Phase 3 Randomized Clinical Trial of the Safety and Efficacy of Travoprost Intraocular Implant in Patients with Open-Angle Glaucoma or Ocular Hypertension.

PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering efficacy of 2 models of the travoprost intraocular implant (fast-eluting [FE] and slow-eluting [SE] types) from 1 of 2 phase 3 trials (the GC-010 trial). DESIGN: Multicenter, randomized, double-masked, sham-controlled, noninferiority trial. PARTICIPANTS: Patients with open-angle glaucoma or ocular hypertension having an unmedicated baseline mean diurnal IOP (average of 8 am, 10 am, and 4 pm time points) of ≥ 21 mmHg, and IOP of ≤ 36 mmHg at each of the 8 am, 10 am, and 4 pm timepoints at baseline. METHODS: Study eyes were randomized to the travoprost intraocular implant (FE implant [n = 200] or SE implant [n = 197] model) or to timolol ophthalmic solution 0.5% twice daily (n = 193). MAIN OUTCOME MEASURES: The primary outcome was mean change from baseline IOP in the study eye at 8 am and 10 am, at each of day 10, week 6, and month 3. Safety outcomes included adverse events (AEs) and ophthalmic assessments. RESULTS: Mean IOP reduction from baseline over the 6 time points ranged from 6.6 to 8.4 mmHg for the FE implant group, from 6.6 to 8.5 mmHg for the SE implant group, and from 6.5 to 7.7 mmHg for the timolol group. The primary efficacy end point was met; the upper limit of the 95% confidence interval of the difference between the implant groups and the timolol group was < 1 mmHg at all 6 time points. Study eye AEs, most of mild or moderate severity, were reported in 21.5%, 27.2%, and 10.8% of patients in the FE implant, SE implant, and timolol groups, respectively. The most common AEs included iritis (FE implant, 0.5%; SE implant, 5.1%), ocular hyperemia (FE implant, 3.0%; SE implant, 2.6%), reduced visual acuity (FE implant, 1.0%; SE implant, 4.1%; timolol, 0.5%), and IOP increased (FE implant, 3.5%; SE implant, 2.6%; timolol, 2.1%). One serious study eye AE occurred (endophthalmitis). CONCLUSIONS: The travoprost intraocular implant demonstrated robust IOP reduction over the 3-month primary efficacy evaluation period after a single administration. The IOP-lowering efficacy in both implant groups was statistically and clinically noninferior to that in the timolol group, with a favorable safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

An Innovative Method to Generate Bromine Monochloride for Trace Hg Analysis.

This work presents a new method for generating a BrCl solution, starting from the commercially available dibromodimethylhydantoin (DBDMH). This method is notable due to the straightforward, safe and clean performance, being based on a simple addition of DBDMH into aqueous HCl. The whole procedure is finished in about 20 min. An advantage of the proposed method is avoiding of tedious reagents pre-cleaning by prolonged thermal treatment, spontaneous overheating and excessive vapor evolution. The resulting BrCl stabilization reagent is low enough in mercury content to be directly used in trace mercury analysis. A thorough study of the BrCl solutions prepared by this method showed that they conform in all respects to US EPA 1631e/2002 requirements.

3D Printed Platform for Impedimetric Sensing of Liquids and Microfluidic Channels.

Fused deposition modeling 3D printing (FDM-3DP) employing electrically conductive filaments has recently been recognized as an exceptionally attractive tool for the manufacture of sensing devices. However, capabilities of 3DP electrodes to measure electric properties of materials have not yet been explored. To bridge this gap, we employ bimaterial FDM-3DP combining electrically conductive and insulating filaments to build an integrated platform for sensing conductivity and permittivity of liquids by impedance measurements. The functionality of the device is demonstrated by measuring conductivity of aqueous potassium chloride solution and bottled water samples and permittivity of water, ethanol, and their mixtures. We further implement an original idea of applying impedance measurements to investigate dimensions of 3DP channels as base structures of microfluidic devices, complemented by their optical microscopic analysis. We demonstrate that FDM-3DP allows the manufacture of microchannels of width down to 80 µm.

Health effects of exposure to isocyanates in a car factory.

OBJECTIVES: Isocyanates are known to induce occupational diseases. The aim of this work was to assess the health effects of exposure to isocyanates and to test the sensitivity of selected parameters for early detection of isocyanate-related allergic diseases. METHODS: In total, 35 employees from one factory were tested: 26 workers exposed to isocyanates (exposed group) and nine office workers (control group). All subjects filled in a questionnaire regarding possible health problems. Fractional exhaled nitric oxide (FeNO) and spirometry were measured for each subject at the same time during two consecutive working days. A urine sample was taken for a biological exposure test (BET). RESULTS: No significant difference was found between the exposed and control groups for spirometry parameters and FeNO. However, in the exposed group, FeNO was highly elevated (> 50 ppb) in five subjects (all reporting health problems at the workplace, all with normal spirometry and non-smokers). The BET revealed a significant difference (p < 0.001) between the exposed and control groups for 4,4´-methylenediphenyl diamine (MDA) in the urine. CONCLUSIONS: Our examination showed the usefulness of the BET in monitoring of workplace exposure to isocyanates and the importance of FeNO in monitoring of allergic inflammation of airways in non-smoking employees with normal spirometry.

Estimation of Hg(II) in Soil Samples by Bioluminescent Bacterial Bioreporter E. coli ARL1, and the Effect of Humic Acids and Metal Ions on the Biosensor Performance.

Mercury is a ubiquitous environmental pollutant of dominantly anthropogenic origin. A critical concern for human health is the introduction of mercury to the food chain; therefore, monitoring of mercury levels in agricultural soil is essential. Unfortunately, the total mercury content is not sufficiently informative as mercury can be present in different forms with variable bioavailability. Since 1990, the use of bioreporters has been investigated for assessment of the bioavailability of pollutants; however, real contaminated soils have rarely been used in these studies. In this work, a bioassay with whole-cell bacterial bioreporter Escherichia coli ARL1 was used for estimation of bioavailable concentration of mercury in 11 soil samples. The bioreporter emits bioluminescence in the presence of Hg(II). Four different pretreatments of soil samples prior to the bioassay were tested. Among them, laccase mediated extraction was found to be the most suitable over water extraction, alkaline extraction, and direct use of water-soil suspensions. Nevertheless, effect of the matrix on bioreporter signal was found to be severe and not possible to be completely eliminated by the method of standard addition. In order to elucidate the matrix role, influences of humic acid and selected metal ions present in soil on the bioreporter signal were tested separately in laboratory solutions. Humic acids were found to have a positive effect on the bioreporter growth, but a negative effect on the measured bioluminescence, likely due to shading and Hg binding resulting in decreased bioavailability. Each of the tested metal ions solutions affected the bioluminescence signal differently; cobalt (II) positively, iron (III) negatively, and the effects of iron (II) and nickel (II) were dependent on their concentrations. In conclusion, the information on bioavailable mercury estimated by bioreporter E. coli ARL1 is valuable, but the results must be interpreted with caution. The route to functional bioavailability bioassay remains long.

Markers of oxidative stress after three days of nanoTiO2 sunscreen use in humans: a pilot study.

OBJECTIVE: Recent experimental studies point to a high reactivity of nanoparticles and the potential of sunscreens to penetrate the skin. We measured 20 markers of oxidative stress and inflammation to find out whether skin exposure to nanoTiO2 sunscreen may elevate the level of the markers in exhaled breath condensate (EBC) and urine of exposed subjects, as was suggested by our earlier study. METHODS: Six volunteers (3 males and 3 females), with a mean age of 48.0 ± 6.7 years, used commercial sunscreen for three days continuously. The first samples were collected before the test. The second samples were collected on day 4, before the sunscreen was washed off, and the third samples on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, aldehydes C6-C12, 8-isoProstaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes B4, C4, D4, and E4, using liquid chromatography-electrospray ionisation-tandem mass spectrometry. RESULTS: In the urine, 4-hydroxy-trans-hexenal was significantly higher in post-exposure sample 2, and the same trend was seen in all urinary markers. In EBC, no difference was seen between the mean values of 20 post-test markers as compared with pre-test samples. CONCLUSION: This study suggests potential side effects of the sunscreen - borderline elevation of markers of oxidative stress/inflammation - which may relate to the absorption of the nanoTiO2, and the non-significant difference may be explained by the small number of subjects. The effect was not seen in EBC, where nanoTiO2 was not found. A larger study is needed, as according to our previous study, the beneficial effect of the sunscreen to suppress oxidative stress caused by UV radiation may be questioned.

Larch Tree Rings as a Tool for Reconstructing 20th Century Central European Atmospheric Mercury Trends.

We propose the tree rings of European Larch ( Larix decidua) as a widely available and reliable geochemical archive of local and regional changes in atmospheric mercury (Hg). Mean Hg concentrations in larch tree rings from 8 background sites across the Czech Republic ranged from 2.2 to 4.8 µg kg-1; the maximum concentrations occurred in the period 1951-1970. At 3 sites impacted by Hg-emission sources [gold amalgamation processing, caustic soda production, and lead (Pb) ore smelting] mean larch tree ring Hg concentrations were significantly elevated relative to background sites. Changes in larch tree ring Hg concentrations were temporally coherent with known activities at the sites that would alter Hg emissions; the nearly simultaneous response in tree rings indicated little or no translocation of Hg within the larch bole. Based on the present-day atmospheric Hg concentration of 1.63 ng m-3 at the intensively monitored Czech Global Mercury Observation System site and the most recent mean tree ring Hg concentration of 2.8 µg kg-1 in co-located larch trees, we developed a simple distribution model of Hg between the atmosphere and larch tree rings. We applied the model using observed changes of Hg in larch tree rings from the countrywide background sites to reconstruct past atmospheric Hg concentrations in central Europe. Modeled Hg concentrations were in agreement with annual means from the European Monitoring and Evaluation Programme observatories.

Use of Out-of-Hospital Ethanol Administration to Improve Outcome in Mass Methanol Outbreaks.

STUDY OBJECTIVE: Methanol poisoning outbreaks are a global public health issue, with delayed treatment causing poor outcomes. Out-of-hospital ethanol administration may improve outcome, but the difficulty of conducting research in outbreaks has meant that its effects have never been assessed. We study the effect of out-of-hospital ethanol in patients treated during a methanol outbreak in the Czech Republic between 2012 and 2014. METHODS: This was an observational case-series study of 100 hospitalized patients with confirmed methanol poisoning. Out-of-hospital ethanol as a "first aid antidote" was administered by paramedic or medical staff before the confirmation of diagnosis to 30 patients; 70 patients did not receive out-of-hospital ethanol from the staff (12 patients self-administered ethanol shortly before presentation). RESULTS: The state of consciousness at first contact with paramedic or medical staff, delay to admission, and serum methanol concentration were similar among groups. The median serum ethanol level on admission in the patients with out-of-hospital administration by paramedic or medical staff was 84.3 mg/dL (interquartile range 32.7 to 129.5 mg/dL). No patients with positive serum ethanol level on admission died compared with 21 with negative serum ethanol level (0% versus 36.2%). Patients receiving out-of-hospital ethanol survived without visual and central nervous system sequelae more often than those not receiving it (90.5% versus 19.0%). A positive association was present between out-of-hospital ethanol administration by paramedic or medical staff, serum ethanol concentration on admission, and both total survival and survival without sequelae of poisoning. CONCLUSION: We found a positive association between out-of-hospital ethanol administration and improved clinical outcome. During mass methanol outbreaks, conscious adults with suspected poisoning should be considered for administration of out-of-hospital ethanol to reduce morbidity and mortality.

Markers of nucleic acids and proteins oxidation among office workers exposed to air pollutants including (nano)TiO2 particles.

OBJECTIVES: Experimental studies using nanoscale TiO2 have documented lung injury, inflammation, oxidative stress, and genotoxicity. Human health data are extremely scarce. METHODS: In exhaled breath condensate (EBC) and urine of 22 office employees occupationally exposed to TiO2 during their visit in the production workshops for average 14±9 min/day a panel of biomarkers of nucleic acids and proteins oxidation was studied, specifically 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), 5-hydroxymethyl uracil (5-OHMeU), o-tyrosine (o-Tyr), 3-chlorotyrosine (3-ClTyr), and 3-nitrotyrosine (3-NOTyr). Examination was performed also in 14 comparable controls. RESULTS: The median respirable TiO2 mass concentration in the workshops was 0.40 mg/m3, median number concentration was 2.32×104 particles/cm3 with 80% of the particles being <100 nm in diameter. All 6 markers of oxidation were elevated in EBC in factory office employees relative to controls (p<0.01). Significant association was found between their job in TiO2 production plant and 5 markers of oxidation (except 3-NOTyr) in the EBC in multivariate analysis. No elevation of markers was detected in the urine. CONCLUSION: This pilot study suggests that even short nanoTiO2 exposure may lead to pulmonary oxidative stress; however this effect may be short-term and reversible. The clinical significance of these findings is unclear and more studies are needed.

Preconcentration and detection of mercury with bioluminescent bioreporter E. coli ARL1.

Cell wall envelopes treated with sodium hydroxide and spray-dried were used as mercury sorbents. The sorbent having sorption capacity 17.7 ± 0.1 µmol/g determined was employed for preconcentration of mercury containing 1-10 ng/L. After preconcentration, bioavailable mercury was detected in samples of soil, stream, and tap water via induction of bioluminescence of E. coli ARL1. Iron and manganese at concentrations of tenth microgram per liter interfered bioluminescence detection of mercury. In tap water was detected semiquantitatively 0.127 ± 0.1 nmol/L by the induction of bioluminescence of E. coli ARL1 in medium with tryptone after preconcentration using a method of standard addition.

The influence of sample drying procedures on mercury concentrations analyzed in soils.

Methods commonly used for soil sample preparation may be unsuitable for measuring Hg concentrations due to the possible loss of volatile Hg species when drying at higher temperatures. Here, the effects of freeze-drying, air drying at 25°C and oven-drying at 105°C on Hg concentrations in two soil types and three standard reference materials were tested. Two soils with different levels of Hg contamination and three reference materials were examined. A systematic decrease of Hg concentrations was observed in air-dried (24 %) and oven-dried (3 %) contaminated upland soils in comparison to freeze-dried control samples. The 105°C oven drying also led to loss of Hg from reference materials (5 %-8 % in comparison with the certified Hg concentration). Different results from the drying of sterilized reference materials and natural soils were probably related to the extent of microbiological activity, demonstrating the importance of this parameter in sample preparation for Hg analysis.

Intermittent hemodialysis is superior to continuous veno-venous hemodialysis/hemodiafiltration to eliminate methanol and formate during treatment for methanol poisoning.

During an outbreak of methanol poisonings in the Czech Republic in 2012, we were able to study methanol and formate elimination half-lives during intermittent hemodialysis (IHD) and continuous veno-venous hemodialysis/hemodiafiltration (CVVHD/HDF) and the relative impact of dialysate and blood flow rates on elimination. Data were obtained from 11 IHD and 13 CVVHD/HDF patients. Serum methanol and formate concentrations were measured by gas chromatography and an enzymatic method. The groups were relatively comparable, but the CVVHD/HDF group was significantly more acidotic (mean pH 6.9 vs. 7.1 IHD). The mean elimination half-life of methanol was 3.7 and formate 1.6 h with IHD, versus 8.1 and 3.6 h, respectively, with CVVHD/HDF (both significant). The 54% greater reduction in methanol and 56% reduction in formate elimination half-life during IHD resulted from the higher blood and dialysate flow rates. Increased blood and dialysate flow on the CVVHD/HDF also increased elimination significantly. Thus, IHD is superior to CVVHD/HDF for more rapid methanol and formate elimination, and if CVVHD/HDF is the only treatment available then elimination is greater with greater blood and dialysate flow rates.

Quarter century of mercury litterfall at a coniferous forest responding to climate change, Central Europe.

This work evaluated the 25-year-long trends (1994-2018) in mercury (Hg) concentrations and fluxes in spruce litterfall at a forest research plot Nacetín (NAC) recovering from acidic deposition in the Ore Mountains, Czech Republic. The mean litterfall Hg deposition averaged 51 ± 18 µg m-2 year-1, which has been the highest litterfall Hg deposition reported up to date on the European continent. In contrast, the wet deposition (2017-2019) was an order of magnitude lower averaging at 2.5 ± 1.5 µg m-2 year-1. All the spruce litterfall components bark, twigs, needles, cones, and a mixture of unidentified fragments had elevated mean Hg concentrations relative to background sites averaging 256 ± 77, 234 ± 62, 119 ± 23, 95 ± 14, and 44 ± 15 µg kg-1, respectively. Elevated litterfall Hg deposition and concentrations were attributed to the nearby local Hg emission source-coal-fired power plants. Temporally, the decrease of Czech Hg emissions since the 1990s was reflected by the decreasing trend of Hg concentrations in litterfall bark, cones, and twigs, while in needles and other material, Hg increased but insignificantly. Total litterfall ratios of Hg/C, Hg/N, and Hg/S were lower than those in soil O horizons averaging at 0.23 ± 0.04, 9.5 ± 2.0, and 170 ± 37 µg g-1, respectively. Since the beginning of monitoring, total litterfall Hg/C exhibited no trend, Hg/N decreased, and Hg/S increased. The litterfall biomass deposition averaging at 469 ± 176 g m-2 year-1 increased through time resulting in an increased Hg litterfall deposition at NAC by 1.1 µg m-2 year-1 despite the decreases in Czech Hg emissions. Peaks of annual litterfall Hg deposition up to 96 µg m-2 year-1 at NAC during the 25 years of monitoring resulted from weather extremes such as rime-snow accumulation, wind gusts, droughts, and insect infestation, which all significantly affected the annual biomass deposition. Based on our observations, further increases in biomass and litterfall Hg deposition rates can be expected due to the onset of bark beetle infestation and the increasing number of droughts caused by climate change.

Efficacy and Safety of the Travoprost Intraocular Implant in Reducing Topical IOP-Lowering Medication Burden in Patients with Open-Angle Glaucoma or Ocular Hypertension.

PURPOSE: A randomized, double-masked, multicenter, phase 2 trial to evaluate the long-term safety and efficacy of travoprost intraocular implant, an extended-release drug delivery system designed to provide uninterrupted sustained intraocular pressure (IOP)-lowering therapy, thereby reducing patient treatment burden and improving adherence with IOP-lowering medication. METHODS: Patients with open-angle glaucoma or ocular hypertension were administered a fast-eluting implant (FE implant, n = 51) and received twice-daily (BID) placebo eye drops, a slow-eluting (SE implant, n = 54) and received BID placebo eye drops, or underwent a sham surgical procedure and received BID timolol 0.5% (n = 49). IOP was measured at baseline, day 1-2, day 10, week 4, week 6, month 3, and every 3 months thereafter through 36 months. Efficacy was evaluated by mean change from 8:00 AM unmedicated baseline IOP through month 36, and the percentage of patients receiving the same or fewer topical IOP-lowering medications as at screening (pre-study). Safety was evaluated by adverse events and ophthalmic parameters. RESULTS: Clinically and statistically relevant IOP-lowering treatment effects were observed through month 36 after a single administration of the travoprost implant compared with BID timolol with mean IOP reductions ranging from 7.6 to 8.8 mmHg for the FE implant group, from 7.3 to 8.0 mmHg for the SE implant group, and from 7.3 to 7.9 for the timolol group at the 8:00 AM timepoint (P < 0.0001 for all treatment groups at all visits). At months 12, 24, and 36, a greater percentage of FE and SE implant patients versus timolol patients were well controlled on the same or fewer topical IOP-lowering medications compared with screening with 63 and 69% for the FE and SE implants groups, respectively, versus 45% for the timolol group at month 36. The safety profile of the implant was favorable; there were no dislodgements, no explantations, no adverse events of conjunctival hyperemia or periorbital fat atrophy, no discontinuations due to study eye adverse events, nor any serious adverse events in the study eye. Comparable changes from baseline in corneal endothelial cell counts were observed in the three treatment groups over the 36 months. CONCLUSION: The travoprost intraocular implant demonstrated robust IOP-lowering and substantially reduced topical IOP-lowering medication burden for up to 36 months following a single administration, while maintaining a favorable safety profile. The travoprost intraocular implant promises to be a meaningful addition to the interventional glaucoma armamentarium by addressing the key shortcomings of topical IOP-lowering medications, including low adherence and topical side effects while controlling IOP for up to 36 months. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT02754596 registered 28 April 2016.

Travoprost Intracameral Implant Demonstrates Superior IOP Lowering Versus Topical Prostaglandin Analog Monotherapy in Patients with Open-Angle Glaucoma or Ocular Hypertension.

INTRODUCTION: This study was conducted to analyze and compare the intraocular pressure (IOP) treatment effect of the slow-eluting (SE) travoprost intracameral implant to the IOP treatment effect of topical prostaglandin analog (PGA) monotherapy in a subgroup of subjects who were on pre-study PGA monotherapy prior to enrollment in the two pivotal phase 3 trials of the travoprost intracameral implant. METHODS: A combined study population of 133 subjects from two phase 3 trials, who were on topical PGA monotherapy at screening, subsequently underwent a washout period from their topical PGA, and then were randomized and administered an SE travoprost intracameral implant. The subjects were analyzed for the IOP treatment effects of the pre-study topical PGA monotherapy and the in-study SE travoprost intracameral implant. Paired t-tests were used to compare the difference in screening minus post-washout baseline IOP versus month 3 minus post-washout baseline IOP. The IOP-lowering efficacy in eyes administered an SE travoprost intracameral implant was compared to the IOP lowering in the same eyes while on a topical PGA monotherapy prior to study entry. RESULTS: Pre-study topical PGA monotherapy and the SE travoprost intracameral implant demonstrated IOP treatment effects of -5.76 mmHg and -7.07 mmHg, respectively. The IOP-lowering treatment effect was significantly greater by 1.31 mmHg for the SE travoprost intracameral implant relative to pre-study PGA monotherapy (95% confidence interval: -2.01, -0.60; P = 0.0003). CONCLUSIONS: The SE travoprost intracameral implant demonstrated superior IOP-lowering treatment effect versus pre-study topical PGA monotherapy with a superiority margin that was both statistically significant and clinically meaningful. The greater IOP reduction from baseline while on the SE implant versus pre-study topical PGA monotherapy may be a reflection of the optimized adherence and continuous elution of PGA therapy into the anterior chamber achieved with the SE travoprost intracameral implant. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03519386 and NCT03868124.

Travoprost Intracameral Implant for Open-Angle Glaucoma or Ocular Hypertension: 12-Month Results of a Randomized, Double-Masked Trial.

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.

Elevated glutathione in researchers exposed to engineered nanoparticles due to potential adaptation to oxidative stress.

Aim: To find a practical biomonitoring method for researchers exposed to nanoparticles causing oxidative stress. Methods: In a continuation of a study in 2016-2018, biological samples (plasma, urine and exhaled breath condensate [EBC]) were collected in 2019-2020 from 43 researchers (13.8 ± 3.0 years of exposure) and 45 controls. Antioxidant status was assessed using glutathione (GSH) and ferric-reducing antioxidant power, while oxidative stress was measured as thiobarbituric acid reactive substances, all using spectrophotometric methods. Researchers' personal nanoparticle exposure was monitored. Results: Plasma GSH was elevated in researchers both before and after exposure (p < 0.01); postexposure plasma GSH correlated with nanoparticle exposure, and GSH in EBC increased. Conclusion: The results suggest adaptation to chronic exposure to nanoparticles, as monitored by plasma and EBC GSH.

What is this study about? Identifying markers of oxidative stress and/or adaptation to oxidation stress could offer tools for monitoring exposure to nanoparticles in exposed researchers. In this study, we question whether these markers correlate with their personal exposure during the shift. What were the results? We found that exposure to nanoparticles correlated with the antioxidant marker glutathione, which is higher in workers who are already pre-exposed. What do the results mean? This study suggests that the researchers have adapted to nanoparticle exposure and are ready to combat oxidative stress. However, the similarity with increased markers of oxidative stress from asbestos and silica exposure, including nucleic acid oxidation, previously found in these researchers highlights the need for further research in this area to better understand and prevent potential future effects.

Climate-forced Hg-remobilization associated with fern mutagenesis in the aftermath of the end-Triassic extinction.

The long-term effects of the Central Atlantic Magmatic Province, a large igneous province connected to the end-Triassic mass-extinction (201.5 Ma), remain largely elusive. Here, we document the persistence of volcanic-induced mercury (Hg) pollution and its effects on the biosphere for ~1.3 million years after the extinction event. In sediments recovered in Germany (Schandelah-1 core), we record not only high abundances of malformed fern spores at the Triassic-Jurassic boundary, but also during the lower Jurassic Hettangian, indicating repeated vegetation disturbance and stress that was eccentricity-forced. Crucially, these abundances correspond to increases in sedimentary Hg-concentrations. Hg-isotope ratios (δ202Hg, Δ199Hg) suggest a volcanic source of Hg-enrichment at the Triassic-Jurassic boundary but a terrestrial source for the early Jurassic peaks. We conclude that volcanically injected Hg across the extinction was repeatedly remobilized from coastal wetlands and hinterland areas during eccentricity-forced phases of severe hydrological upheaval and erosion, focusing Hg-pollution in the Central European Basin.

Trends in CNS affecting drugs in the calls to the Toxicological Information Center from 1997 to 2012.

OBJECTIVES: To analyze the number and trends in calls to the Toxicological Information Center (TIC) concerning pharmaceutical poisoning retrospectively during the past 15 years and to compare selected characteristics of the poisonings. DESIGN: Inquiries arising from drug poisonings in the years 1997-2012 were extracted and evaluated from the Czech database recording the consultations of TIC specialists. In addition, their cause, severity and dose evaluation (data electronically collected after 2005) were compared in the years 2005-2012 using standard statistical methods. RESULTS: During 15 years total 152,649 calls due to all types of potentially toxic agents were recorded in the TIC database. Central nervous system (CNS) affecting drugs represented 39.8% of calls due to all pharmaceutical poisonings. The proportion of adults was 72.2% and women comprised 64.4% of all patients. Whereas the number of calls caused by poisoning with tricyclic antidepressants (TCAs) and barbiturates decreased (by 366.7% and 340%, respectively), the calls due to selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines overdose increased (by 1347.4% and 359.8%). The dose of CNS affecting drugs in 2005-2012 was considered lethal in 14.6% of the inquiries due to barbiturates and 8.6% due to TCAs, but only in 1.6% calls due to SSRIs and 0.5% of benzodiazepines. The highest percentage of medications errors was found during the treatment with barbiturates (16.4%). CONCLUSIONS: The current drugs prescription with improved safety profiles brings the beneficial effect of lowering the severity of poisonings and better prognosis of intoxications as observed in the TIC statistics.

Mobilization of aluminum by the acid percolates within unsaturated zone of sandstones.

The area of the Black Triangle has been exposed to extreme levels of acid deposition in the twentieth century. The chemical weathering of sandstones found within the Black Triangle became well-known phenomenon. Infiltration of acid rain solutions into the sandstone represents the main input of salt components into the sandstone. The infiltrated solutions--sandstone percolates--react with sandstone matrix and previously deposited materials such as salt efflorescence. Acidic sandstone percolates pH 3.2-4.8 found at ten sites within the National Park Bohemian Switzerland contained high Al-tot (0.8-10 mg L(-1)) concentrations and high concentrations of anions SO4 (5-66 mg L(-1)) and NO3 (2-42 mg L(-1)). A high proportion (50-98 %) of Al-tot concentration in acid percolates was represented by toxic reactive Al(n+). Chemical equilibrium modeling indicated as the most abundant Al species Al(3+), AlSO4 (+), and AlF(2+). The remaining 2-50 % of Al-tot concentration was present in the form of complexes with dissolved organic matter Al-org. Mobilization and transport of Al from the upper zones of sandstone causes chemical weathering and sandstone structure deterioration. The most acidic percolates contained the highest concentrations of dissolved organic material (estimated up to 42 mg L(-1)) suggesting the contribution of vegetation on sandstone weathering processes. Very low concentrations of Al-tot in springs at BSNP suggest that Al mobilized in unsaturated zone is transported deeper into the sandstone. This process of mobilization could represent a threat for the water quality small-perched aquifers.