A comfort comparison of travoprost BAK-free 0.004% versus latanoprost 0.005% in patients with primary open-angle glaucoma or ocular hypertension

David A Godfrey1, Lee S Peplinski2, Jeanette A Stewart3, William C Stewart31Glaucoma Associates of Texas, Dallas, TX, USA; 2Kentuckiana Institute for Eye Research, Louisville, KY, USA; 3PRN Pharmaceutical Research Network, LLC, Dallas, TX, USAPurpose: To determine the short-term comfort after a single dose of travoprost BAK-free compared to latanoprost in primary open-angle glaucoma or ocular hypertensive patients.Design: Prospective, double-masked, randomized comparison of two separate active agents dosed once in opposite eyes.Methods: At Visit 1, qualified patients began a glaucoma medicine-free period for three days. At Visit 2, patients were randomly assigned to travoprost BAK-free or latanoprost in opposite eyes. Following dosing in each eye, patients completed a visual analog scale (VAS score, 0–100 mm) at specified time intervals and a comfort survey.Results: In 54 completed subjects, no difference existed five seconds after dosing, in comfort on the VAS between latanoprost (7.1 ± 16.2 mm) and travoprost BAK-free (7.8 ± 16.1 mm, P = 0.53). Also no differences existed between treatments following dosing for discomfort at individual timepoints past five seconds, peak discomfort or the time required to return to baseline comfort (P > 0.05). In addition, the comfort survey demonstrated no difference between products for burning, stinging, foreign body sensation, overall comfort and general acceptance between the products, both for absolute levels and changes from baseline (P > 0.05).Conclusion: Following a single instillation, both latanoprost and travoprost BAK-free exhibit similar comfort scores.Keywords: comfort, travoprost BAK-free, latanoprost, glaucoma, ocular hypertensio

Efficacy, safety, and tolerability of travoprost 0.004% BAK-free versus prior treatment with latanoprost 0.005% in Japanese patients

Michael J Miyashiro1, Samuel C Lo2, Jeanette A Stewart3, William C Stewart31Ludwig Ophthalmology Centre, Hilo, HI, USA; 2Private Practice, Honolulu, HI, USA; 3PRN Pharmaceutical Research Network, LLC, Dallas, TX, USAObjective: To examine the efficacy, safety, and tolerability of travoprost 0.004% benzalkonium chloride (BAK)-free compared with previous use of latanoprost 0.005% in Japanese patients living in the US who had primary open-angle glaucoma or ocular hypertension.Methods: This was an open-label, multicenter, bilateral, intraindividual, and active-controlled study in which 20 Japanese American patients with primary open-angle glaucoma or ocular hypertension who had been on latanoprost 0.005% monotherapy were changed to monotherapy with travoprost 0.004% BAK-free daily for 12 weeks. Patients were administered the same series of tests to evaluate the efficacy, safety, and tolerability of latanoprost at the baseline visit and of travoprost BAK-free at the week 12 visit.Results: No significant difference in mean intraocular pressure (IOP) was observed between latanoprost monotherapy at baseline and travoprost BAK-free monotherapy after 12 weeks (P = 0.76), nor were significant differences noted in mean ocular hyperemia, visual acuity, corneal fluorescein staining, or overall scores from the Ocular Surface Disease Index. Patients had a significantly shorter mean tear breakup time while on latanoprost compared with travoprost BAK-free (P = 0.0094). Significantly more patients preferred travoprost BAK-free monotherapy over latanoprost monotherapy (14 versus 6; P = 0.011).Conclusion: The results of this study suggest that Japanese American patients transitioned from latanoprost 0.005% monotherapy to travoprost 0.004% BAK-free can expect similar IOP control and some improvement in anterior segment signs. This transition study showed a strong patient preference for travoprost BAK-free over latanoprost, at a ratio of more than 2:1.Keywords: glaucoma, intraocular pressure, latanoprost, prostaglandin analog, travopros

Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared with prior prostaglandin therapy

J Charles Henry1, James H Peace2, Jeanette A Stewart3,4, William C Stewart3,41Little Rock Eye Clinic, Little Rock, AR, USA; 2Diabetic Eye Medical Clinic, Inglewood, CA, USA; 3PRN Pharmaceutical Research Network, LLC, Dallas,TX, USA; 4Carolina Eye Institute, University of South Carolina, School of Medicine, Columbia, SC, USAPurpose: To evaluate the efficacy, safety and tolerability of changing to travoprost BAK-free from prior prostaglandin therapy in patients with primary open-angle glaucoma or ocular hypertension.Design: Prospective, multi-center, historical control study.Methods: Patients treated with latanoprost or bimatoprost who needed alternative therapy due to tolerability issues were enrolled. Patients were surveyed using the Ocular Surface Disease Index (OSDI) to evaluate OSD symptoms prior to changing to travoprost BAK-free dosed once every evening. Patients were re-evaluated 3 months later.Results: In 691 patients, travoprost BAK-free demonstrated improved mean OSDI scores compared to either latanoprost or bimatoprost (p < 0.0001). Patients having any baseline OSD symptoms (n = 235) demonstrated significant improvement after switching to travoprost BAK-free (p < 0.0001). In 70.2% of these patients, symptoms were reduced in severity by at least 1 level. After changing medications to travoprost BAK-free, mean intraocular pressure (IOP) was significantly decreased (p < 0.0001). Overall, 72.4% preferred travoprost BAK-free (p < 0.0001, travoprost BAK-free vs prior therapy). Travoprost BAK-free demonstrated less conjunctival hyperemia than either prior therapy (p < 0.0001).Conclusions: Patients previously treated with a BAK-preserved prostaglandin analog who are changed to travoprost BAK-free have clinically and statistically significant improvement in their OSD symptoms, decreased hyperemia, and equal or better IOP control.Keywords: glaucoma, prostaglandin analog, travoprost, latanoprost, bimatoprost, preservative, benzalkonium chloride, ocular surface diseas

Phage annealing proteins promote oligonucleotide-directed mutagenesis in Escherichia coli and mouse ES cells

BACKGROUND: The phage protein pairs, RecE/RecT from Rac or Redα/Redβ from λ, initiate efficient double strand break repair (DSBR) in Escherichia coli that has proven very useful for DNA engineering. These phage pairs initiate DSBR either by annealing or by another mechanism that is not defined. RESULTS: Here we report that these proteins also mediate single strand oligonucleotide repair (ssOR) at high efficiencies. The ssOR activity, unlike DSBR, does not require a phage exonuclease (RecE or Redα) but only requires a phage annealing protein (RecT or Redβ). Notably, the P22 phage annealing protein Erf, which does not mediate the same DSBR reactions, also delivers ssOR activity. By altering aspects of the oligonucleotides, we document length and design parameters that affect ssOR efficiency to show a simple relationship to homologies either side of the repair site. Notably, ssOR shows strand bias. Oligonucleotides that can prime lagging strand replication deliver more ssOR than their leading complements. This suggests a model in which the annealing proteins hybridize the oligonucleotides to single stranded regions near the replication fork. We also show that ssOR is a highly efficient way to engineer BACs and can be detected in a eukaryotic cell upon expression of a phage annealing protein. CONCLUSION: Phage annealing proteins can initiate the recombination of single stranded oligonucleotides into endogenous targets in Escherichia coli at very high efficiencies. This expands the repertoire of useful DNA engineering strategies, shows promise for applications in eukaryotic cells, and has implications for the unanswered questions regarding DSBR mediated by RecE/RecT and Redα/Redβ

A new measure of patient satisfaction with ocular hypotensive medications: The Treatment Satisfaction Survey for Intraocular Pressure (TSS-IOP)

PURPOSE: To validate the treatment-specific Treatment Satisfaction Survey for Intraocular Pressure (TSS-IOP). METHODS: Item content was developed by 4 heterogeneous patient focus groups (n = 32). Instrument validation involved 250 patients on ocular hypotensive medications recruited from ophthalmology practices in the Southern USA. Participants responded to demographic and test questions during a clinic visit. Standard psychometric analyses were performed on the resulting data. SAMPLE: Of the 412 patients screened, 253 consented to participate, and 250 provided complete datasets. The sample included 44% male (n = 109), 44% Black (n = 109) and 57% brown eyed (n = 142) participants, with a mean age of 64.6 years (SD 13.1) and a history of elevated IOP for an average of 8.4 yrs (SD 7.8). A majority was receiving monotherapy (60%, n = 151). RESULTS: A PC Factor analysis (w/ varimax rotation) of the 31 items yielded 5 factors (Eigenvalues > 1.0) explaining 70% of the total variance. Weaker and conceptually redundant items were removed and the remaining 15 items reanalyzed. The satisfaction factors were; Eye Irritation (EI; 4 items), Convenience of Use (CofU; 3 items), Ease of Use (EofU; 3 items), Hyperemia (HYP; 3 items), and Medication Effectiveness (EFF; 2 items). Chronbach's Alphas ranged from .80 to .86. Greater distributional skew was found for less common experiences (i.e., HYP & EI with 65% & 48.4% ceilings) than for more common experiences (i.e., EofU, CofU, EFF with 10.8%, 20.8% & 15.9% ceilings). TSS-IOP scales converged with conceptually related scales on a previously validated measure of treatment satisfaction, the TSQM (r = .36 to .77). Evidence of concurrent criterion-related validity was found. Patients' symptomatic ratings of eye irritation, hyperemia and difficulties using the medication correlated with satisfaction on these dimensions (r = .30-.56, all p < .001). Clinicians' ratings of IOP control, severity of side effects and problematic medication use correlated with patients' satisfaction scores on these dimensions (r = .13-.26, all p < .01). CONCLUSIONS: This study provides initial evidence that the TSS-IOP is a reliable and valid measure, assessing patients' satisfaction with ocular hypotensive medications

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gressed patients (1.3, p = 0.005). A multivariate regression analysis showed higher mean, peak and variance of IOP, number of glaucoma medications at the final visit and presence of a disc hemorrhage (n = 5) as independent risk factors for progression (p ^ 0.05). Conclusion: IOP reduction in XFG may be essential in reducing disease progression. The presence of disc hemorrhage in XFG may suggest an increased probability of progression despite treatment to within the normal IOP range

Assessing the causal association of glycine with risk of cardio-metabolic diseases.

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.N. G. F. and F.I. acknowledge funding from Medical Research Council Epidemiology Unit MC_UU_12015/5. N.G.F. and N. J. W. acknowledge funding from the NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). S. B. is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). J. D. is funded by the National Institute for Health Research [Senior Investigator Award]. N. J. W. and C. L. acknowledge funding from the Medical Research Council Epidemiology Unit (MC_UU_12015/1)

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

Background: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. Methodology/Principal Findings: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value ,3.31E-6; V$CREBP1_Q2, p-value ,9.93E-6, V$YY1_02, p-value ,1.65E-5). Conclusions/Significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation

Chronic Obstructive Pulmonary Disease Is Associated with Low Levels of Vitamin D

Introduction: COPD patients may be at increased risk for vitamin D (25(OH)D) deficiency, but risk factors for deficiency among COPD patients have not been extensively reported. Methods: Serum 25(OH)D levels were measured by liquid chromatography double mass spectrometry in subjects aged 40–76 years from Western Norway, including 433 COPD patients (GOLD stage II-IV) and 325 controls. Levels <20 ng/mL defined deficiency. Season, sex, age, body mass index (BMI), smoking, GOLD stage, exacerbation frequency, arterial oxygen tension (PaO2), respiratory symptoms, depression (CES-D score≥16), comorbidities (Charlson score), treatment for osteoporosis, use of inhaled steroids, and total white blood count were examined for associations with 25(OH)D in both linear and logistic regression models. Results: COPD patients had an increased risk for vitamin D deficiency compared to controls after adjustment for seasonality, age, smoking and BMI. Variables associated with lower 25(OH)D levels in COPD patients were obesity ( = −6.63), current smoking ( = −4.02), GOLD stage III- IV ( = −4.71, = −5.64), and depression ( = −3.29). Summertime decreased the risk of vitamin D deficiency (OR = 0.22). Conclusion: COPD was associated with an increased risk of vitamin D deficiency, and important disease characteristics were significantly related to 25(OH)D levels