Injectable Fluocinolone Acetonide Long-Acting Implant for Noninfectious Intermediate Uveitis, Posterior Uveitis, and Panuveitis: Two-Year Results.

PURPOSE: To determine the effect of an injectable fluocinolone acetonide implant (FAi) in eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN: Noncomparative, interventional, dose-randomized, dose-masked, prospective, individual, investigator-sponsored investigational new drug study. PARTICIPANTS: Eleven eyes of 11 participants with a history of recurrent noninfectious intermediate uveitis, posterior, or panuveitis. METHODS: Participants were randomized to receive either a low- or a high-dose FAi. Eyes were observed on day 0 (day the implant was injected) and then at regular intervals through 2 years. MAIN OUTCOME MEASURES: Ocular inflammation, visual acuity, anti-inflammatory medication use, and safety parameters before and after FAi implantation. RESULTS: All participants were followed up for 2 years. At baseline, mean study eye visual acuity was 0.56 logarithm of the minimum angle of resolution (logMAR; standard deviation [SD], 0.43 logMAR). These values improved significantly to +0.25 logMAR (SD, 0.14 logMAR) and +0.17 logMAR (SD, 0.14 logMAR) at 12 and 24 months after implantation, respectively (P = 0.041 and P = 0.016, respectively). The average number of inflammation recurrences in the 12 months before implantation was 1.54 episodes per eye. None of the study eyes experienced a recurrence during the follow-up period. Of the 6 participants who continued receiving systemic medication after implantation, the dosage was reduced in 4 participants. Five of 11 eyes received an average of 1.6 posterior sub-Tenon triamcinolone acetonide (PSTA) injections in the 12 months preceding implantation. None required a PSTA injection after FAi implantation. The most common adverse event was intraocular pressure (IOP) rise. At baseline, 1 study eye (9%) required pressure-lowering drops; 2 additional study eyes (18%) required them during the follow-up period. Filtering procedures were performed in 2 of these eyes (18.1%). No FAi explantations were required, nor were any participants lost to follow-up during the investigation. CONCLUSIONS: It is feasible to place a long-acting FAi in an outpatient setting, without prolonged adverse events attributed to the implant injection procedure. The FAi effectively controlled intraocular inflammation in all eyes in the study, and at the last follow-up, all implanted eyes demonstrated an improvement in visual acuity. Elevated IOP that occurred in 18% of FAi-implanted eyes was managed by standard means. The FAi implant is a promising approach for patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis who do not respond to, or are intolerant to, conventional therapy.

Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema.

PURPOSE: To present the safety and efficacy of intravitreal implants releasing 0.2 µg/day fluocinolone acetonide (FAc) in patients with chronic versus nonchronic diabetic macular edema (DME). To assess ocular characteristics, anatomic changes, and re-treatment and ancillary therapies that may explain the differential treatment effect seen with intravitreal implants releasing FAc 0.2 µg/day in patients with chronic and nonchronic DME. An overall benefit-to-risk assessment for the FAc 0.2-µg/day and FAc 0.5-µg/day doses has been reported previously. DESIGN: Preplanned subgroup analysis of chronic (duration of diagnosis, ≥3 years) and nonchronic (duration of diagnosis, <3 years) DME in patients from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Patients with persistent DME despite 1 or more macular laser treatment were randomized 1:2:2 to sham injection (n = 185), FAc 0.2 µg/day (n = 375), or FAc 0.5 µg/day (n = 393). METHODS: Patients received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on re-treatment criteria, additional masked study drug could be given after 1 year. MAIN OUTCOME MEASURES: Percentage of patients with improvement of 15 letters or more from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS: At month 36, the difference between FAc 0.2 µg/day and sham control in the percentage of patients who gained 15 letters or more was significantly greater in chronic DME patients (FAc 0.2 µg/day, 34.0% vs. sham, 13.4%; P<0.001), compared with patients with nonchronic DME (FAc 0.2 µg/day, 22.3% vs. sham, 27.8%; P = 0.275). The greater response in patients with chronic DME was not associated with baseline ocular characteristics, changes in anatomic features, or differences in re-treatment or ancillary therapies. The ocular adverse event profile for FAc 0.2 µg/day was similar regardless of DME duration. CONCLUSIONS: This is the first published analysis correlating duration of diagnosis of DME with treatment effect. In patients with chronic DME, FAc 0.2 µg/day provides substantial visual benefit for up to 3 years and would provide an option for patients who do not respond to other therapy.

Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial.

PURPOSE: We studied the 3-year efficacy and safety results of a 4-year study evaluating fluocinolone acetonide (FA) intravitreal implants in eyes with persistent or recurrent diabetic macular edema (DME). DESIGN: Prospective, evaluator-masked, controlled, multicenter clinical trial. PARTICIPANTS: We included 196 eyes with refractory DME. METHODS: Patients were randomized 2:1 to receive 0.59-mg FA implant (n = 127) or standard of care (SOC additional laser or observation; n = 69). The implant was inserted through a pars plana incision. Visits were scheduled on day 2, weeks 1, 3, 6, 12, and 26, and thereafter every 13 weeks through 3 years postimplantation. MAIN OUTCOME MEASURES: The primary efficacy outcome was ≥15-letter improvement in visual acuity (VA) at 6 months. Secondary outcomes included resolution of macular retinal thickening and Diabetic Retinopathy Severity Score (DRSS). Safety measures included incidence of adverse events (AEs). RESULTS: Overall, VA improved ≥3 lines in 16.8% of implanted eyes at 6 months (P=0.0012; SOC, 1.4%); in 16.4% at 1 year (P=0.1191; SOC, 8.1%); in 31.8% at 2 years (P=0.0016; SOC, 9.3%); and in 31.1% at 3 years (P=0.1566; SOC, 20.0%). The number of implanted eyes with no evidence of retinal thickening at the center of the macula was higher than SOC eyes at 6 months (P<0.0001), 1 year (P<0.0001; 72% vs 22%), 2 years (P=0.016), and 3 years (P=0.861). A higher rate of improvement and lower rate of decline in DRSS occurred in the implanted group versus the SOC group at 6 months (P=0.0006), 1 year (P=0.0016), 2 years (P=0.012), and 3 years (P=0.0207). Intraocular pressure (IOP) ≥30 mmHg was recorded in 61.4% of implanted eyes (SOC, 5.8%) at any time and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% (SOC, 20%) had cataract extraction by 4 years. CONCLUSIONS: The FA intravitreal implant met the primary and secondary outcomes, with significantly improved VA and DRSS and reduced DME. The most common AEs included cataract progression and elevated IOP. The 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Persons with acquired profound hearing loss (APHL): how do they and their families adapt to the challenge?

The study examined the impact of acquired profound hearing loss (APHL) on the relationship between the hearing impaired person and their normally hearing close family member, usually a partner, and identified the kinds of adjustment leading to maintenance or deterioration of the relationship. The participants were 25 people with APHL and 25 family members, interviewed separately in their own home. Analysis of the interview transcripts adopted a grounded theory methodology. The different levels of analysis were linked in terms of a core category based on the social construction of a committed relationship. The conceptual codes were grouped as: (a) aural impairments giving rise to the need for adjustment; (b) pragmatic adjustments to spoken communication and family activities; (c) managing the adjustments without negative consequences; (d) adjustments leading to negative interaction. The results suggest that APHL places considerable strain on relationships and increases their vulnerability to failure, consistent with previous research. They highlight the need for professional support and suggest that a systemic conceptual framework is needed that includes the public response to profound hearing impairment.

Efficacy of low-release-rate fluocinolone acetonide intravitreal implants to treat experimental uveitis.

OBJECTIVE: To determine the efficacy of 0.5-mg and 0.1-mg sustained-release fluocinolone acetonide intravitreal implants to inhibit ocular inflammation in a rabbit model of severe uveitis. METHODS: The in vitro pharmacokinetic profile of both the 0.5-mg and 0.1-mg sustained-release fluocinolone intravitreal implants was determined during a 10-day period. A sustained-release fluocinolone acetonide intravitreal implant with a release rate of either 0.5 microg/d (n = 16) or 0.1 microg/d (n = 16) was implanted into the vitreous cavity of the right eye in albino rabbits after a subcutaneous injection of tuberculin antigen. Control animals (n = 14) received empty devices. Uveitis was induced with an intravitreal tuberculin antigen injection. A masked observer graded anterior chamber flare, anterior chamber cells, vitreous opacity, and inflammation on histologic sections. RESULTS: In vitro, the drug was released from both devices in a linear manner. In vivo, treated eyes were significantly less inflamed than untreated eyes (P< or =.02). Inflammation was suppressed to a greater degree with the 0.5-microg/d implant compared with the 0.1-microg/d implant. CONCLUSION: Sustained-release fluocinolone intravitreal implants suppress ocular inflammation in a rabbit model of severe uveitis. CLINICAL RELEVANCE: The efficacy demonstrated with the 0.1-microg/d implant provides the rationale for future human studies with lower-release-rate implants than are currently used in noninfectious uveitis clinical trials.

The effect of link nurses on hospital readmission rates.

This study investigates whether visits to a patient early post-discharge by a member of the ward team (locality link nurse) reduces psychiatric hospital readmission rates for older people and improves the physical and psychological state of the patient. This is a summary of the paper the full version can be accessed at nursingtimes.net.

Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis.

PURPOSE: To investigate the safety and efficacy of a fluocinolone acetonide intravitreal implant in the treatment of noninfectious posterior uveitis. DESIGN: Noncomparative interventional case series, dose randomized, dose masked, prospective. PARTICIPANTS: Thirty-six eyes of 32 patients with a history of recurrent noninfectious posterior uveitis. METHODS: Patients were randomized to receive either a 0.59-mg or a 2.1-mg fluocinolone acetonide intravitreal implant. Patients were observed every 4 to 6 weeks for the first 3 months and then every 3 months thereafter. MAIN OUTCOME MEASURES: Preoperative and postoperative ocular inflammation, visual acuity (VA), antiinflammatory medication use, and safety. RESULTS: Mean follow-up duration was 683+/-461 days (range, 204-1817). Mean baseline visual acuity for the device-implanted eyes was +1.1 logarithm of the minimum angle of resolution (logMAR) units (20/250), which improved significantly to +0.81 logMAR units (20/125) at 30 months (P<0.05). Inflammation was effectively controlled over the follow-up period. The average number of recurrences in the 12 months before implantation was 2.5 episodes per eye. None of these eyes experienced a recurrence for the first 2 years after implantation. There was a reduction in systemic and local therapy use in the device-implanted eyes; of the patients who remained on systemic medication after implantation, dosage was reduced in 68%. The posterior sub-Tenon's capsule injection rate significantly decreased from a mean of 2.2 injections per eye per year to 0.07 injections per eye per year (P<0.0001) The most common adverse event was intraocular pressure (IOP) rise. At baseline, 11.0% of eyes used pressure-lowering agents, versus 56.1% over the follow-up period (P = 0.005). Filtering procedures were performed in 7 (19.4%) eyes. Four of the 8 phakic eyes, each of which had some level of cataract at device implantation, subsequently underwent cataract extraction. There were no device explantations or patients lost to follow-up during the investigation. CONCLUSION: The fluocinolone acetonide intravitreal implant effectively controlled intraocular inflammation in the studied population. Elevated IOP and cataracts that occurred in fluocinolone device-implanted eyes were managed by standard means. The fluocinolone acetonide sustained drug delivery implant seems to be promising in patients with posterior uveitis who do not respond to or are intolerant to conventional treatment.

"This villa life": town planning, suburbs and the "new social order" in early twentieth-century Sydney.

In Australia, social reformers approached the new century and post-First World War reconstruction with the hope of establishing a "new social order" based on national efficiency and class harmony. This was to be delivered through the new science of town planning. The would-be reformers posited themselves as an intellectual vanguard which would provide leadership and assist in establishing an enlightened bureaucracy of professional public servants who would also lead the way to social betterment. Their project, however, had collapsed by the end of the war. Lacking collective political clout, the nascent planning professionals' influence declined as the political environment became more conservative in the 1920s. Reformist and radical features of town planning were stripped from suburban agendas. Suburbs, once held up as the cradle of the 'new social order', were to become places for quarantining class and reinvigorating liberalism.

Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats.

PURPOSE: To study the neuroprotective properties of low-dose, sustained-release intravitreous fluocinolone acetonide (FA) in transgenic S334ter-4 rats. METHODS: S334ter-4 rats aged 4 weeks were divided into four groups: 0.5 microg/d FA-loaded intravitreous drug delivery implant (IDDI); 0.2 microg/d FA-loaded IDDI; inactive IDDI; and unoperated controls. Electroretinography (ERG) was performed before surgery and every 2 weeks after surgery for 8 weeks. When the rats were 12 weeks of age, outer nuclear layer (ONL) and inner nuclear layer (INL) thicknesses were measured. Microglial cell counts were obtained from retinal wholemounts labeled for Iba-1. RESULTS: At the end of the study, unoperated and inactive IDDI-implanted rats demonstrated 50% to 60% reductions in ERG amplitudes compared with those recorded at 4 weeks (P < 0.001 for both groups). FA 0.2-microg/d animals demonstrated 15% amplitude attenuation, while FA 0.5-microg/d animals showed 30% reduction. ONL thickness in FA 0.2-microg/d-treated eyes was 25.8% +/- 2.3% higher than in control group eyes (P < 0.001) and 30.0% +/- 2.1% higher than in inactive IDDI-implanted eyes (P < 0.001). In FA 0.5-microg/d-treated eyes, ONL thickness was 22.4% +/- 2.8% higher than in control group eyes (P < 0.001) and 22.3% +/- 3.7% higher than in inactive IDDI-implanted eyes (P < 0.01). No statistically significant difference was observed between the two control groups. No statistically significant difference between the two FA-treated groups was found. FA-treated groups demonstrated significantly fewer activated microglial cells than control groups. CONCLUSIONS: Chronic intravitreous infusion of FA preserves ONL cell morphology and ERG a- and b-wave amplitudes and reduces retinal neuroinflammation in S334ter rats. Based on these findings, the synthetic corticosteroid FA may promise a therapeutic role in patients with retinal degeneration.

Fluocinolone inhibits VEGF expression via glucocorticoid receptor in human retinal pigment epithelial (ARPE-19) cells and TNF-alpha-induced angiogenesis in chick chorioallantoic membrane (CAM).

PURPOSE: The purpose of this study was to determine whether fluocinolone inhibits vascular endothelial growth factor (VEGF) expression in a retinal pigment epithelial cell line (ARPE-19) and TNF-alpha-induced angiogenesis in chick chorioallantoic membrane (CAM) assay. METHODS: The dose-dependent effect of fluocinolone (0.0001-1 microM) on VEGF secretion, VEGF mRNA expression, and cytotoxicity was determined in confluent monolayers of ARPE-19 cells using ELISA, RT-PCR, and MTT assay, respectively. The effect of a glucocorticoid receptor antagonist (RU486) on fluocinolone-mediated VEGF expression was determined. The effect of fluocinolone in inhibiting TNF-alpha-induced angiogenesis was determined using chick chorioallantoic membrane (CAM) assay. The dose-dependent effect of fluocinolone (0.0001-1 microM) in inhibiting 1% serum-stimulated ARPE-19 cell proliferation was determined using BrdU labeling assay. RESULTS: At concentrations devoid of cytotoxicity, fluocinolone inhibited VEGF secretion as well as mRNA expression in ARPE-19 cells. RU486 (1 microM) treatment prevented inhibition of VEGF secretion and VEGF mRNA expression by fluocinolone (0.1 microM). Fluocinolone (50 ng/egg) inhibited angiogenesis induced by TNF-alpha. The ARPE-19 cell proliferation was inhibited by fluocinolone in a dose-dependent manner. CONCLUSIONS: Fluocinolone inhibited VEGF expression in ARPE-19 cells via its glucocorticoid receptor activity. In addition, fluocinolone inhibited proliferation of ARPE-19 cells and TNF-alpha-induced angiogenesis in chorioallantoic membranes.

Photoreceptor neuroprotection in RCS rats via low-dose intravitreal sustained-delivery of fluocinolone acetonide.

PURPOSE: To study the neuroprotective effects of intravitreal fluocinolone acetonide (FA) in Royal College of Surgeons (RCS) rats. METHODS: Five-week-old RCS rats were divided into four groups: 0.5 microg/d FA-loaded intravitreal drug-delivery implant (IDDI); 0.2 microg/d FA-loaded IDDI; inactive IDDI; and nonsurgical control. Electroretinography (ERG) and intraocular pressure (IOP) measurements were performed before surgery and weekly thereafter. Thicknesses of the retinal outer (ONL) and inner (INL) nuclear layers were evaluated at 9 weeks of age. ED-1-labeled activated microglia were counted. Total microglial cell counts were made by using Iba-1 antibody labeling. RESULTS: At 9 weeks, control groups demonstrated an 80% reduction in ERG amplitudes (P < 0.001 for both groups). FA-treated groups demonstrated no statistically significant attenuation of ERG amplitudes at the end of the study, compared with the initial ERGs. Intraocular pressure (IOP) remained normal in all groups. ONL thickness in FA 0.2 microg/d-treated eyes was 2.1 +/- 0.5 times greater than in nonsurgical eyes (P < 0.001) and 3.4 +/- 0.7 times greater than in inactive IDDI-treated eyes (P < 0.0001). In FA 0.5 microg/d-treated eyes, ONL thickness was 1.5 +/- 0.1 times higher than in nonsurgical controls (P < 0.05) and 2.4 +/- 0.4 times higher than in inactive IDDI-treated eyes (P < 0.01). INL thickness was not different among groups. FA-treated eyes demonstrated significantly fewer activated microglia (P < 0.001) and overall number of microglia in the photoreceptor and outer debris zone layers (P < 0.001), compared with control groups. CONCLUSIONS: Chronic intravitreal infusion of FA is neuroprotective in RCS rats, preserves ONL morphology and ERG amplitudes and reduces retinal neuroinflammation. These findings may have a therapeutic role in human photoreceptor cell degenerations.

Acquired profound hearing loss: mental health and other characteristics of a large sample.

The study investigated the mental health and other characteristics of people with acquired profound hearing loss (APHL) and contrasted this group with acquired hearing loss (AHL) in general. A survey was completed over the internet by 95 adults and by 27 people who had attended a one-week course of rehabilitation. The latter group completed questionnaires of anxiety and depression, post-traumatic stress, and hearing handicap. The survey covered a wide range of factors associated with the history of hearing loss and evaluated previous contacts with professional services. The data from the two samples were very similar and were combined. The results indicated the existence of sudden and progressive onset groups, reliance on lip-reading, a severe effect of tinnitus, and some support for the conclusion that the psychosocial impact was greater in APHL than in AHL. A subgroup of APHL was severely distressed and handicapped. Respondents valued medical and audiological services but there was little evidence that previous counselling and support had been helpful. Recommendations for rehabilitation are briefly discussed.

Novel antiglaucoma prodrugs and codrugs of ethacrynic acid.

The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.

A phase I trial of continuously infused intratumoral bleomycin for the treatment of recurrent glioblastoma multiforme.

Intratumoral (IT) chemotherapy has theoretical advantages in the treatment of brain tumors. The blood-brain barrier is not a factor in drug delivery, and large concentrations of drug can be instilled in the tumor with little systemic toxicity. Bleomycin has activity against gliomas and is a cell cycle selective agent whose efficacy should be enhanced by continuous infusion. We performed a phase I trial to test the feasibility of IT chemotherapy using a refillable, sustained release device, and to determine the maximum tolerable dose of IT bleomycin. The study was an open-ended dose escalation study. A modified Ommaya reservoir (containing a semipermeable membrane) was implanted with the delivery tube in the center of the tumor. Groups of three patients with recurrent glioblastoma multiforme were entered at progressively higher dose levels of bleomycin. The study closed when all patients at a given starting dose level developed toxicity. Nine patients received doses ranging from 5 to 34 U/wk; the median total cumulative dose was 195 U. No dose limiting systemic toxicity was detected. Neurologic toxicity occurred only at doses above 16 U/wk. We conclude that continuously infused IT bleomycin is well tolerated; the MTD (and recommended dose for a phase II efficacy trial) of IT bleomycin is 16 U/wk.