatmounts. Results: Mice remaining in red-tinted cages had a significantly greater PRL thickness than those housed in untinted cages at all time points. Red housing also led to a highly significant rescue of retinal function as determined by both dark- and light-adapted ERG responses. IHC further revealed a dramatic benefit on cone morphology and number in the red- as compared with the clear-housed group. Conclusions: Limitation of short-wavelength light exposure significantly slows degeneration in the RhoP23H/+ mouse model. Red filters may represent a cost-effective and low-risk treatment for patients with rod-cone dystrophy in whom a sectoral phenotype is noted.

Progress in the development of novel therapies for choroideremia.

INTRODUCTION: There are no currently approved treatments for choroideremia, an X-linked progressive inherited retinal degeneration that leads to blindness by middle age. Several treatment options are being explored, but with major advances in adeno-associated vector (AAV) gene replacement therapy that has reached phase III clinical trials. AREAS COVERED: In this review we discuss new insights into the clinical phenotyping and genetic testing of choroideremia patients, that aid disease characterisation, progression and patient inclusion into clinical trials. Recent advances in in-vitro studies have resulted in the development of functional assays that can be used to confirm the diagnosis in challenging cases and to quantify vector potency for use in clinical trials. We review the progress in current gene therapy trials and some considerations towards gene therapy approval for the treatment of choroideremia. Lastly, we discuss developments in alternative therapies including optogenetics. EXPERT COMMENTARY: AAV gene replacement therapy is the most promising treatment strategy for choroideremia, that has developed exponentially over the last few years with a phase III clinical trial now underway. Optogenetics is a promising alternative strategy that might be applicable in late stages of degeneration.

Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice.

BACKGROUND: Adeno-associated virus serotype 2 (AAV2) vectors show considerable promise for ocular gene transfer. However, one potential barrier to efficacious long-term therapy is the development of immune responses against the vector or transgene product. METHODS: We evaluated cellular and humoral responses in mice following both single and repeated subretinal administration of AAV2, and examined their effects on RPE65 and green fluorescent protein transgene expression. RESULTS: Following subretinal administration of vector, splenocytes and T-cells from draining lymph nodes showed minimal activation following stimulation by co-culture with AAV2. Neutralizing antibodies (NAbs) were not detected in the ocular fluids of any mice receiving AAV2 or in the serum of mice receiving a lower dose. NAbs were present in the serum of a proportion of mice receiving a higher dose of the vector. Furthermore, no differences in immunoglobulin titre in serum or ocular fluids against RPE65 protein or AAV2 capsid between treated and control mice were detected. Histological examination showed no evidence of retinal toxicity or leukocyte infiltration compared to uninjected eyes. Repeat administration of low-dose AAV.hRPE65.hRPE65 to both eyes of RPE65(-/-) mice resulted in transgene expression and functional rescue, but re-administration of high-dose AAV2 resulted in boosted NAb titres and variable transgene expression in the second injected eye. CONCLUSIONS: These data, which were obtained in mice, suggest that, following subretinal injection, immune responses to AAV2 are dose-dependent. Low-dose AAV2 is well tolerated in the eye, with minimal immune responses, and transgene expression after repeat administration of vector is achievable. Higher doses lead to the expression of NAbs that reduce the efficacy of repeated vector administration.

Erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric nutrition in critically ill patients.

BACKGROUND: The purpose of this study is to evaluate erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric enteral nutrition (EN). METHODS: Twenty critically ill patients with a gastric residual >150 mL while receiving EN were randomized to receive 4 intravenous doses of erythromycin 250 mg or metoclopramide 10 mg, each administered every 6 hours. Acetaminophen 975 mg was administered enterally at baseline and after the fourth dose. Acetaminophen peak plasma concentration (Cmax), concentration at 60 minutes (C(60)), time to Cmax (Tmax), and area under the concentration-time curve from 0 to 60 minutes (AUC(0-60)) were determined. Residual volumes and feeding rates were recorded. RESULTS: Compared with baseline, erythromycin increased Cmax (9.5 +/- 6.1 mg/L to 17.7 +/- 11.9 mg/L, P < .01), C(60) (5.4 +/- 3.5 mg/L to 12.9 +/- 7.6 mg/L, P < .01), and AUC(0-60) (3.5 +/- 3.0 mg.h/L to 12.5 +/- 8.7 mg.h/L, P < .01), while metoclopramide increased only AUC(0-60) (4.4 +/- 2.8 mg.h/L to 9.5 +/- 3.8 mg.hr/L, P < .05). Neither agent significantly reduced Tmax. Both erythromycin and metoclopramide reduced residual volumes (122 +/- 48 mL to 36 +/- 48 mL, P < .01, and 103 +/- 88 mL to 21 +/- 23 mL, P < .05, respectively) and allowed increased feeding rates (17 +/- 23 mL/h to 45 +/- 21 mL/h, P < .05, and 14 +/- 17 mL/h to 44 +/- 22 mL/h, P < .05, respectively). CONCLUSIONS: Both agents facilitate tolerance to intragastric EN, but erythromycin may be more effective than metoclopramide for enhancing gastric motility.

Implementing and assessing an evidence-based electrolyte dosing order form in the medical ICU.

UNLABELLED: The purpose of this study was to evaluate the efficacy, safety, and nursing acceptability of a nursing initiated, evidence-based order form to replace potassium, magnesium, and phosphate in the MICU. METHODS: This retrospective study compared patients receiving electrolyte replacement with the order form to matched historical control patients receiving traditional electrolyte replacement (no order form). The primary outcomes were absolute change in serum concentrations and the proportion of doses achieving normal serum concentrations. Other outcomes were adverse events as documented in the medical record and nursing acceptability as assessed by survey. RESULTS: The 2 groups (12 in each group) were similar. The order form and control groups received 36 and 62 potassium doses, 14 and 48 magnesium doses, and 34 and 13 phosphorus doses, respectively. Doses of all three electrolytes were significantly larger with the order form. Absolute changes in potassium, magnesium, and phosphorus serum concentrations for the order form group and control group were 0.36+/-0.42 versus 0.11+/-0.43 mmol/l (p<0.01), 0.56+/-0.69 versus 0.13+/-0.40 mequiv./l (p=0.07), and 0.53+/-0.82 versus 0.66+/-0.83 mg/dl (p=0.63), respectively. Normal serum concentrations achieved for each electrolyte replacement dose in the order form group and control group were 72% versus 18% (p<0.001), 86% versus 21% (p<0.001), and 47% versus 62% (p=0.57), respectively. No adverse events occurred. The nursing survey showed satisfaction and comfort using the order form. CONCLUSIONS: The use of the order form provided greater efficiency for replacing potassium and magnesium but not phosphorus without increasing the occurrence of adverse events. The order form was well received by nursing staff.

Enteral glutamine supplementation in critically ill patients with burn injuries: a retrospective case-control evaluation.

STUDY OBJECTIVES: To evaluate the clinical application of enteral glutamine supplementation in critically ill patients and compare the frequency of nosocomial infections in these patients with a historical control group in a burn intensive care unit (BICU), and to assess lengths of stay in the hospital and BICU, mortality rates, and safety profile of glutamine. DESIGN: Retrospective case-control descriptive study. SETTING: A university-affiliated hospital BICU. PATIENTS: Seventeen patients receiving enteral glutamine supplementation and 15 historical control patients who were admitted to the BICU for thermal burn injuries from January 1, 2001-September 30, 2004. MEASUREMENTS AND MAIN RESULTS: Data for patients receiving enteral glutamine supplementation were identified through the pharmacy database, and data for the control patients were identified through the BICU patient registry. No significant differences were noted in baseline characteristics or nutritional parameters and outcomes between the two groups. The mean daily dose and duration of glutamine were 0.52 g/kg and 21.6 days, respectively. The mean number of infections/patient between the glutamine and control groups was similar (2.47 and 2.73, respectively) as was the number of gram-negative infections (1.29 and 1.20, respectively). Bloodstream infections occurred more frequently in the glutamine group (24 vs 8 patients, p=0.0006); however, cellulitis (4 vs 11, p=0.05) and pneumonia (9 vs 15, p=0.15) occurred less often. For the glutamine group versus control group, BICU length of stay (17.9 vs 15.3 days, p=NS), hospital length of stay (32.3 vs 26 days, p=NS), and mortality rates (0% vs 6.7%, p=NS) were similar between groups. No adverse events were attributed to glutamine supplementation. CONCLUSION: Enteral glutamine supplementation was not associated with a change in the cumulative rate of infectious complications compared with the control group, but this was attributed to more cases of bloodstream infections and fewer cases of pneumonia and cellulitis in the glutamine group. Large, prospective, randomized trials designed to detect small but clinically relevant outcomes are needed to definitively determine the effect of enteral glutamine supplementation in the BICU population.