The Orphan Drug for Acanthamoeba Keratitis (ODAK) Trial: PHMB 0.08% (Polihexanide) and Placebo versus PHMB 0.02% and Propamidine 0.1%

Purpose: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml)+ propamidine 0.1% (1 mg/ml) with PHMB 0.08% (0.8 mg/ml)+ placebo (PHMB 0.08%) for Acanthamoeba keratitis (AK) treatment. Design: Prospective, randomized, double-masked, active-controlled, multicenter phase 3 study (ClinicalTrials.gov identifier, NCT03274895). Participants: One hundred thirty-five patients treated at 6 European centers. Methods: Principal inclusion criteria were 12 years of age or older and in vivo confocal microscopy with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis who were using topical steroids and antiviral and antifungal drugs before randomization. Principal exclusion criteria were concurrent herpes or fungal keratitis and use of antiamebic therapy (AAT). Patients were randomized 1:1 using a computer-generated block size of 4. This was a superiority trial having a predefined noninferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20-percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (MCR; without surgery or change of AAT) within 12 months, cure defined by clinical criteria 90 days after discontinuing anti-inflammatory agents and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes. Main Outcome Measures: The main outcome measure was MCR within 12 months, with secondary outcomes including best-corrected visual acuity and treatment failure rates. Safety outcomes included adverse event rates. Results: One hundred thirty-five participants were randomized, providing 127 in the full-analysis subset (61 receiving PHMB 0.02%+ propamidine and 66 receiving PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR within 12 months was 86.6% (unadjusted, 88.5%) for PHMB 0.02%+ propamidine and 86.7% (unadjusted, 84.9%) for PHMB 0.08%; the noninferiority requirement for PHMB 0.08% was met (adjusted difference, 0.1 percentage points; lower one-sided 95% confidence limit, –8.3 percentage points). Secondary outcomes were similar for both treatments and were not analyzed statistically: median best-corrected visual acuity of 20/20 and an overall treatment failure rate of 17 of 127 patients (13.4%), of whom 8 of 127 patients (6.3%) required therapeutic keratoplasty. No serious drug-related adverse events occurred. Conclusions: PHMB 0.08% monotherapy may be as effective (or at worse only 8 percentage points less effective) as dual therapy with PHMB 0.02%+ propamidine (a widely used therapy) with medical cure rates of more than 86%, when used with the trial treatment delivery protocol in populations with AK with similar disease severity. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Time-trend and variations in the proportion of second-eye cataract surgery

<p>Abstract</p> <p>Background</p> <p>Despite recommendations for greater use of second-eye cataract surgery and the bilateral progression of the disease, there is a substantial proportion of unmet need for this treatment. Few studies have explored the factors associated with second-eye cataract surgery utilisation. The objective of our study was to estimate the proportion of second-eye cataract surgery, evaluate its time-trend, and explore differences in utilisation by patients' gender, age, and region of residence.</p> <p>Methods</p> <p>All senile cataract surgeries performed between 1999 and 2002 in the public health system of Catalonia (Spain) were obtained from the Minimum Data Set. The proportion of second-eye surgery from November 2000 to December 2002 was calculated. The time-trend of this proportion was characterised through linear regression models with the logarithmic transformation of time.</p> <p>Results</p> <p>The proportion of second-eye surgery was 30.0% and showed an increasing trend from 24.8% (95% Confidence Interval [CI] 21.6; 26.1) in November 2000 to 31.8% (95% CI 31.4; 33.6) in December 2002. This proportion was 1.9% (95% CI 0.9; 2.9) higher in women (p < 0.001) and held constant across time. Male patients aged less than 60 had the lowest proportion (22.6%; 95% CI 22.4; 22.9) and females between 70 and 79 had the highest proportion (27.4%; 95% CI 26.9; 27.9). The time-trend for the proportion of second-eye surgery in those aged over 80 years was greater than for younger ages, showing an increase of 9% at the end of the period for both males and females. Variations between regions decreased over time because regions with the lowest initial proportions of second-eye surgery (approximately 17%) showed a greater increase over the study period.</p> <p>Conclusion</p> <p>We predict greater utilization of second-eye surgery in patients aged 70 to 79 years and in women. A greater increase in the utilisation rates of second-eye surgery is expected in the regions with lower proportions and in older patients. The observed trend suggests that there will be a substantial proportion of unmet need for bilateral surgery.</p

A phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults

PMCID: PMC3221299Objectives Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults. Design This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis. Results MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable. Conclusion MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.Wellcome Trust (grant no WT076943MA), TBVAC (an EU 6th Framework programme grant) and The National Institute of Health Research Oxford Biomedical Research Centr

Is the NEI-VFQ-25 a useful tool in identifying visual impairment in an elderly population?

BACKGROUND: The use of self-report questionnaires to substitute for visual acuity measurement has been limited. We examined the association between visual impairment and self reported visual function in a population sample of older people in the UK. METHODS: Cross sectional study of people aged more than 75 years who initially participated in a trial of health screening. The association between 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ) scores and visual impairment (defined as an acuity of less than 6/18 in the better eye) was examined using logistic regression. RESULTS: Visual acuity and NEI-VFQ scores were obtained from 1807 participants (aged 77 to 101 years, 36% male), from 20 general practices throughout the UK. After adjustment for age, gender, practice and NEI-VFQ sub-scale scores, those complaining of poor vision in general were 4.77 times (95% CI 3.03 to 7.53) more likely to be visually impaired compared to those who did not report difficulty. Self-reported limitations with social functioning and dependency on others due to poor vision were also associated with visual impairment (odds ratios, 2.52, 95% CI 1.55 to 4.11; 1.73, 95% CI 1.05 to 2.86 respectively). Those reporting difficulties with near vision and colour vision were more likely to be visually impaired (odds ratios, 2.32, 95% CI 1.30 to 4.15; 2.25, 95% CI 1.35 to 3.73 respectively). Other NEI-VFQ sub-scale scores were unrelated to measures of acuity. Similar but weaker odds ratios were found with reduced visual acuity (defined as less than 6/12 in the better eye). Although differences in NEI-VFQ scores were small, scores were strongly associated with visual acuity, binocular status, and difference in acuity between eyes. CONCLUSION: NEI-VFQ questions regarding the quality of general vision, social functioning, visual dependency, near vision and colour vision are strongly and independently associated with an objective measure of visual impairment in an elderly population

A Novel, Non-Apoptotic Role for Scythe/BAT3: A Functional Switch between the Pro- and Anti-Proliferative Roles of p21 during the Cell Cycle

BACKGROUND: Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis has been extensively studied. However, since the developmental defects observed in Bat3-null mouse embryos cannot be explained solely by defects in apoptosis, we investigated whether BAT3 is also involved in cell-cycle progression. METHODS/PRINCIPAL FINDINGS: Using a stable-inducible Bat3-knockdown cellular system, we demonstrated that reduced BAT3 protein level causes a delay in both G1/S transition and G2/M progression. Concurrent with these changes in cell-cycle progression, we observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21, which is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Our findings indicate that in Bat3-knockdown cells, p21 continues to be synthesized during cell-cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent delay in cell-cycle progression. Finally, we showed that BAT3 co-localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. CONCLUSION: Our study reveals a novel, non-apoptotic role for BAT3 in cell-cycle regulation. By maintaining a low p21 protein level during the G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 to S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation by cyclin A/Cdk2, an event required for G2/M progression. BAT3 modulates these pro- and anti-proliferative roles of p21 at least in part by regulating cyclin A abundance, as well as p21 translocation between the cytoplasm and the nucleus to ensure that it functions in the appropriate intracellular compartment during each phase of the cell cycle.Dissertatio

GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d. It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM. We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice. Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h. Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania