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Introduction This prospective, multicenter, randomized, double-masked pivotal phase 3 trial evaluated the efficacy and safety of the travoprost intracameral SE-implant (slow-eluting implant, the intended commercial product) and FE-implant (fast-eluting implant, included primarily for masking purposes) compared to twice-daily (BID) timolol ophthalmic solution, 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods The trial enrolled adult patients with OAG or OHT with an unmedicated mean diurnal intraocular pressure (IOP) of ≥ 21 and unmedicated IOP ≤ 36 mmHg at each diurnal timepoint (8  a.m. , 10  a.m. , and 4  p.m. ) at baseline. The eligible eye of each patient was administered an SE-implant, an FE-implant or had a sham administration procedure. Patients who received an implant were provided placebo eye drops to be administered BID and patients who had the sham procedure were provided timolol eye drops to be administered BID. The primary efficacy endpoint, for which the study was powered, was mean change from baseline IOP at 8  a.m. and 10  a.m. at day 10, week 6, and month 3. Non-inferiority was achieved if the upper 95% confidence interval (CI) on the difference in IOP change from baseline (implant minus timolol) was < 1.5 mmHg at all six timepoints and < 1 mmHg at three or more timepoints. The key secondary endpoint was mean change from baseline IOP at 8  a.m. and 10  a.m. at month 12. Non-inferiority at month 12 was achieved if the upper 95% CI was < 1.5 mmHg at both timepoints. Safety outcomes included treatment-emergent adverse events (TEAEs) and ophthalmic assessments. Results A total of 590 patients were enrolled at 45 sites and randomized to one of three treatment groups: 197 SE-implant (the intended commercial product), 200 FE-implant, and 193 timolol. The SE-implant was non-inferior to timolol eye drops in IOP lowering over the first 3 months, and was also non-inferior to timolol at months 6, 9, and 12. The FE-implant was non-inferior to timolol over the first 3 months, and also at months 6 and 9. Of those patients who were on glaucoma medication at screening, a significantly greater proportion of patients in the SE- and FE-implant groups (83.5% and 78.7%, respectively) compared to the timolol group (23.9%) were on fewer topical glaucoma medications at month 12 compared to screening ( P  < 0.0001, chi-square test). TEAEs, mostly mild, were reported in the study eyes of 39.5% of patients in the SE-implant group, 34.0% of patients in the FE-implant group and 20.1% of patients in the timolol group. Conclusions The SE-travoprost intracameral implant demonstrated non-inferiority to timolol over 12 months whereas the FE-implant demonstrated non-inferiority over 9 months. Both implant models were safe and effective in IOP lowering in patients with OAG or OHT. Trial Registration ClinicalTrials.gov identifier, NCT03519386.

Background: The travoprost intracameral implant and cataract surgery both lower intraocular pressure (IOP). Objectives: We evaluated the safety and IOP-lowering effect at 3 months following administration of travoprost intracameral implant in combination with cataract surgery. Design: Prospective, 12-month, open-label, single-arm trial. Methods: We enrolled patients with age-related cataracts and open-angle glaucoma or ocular hypertension in the same eye. At baseline, patients were required to have an unmedicated mean diurnal IOP (average of 8:00 am, 10:00 am, and 4:00 pm IOPs) of 24 mmHg or greater, and an IOP of 36 mmHg or less at each of these three timepoints. On the day of the combined procedure (day 1), patients who had uncomplicated phacoemulsification cataract surgery received a travoprost intracameral implant. Follow-up evaluations occurred on day 2–3, week 2, week 6, and month 3 visits. Results: Sixty patients had uncomplicated cataract surgery and received a travoprost intracameral implant. There were no serious adverse events. Study eye adverse events were reported in 8.3% of patients. The most frequently reported adverse event was dry eye (6.7%). At month 3, the mean diurnal IOP change from baseline was −10.6 mmHg (95% confidence interval: −11.2, −9.9; p < 0.0001) from an unmedicated baseline mean diurnal IOP of 25.2 mmHg. In addition, at month 3, 97% of eyes had a 20% or greater mean diurnal IOP reduction from baseline, and 91.0% of eyes had a mean diurnal IOP of 18 mmHg or less. Conclusion: Administration of a travoprost intracameral implant combined with routine cataract surgery was safe. The sizable −10.6 mmHg IOP change from baseline at month 3 was both statistically significant and clinically relevant. Trial registration: NCT06061718, Travoprost Intraocular Implant in Conjunction with Cataract Surgery, https://clinicaltrials.gov/study/NCT06061718. Plain language summary Study assessing the safety and the intraocular pressure lowering effect of administering a travoprost intracameral implant in combination with having cataract surgery in patients with open-angle glaucoma or ocular hypertension Why was the study done? The travoprost intracameral implant is a drug delivery system that is placed directly in the eye to continuously release travoprost to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Cataract surgery also is known to lower intraocular pressure in normal eyes and to a greater extent in eyes with glaucoma or ocular hypertension. Placement of the implant in the anterior chamber angle of the eye and cataract surgery are both done through a small corneal incision. What did the researchers do? The researchers studied the safety and the reduction in intraocular pressure after administering a travoprost intracameral implant during the same procedure as removal of the cataractous lens and administration of an intraocular lens. Sixty patients with open-angle glaucoma had the combined procedure and were followed over a 3-month period to check their intraocular pressure and health of their eye. What did the researchers find? There were no serious safety findings after the combined procedure, with less than 10% of patients having any ocular side effect. The most common side effect was dry eye. At month 3, mean intraocular pressure was reduced significantly from the untreated baseline pressure measured before the combined procedure. What do the findings mean? The study showed that it is safe to combine the placement of the travoprost intracameral implant in the eye during the same procedure as routine cataract surgery. The study also showed that there was a substantial lowering of intraocular pressure at 3 months in patients with open-angle glaucoma.

To develop prevention and treatment modalities for eye injuries, ophthalmologists require epidemiological data on the various types of eye injuries. This study sought to define eye injury patterns in the U.S. armed forces. Data on patterns of eye injury in the armed forces were obtained through voluntary reporting by U.S. military ophthalmologists throughout the world. The reporting format was standardized with the U.S. Eye Injury Registry initial and follow-up report forms. The data were analyzed for significant injury patterns. Data on 112 patients were submitted, representing a broad range of the military population. Data on a total of 96 patients with a 6-month follow-up were analyzed in this study. Immediately after injury, 43% of the patients were noted to have poor vision (worse than 20/200). After treatment, only 20% were noted to have poor vision. Patients lost an average of 21.6 days of work after a severe eye injury. An eye injury is a traumatic and potentially debilitating event. The loss of visual acuity can be drastic, resulting in an extensive recovery period.

Background Lysosomal cysteine protease cathepsin V has previously been shown to exhibit elevated expression in breast cancer tissue and be associated with distant metastasis. Research has also identified that cathepsin V expression is elevated in tumour tissues from numerous other malignancies, but despite this, there has been limited examination of the function of this protease in cancer. Here we investigate the role of cathepsin V in breast cancer in order to delineate the molecular mechanisms by which this protease contributes to tumourigenesis. Methods Lentiviral transductions were used to generate shRNA cell line models, with cell line validation undertaken using RQ-PCR and Western blotting. Phenotypic changes of tumour cell biology were examined using clonogenic and invasion assays. The relationship between GATA3 expression and cathepsin V was primarily analysed using Western blotting. Site-directed mutagenesis was used to generate catalytic mutant and shRNA-resistant constructs to confirm the role of cathepsin V in regulating GATA3 expression. Results We have identified that elevated cathepsin V expression is associated with reduced survival in ER-positive breast cancers. Cathepsin V regulates the expression of GATA3 in ER-positive breast cancers, through promoting its degradation via the proteasome. We have determined that depletion of cathepsin V results in elevated pAkt-1 and reduced GSK-3β expression, which rescues GATA3 from proteasomal degradation. Conclusions In this study, we have identified that cysteine protease cathepsin V can suppress GATA3 expression in ER-positive breast cancers by facilitating its turnover via the proteasome. Therefore, targeting cathepsin V may represent a potential therapeutic strategy in ER-positive breast cancers, by restoring GATA3 protein expression, which is associated with a more favourable clinical outcome.

Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. The UK National Institute for Health Research Health Technology Assessment Programme.

Background: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. Objective: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. Methods: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. Results: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. Discussion: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745

GAF domains are ubiquitous motifs present in cyclic GMP (cGMP)‐regulated cyclic nucleotide phosphodiesterases, certain adenylyl cyclases, the bacterial transcription factor FhlA, and hundreds of other signaling and sensory proteins from all three kingdoms of life. The crystal structure of the Saccharomyces cerevisiae YKG9 protein was determined at 1.9 Å resolution. The structure revealed a fold that resembles the PAS domain, another ubiquitous signaling and sensory transducer. YKG9 does not bind cGMP, but the isolated first GAF domain of phosphodiesterase 5 binds with K d = 650 nM. The cGMP binding site of the phosphodiesterase GAF domain was identified by homology modeling and site‐directed mutagenesis, and consists of conserved Arg, Asn, Lys and Asp residues. The structural and binding studies taken together show that the cGMP binding GAF domains form a new class of cyclic nucleotide receptors distinct from the regulatory domains of cyclic nucleotide‐regulated protein kinases and ion channels.

Objective In this study, we aimed to determine the lifetime prevalence of substance use disorder (SUD) in a Canadian rheumatoid arthritis (RA) cohort and factors associated with SUD in RA. Methods Participants with RA (N = 154) were recruited via rheumatology clinics as part of a larger cohort study of psychiatric comorbidity in immune‐mediated inflammatory diseases. SUD is defined as the uncontrolled use of a substance despite the harmful consequences of its use. To identify lifetime SUD, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition was administered to participants. Participants’ sociodemographic and RA clinical characteristics were also assessed. We examined factors associated with lifetime SUD using unadjusted and adjusted logistic regression modeling. Results Twenty‐three (14.9%) of 154 participants with RA met the criteria for a lifetime diagnosis of SUD. The majority of the participants were women, were White, had postsecondary education, and were on a disease‐modifying antirheumatic drug. Factors associated with increased odds of SUD were male sex (adjusted odds ratio [aOR]: 3.63, 95% confidence interval [CI]: 1.03‐12.73), younger age (aOR: 0.94, 95% CI: 0.90‐0.98), and ever smoking (aOR: 6.44, 95% CI: 1.53‐27.07). Conclusion We found that approximately 1 in 7 individuals with RA had a lifetime diagnosis of SUD, highlighting the importance of identifying and treating SUD in those with RA. In particular, the following factors were associated with higher odds of SUD: male sex, younger age, and smoking behaviors.

This study, based on fluid inclusion petrography, microthermometry and ultraviolet microspectroscopy of inclusion oil, investigates the petroleum charge history at Parsons Pond, western Newfoundland. To address this matter, drill core and cuttings samples of allochthonous and autochthonous strata in the Parson’s Pond area were collected from three exploration wells. Fluid inclusions were examined from fragments of calcite and quartz veins, diagenetic cements in sandstone, and in large hydrothermal dolomite and calcite crystals. Primary aqueous inclusions in authigenic sandstone cements indicate that cementation occurred at relatively shallow depths and low temperatures (<50 °C). Hydrocarbon-bearing fluid inclusions (petroleum, wet gas and gas) are generally restricted to calcite and quartz veins, indicating that petroleum and gas migration at Parson’s Pond is fracture-controlled. No hydrocarbons were observed in the diagenetic cements of the essentially tight sandstones. Fluid inclusion microthermometry and ultraviolet microspectroscopy indicate the presence of multiple generations of hydrocarbon fluid, ranging in composition from ~33 API gravity petroleum to pure CH4. Petrographic evidence suggests that hydrocarbons were generated multiple times during progressive burial and heating. In addition, the distribution of hydrocarbon bearing inclusions with depth suggests that deeper levels are gas-prone, with petroleum confined to relatively shallow depths. Although only gas flow was encountered during the drilling of exploration wells at Parson’s Pond, the presence of petroleum-bearing fluid inclusions in calcite and quartz veins indicates that the historical production from shallow wells in the Parsons Pond area likely tapped small reservoirs of fractured petroliferous strata.

Abstract Objective: To determine whether tight control of blood pressure with either a β blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes. Design: Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a β blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of <150/<85 mm Hg. Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes (mean age 56 years, mean blood pressure 160/94 mm Hg). Of the 758 patients allocated to tight control of blood pressure, 400 were allocated to captopril and 358 to atenolol. 390 patients were allocated to less tight control of blood pressure. Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, death related to diabetes, and all cause mortality. Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography. Results: Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. More patients in the captopril group than the atenolol group took the allocated treatment: at their last clinic visit, 78% of those allocated captopril and 65% of those allocated atenolol were taking the drug (P<0.0001). Captopril and atenolol were equally effective in reducing the risk of macrovascular end points. Similar proportions of patients in the two groups showed deterioration in retinopathy by two grades after nine years (31% in the captopril group and 37% in the atenolol group) and developed clinical grade albuminuria ≥300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg). Conclusion: Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.