Impact of fixed-dose combination Cal/BD foam on the work productivity of patients with psoriasis: results from the 52-week randomized, double-blind, PSO-LONG trial.

BACKGROUND: Psoriasis contributes to unemployment, work impairment, missed workdays and substantial indirect costs due to lost productivity. Combination Cal/BD foam is the only topical that is approved for long-term maintenance treatment of plaque psoriasis for 52 weeks. This is the first known investigation of the effect of topical psoriasis therapy on productivity. OBJECTIVE: To examine the change in work productivity and activity impairment after 4 weeks of treatment with fixed-dose combination calcipotriol 50 µg/g/betamethasone dipropionate 0.5 mg/g (Cal/BD) foam and observe long-term changes after 52 weeks of long-term management (proactive or reactive treatment). METHODS: This is a post-hoc analysis of the PSO-LONG trial - a phase 3, randomized, double-blind, vehicle-controlled, parallel group, international multi-centre trial of treatment with combination Cal/BD foam. Work and activity impairment due to psoriasis were assessed by the Dermatology Life Quality Index (DLQI) and the Work Productivity and Activity Impairment Psoriasis (WPAI:PSO) questionnaire at baseline, week 4, week 28 and week 56. The improvement in hours of work productivity was translated into monthly and annual indirect cost savings estimates for patients in Italy, Sweden, United Kingdom, Canada and Germany. RESULTS: Using fixed-dose combination Cal/BD foam for four weeks significantly reduced psoriasis-related work presenteeism, total work productivity impairment (TWPI) and total activity impairment (TAI) over 56 weeks, with significant improvements observed as early as 4 weeks after the baseline visit. The proportion of patients reporting impact on work productivity (as measured by presenteeism and TWPI) and activity impairment (as measured by both DLQI-Q7b and TAI) also decreased. CONCLUSION: Fixed-dose combination Cal/BD foam used for long-term management of psoriasis significantly reduces psoriasis-related work productivity and activity impairment which may result in substantial indirect cost savings. Clinical Trial Registration NCT02899962, EudraCT number: 2016-000556-95.

Quality of life and patient-perceived symptoms in patients with psoriasis undergoing proactive or reactive management with the fixed-dose combination Cal/BD foam: A post-hoc analysis of PSO-LONG.

BACKGROUND: Psoriasis has important physical and psychosocial effects that extend beyond the skin. Understanding the impact of treatment on health-related quality of life (HRQoL) and patient-perceived symptom severity in psoriasis is key to clinical decision-making. OBJECTIVES: This post hoc analysis of the PSO-LONG trial data assessed the impact of long-term proactive or reactive management with fixed-dose combination calcipotriene 50 µg/g and betamethasone dipropionate 0.5 mg/g (Cal/BD) foam on patient-reported outcomes (PROs) in patients with psoriasis vulgaris. METHODS: Five hundred and twenty-one patients from the Phase 3, randomized, double-blind PSO-LONG trial were included. An initial 4-week, open-label phase of fixed-dose combination Cal/BD foam once daily (QD) was followed by a 52-week maintenance phase, at the start of which patients were randomized to a proactive management arm (Cal/BD foam twice weekly) or reactive management arm (vehicle foam twice weekly). Patient-perceived symptom severity and HRQoL were assessed using the Psoriasis Symptom Inventory (PSI), the Dermatology Life Quality Index (DLQI) and the EuroQol-5D for psoriasis (EQ-5D-5L-PSO). RESULTS: Statistically and clinically significant improvements were observed across all PRO measures. The mean difference (standard deviation) from baseline to Week 4 was -8.97 (6.18) for PSI, -6.02 (5.46) for DLQI and 0.11 (0.15) for EQ-5D-5L-PSO scores. During maintenance, patients receiving reactive management had significantly higher DLQI (15% [p = 0.007]) and PSI (15% [p = 0.0128]) and a numerically lower EQ-5D-5L-PSO mean area under the curve score than patients receiving proactive management (1% [p = 0.0842]). CONCLUSIONS: Cal/BD foam significantly improved DLQI, EQ-5D-5L-PSO and PSI scores during the open-label and maintenance phases. Patients assigned to proactive management had significantly better DLQI and PSI scores and numerically better EQ-5D-5L-PSO versus reactive management. Additionally, baseline flare was associated with worse PROs than the start of a relapse, and patients starting a relapse also had worse PROs than patients in remission.

Slow improvements of metal exposure, health- and breeding conditions of pied flycatchers (Ficedula hypoleuca) after decreased industrial heavy metal emissions.

The environment around metal industries, such as smelters, is often highly contaminated due to continuous deposition of metals. We studied nest box breeding populations of pied flycatchers (Ficedula hypoleuca) in a well-studied pollution gradient from a sulfide ore smelter in Northern Sweden, after reduced aerial metal emissions (by 93-99%) from the smelter. The deposition of arsenic, cadmium, copper and zinc (based on moss samples) reflected the reduced emissions fairly well. However, nestling pied flycatchers had similar concentrations of these elements and mercury in tissues (bone, liver and blood) and feces in the 2000s, as in the 1980s, when the emissions were substantially higher. The exposure to high metal concentrations in the close vicinity of the smelter resulted in inhibited ALAD activities, depressed hemoglobin and hematocrit levels and increased mortality of nestlings. Our results indicate that in the highly contaminated environment around the smelter, nestlings reflected the slowly cycling soil pool, rather than the atmospheric deposition, and the concentration in soils plays an important role for the response of pied flycatchers to reduced atmospheric deposition.

Lead exposure and biological effects in pied flycatchers (Ficedula hypoleuca) before and after the closure of a lead mine in northern Sweden.

Mining activities affect the surrounding environment by increasing exposure to metals. In this study, metal accumulation and its effects on reproduction and health of pied flycatcher (Ficedula hypoleuca) nestlings were monitored before and up to five years after a lead mine and enrichment plant closed down. The lead concentration in moss, nestling blood, liver and feces all indicated decreased lead exposure by at least 31% after closure, although only blood lead decreased significantly. Although the birds responded fairly well to the changed atmospheric deposition (based on moss samples), concentrations were still higher compared with birds in a reference area, and breeding was affected at the mine (smaller clutches and higher mortality). Surviving nestlings suffered from lower hemoglobin levels, mean cell hemoglobin concentrations and inhibited delta-aminolevulinic acid dehydratase activity. Lead poisoning contributed to poor health and adverse reproductive effects, but other factors (e.g. increased parasitic load) probably also affected the birds.

Effects of reduced lead deposition on pied flycatcher (Ficedula hypoleuca) nestlings: tracing exposure routes using stable lead isotopes.

To what extent the lead burden of birds living in strongly contaminated ecosystems is responding to decreased atmospheric lead deposition is not well known. In this study, we measured lead concentrations and stable lead isotope ratios (206pb/207Pb and 208Pb/207Pb) in liver and feces from pied flycatcher nestlings (Ficedula hypoleuca) along a 90 km pollution gradient from the Rönnskär smelter in northern Sweden. Changes in lead concentration in the birds from 1984 to 2006 were used for assessing the recovery of the environment following reduced lead emissions at the smelter. The 206Pb/207Pb and 208Pb/207Pb ratios were used to identify lead sources to the birds. Lead concentrations in liver and feces have decreased since the 1980s, typically by 9-15% (liver) and 18-40% (feces) as a result of a 98% emission reduction. This relatively weak recovery is explained by a transfer of old lead contaminants accumulated in soil to the birds via their prey, which was evident by a 206Pb/207Pb ratio in liver tissue (1.15 +/- 0.01) that overlapped with the ratio in ants (1.16 +/- 0.01) and organic soil horizon (1.17 +/- 0.01) rather than the current atmospheric lead pollution (1.11 +/- 0.01). Our findings suggest that insectivorous birds living around smelters may remain contaminated decades after ceased emissions.

Oxidative stress in pied flycatcher (Ficedula hypoleuca) nestlings from metal contaminated environments in northern Sweden.

Metals have been shown to induce oxidative stress in animals. One of the most metal polluted terrestrial environments in Sweden is the surroundings of a sulfide ore smelter plant located in the northern part of the country. Pied flycatcher nestlings (Ficedula hypoleuca) that grew up close to the industry had accumulated amounts of arsenic, cadmium, mercury, lead, iron and zinc in their liver tissue. The aim of this study was to investigate if pied flycatcher nestlings in the pollution gradient of the industry were affected by oxidative stress using antioxidant molecules and enzyme activities. The antioxidant assays were also evaluated in search for useful biomarkers in pied flycatchers. This study indicated that nestlings in metal contaminated areas showed signs of oxidative stress evidenced by up regulated hepatic antioxidant defense given as increased glutathione reductase (GR) and catalase (CAT) activities and slightly but not significantly elevated lipid peroxidation and glutathione-S-transferase (GST) activities. Stepwise linear regression indicated that lipid peroxidation and CAT activities were influenced mostly by iron, but iron and lead influenced the CAT activity to a higher degree. Positive relationships were found between GST and lead as well as GR activities and cadmium. We conclude that GR, CAT, GST activities and lipid peroxidation levels may function as useful biomarkers for oxidative stress in free-living pied flycatcher nestlings exposed to metal contaminated environments.

Large-scale geographical variation confirms that climate change causes birds to lay earlier.

Advances in the phenology of organisms are often attributed to climate change, but alternatively, may reflect a publication bias towards advances and may be caused by environmental factors unrelated to climate change. Both factors are investigated using the breeding dates of 25 long-term studied populations of Ficedula flycatchers across Europe. Trends in spring temperature varied markedly between study sites, and across populations the advancement of laying date was stronger in areas where the spring temperatures increased more, giving support to the theory that climate change causally affects breeding date advancement.

Joint action of chemicals in algal toxicity tests: influence of response level and dose-response regression model.

The joint toxicity of nonylamine and decylamine and of atrazine and decylamine was evaluated in assays with the green alga Selenastrum capricornutum based on an isobologram method. In this method, curves of constant response, isoboles, are plotted versus concentrations of two toxicants. The response parameter was growth rate based on biomass, and several response levels were used. Dose-response curves were developed for dilution series using fixed ratios between concentrations in toxic units of the compounds. Probit and Weibull dose-response curves were then determined by nonlinear regression. A model for isoboles for partially similar action was used when applicable. The no-effect concentration (NEC or EC0) was estimated based on a newly proposed model containing median effective concentration (EC50) and EC0 as explicit variables. Results show that nonylamine and decylamine are nearly concentration additive at EC50 and EC10 (similarity parameter lambda = 0.70-0.76) and to a lesser extent at EC0. By contrast, the mixtures of atrazine and decylamine show antagonism in that atrazine acts as an antidote to decylamine. The shapes of these isoboles are independent of response level. The EC50 values (mg/L) for chemicals acting singly were 0.090 (nonylamine), 0.039 to 0.044 (decylamine), and 0.225 (atrazine). In order to determine NEC effectively, the level of inhibition must be fairly low, with observed growth rates between 0.6 and 1.0 times the average growth rate of the controls.

Primary biodegradation of veterinary antibiotics in aerobic and anaerobic surface water simulation systems.

The primary aerobic and anaerobic biodegradability at intermediate concentrations (50-5000 microg/l) of the antibiotics olaquindox (OLA), metronidazole (MET), tylosin (TYL) and oxytetracycline (OTC) was studied in a simple shake flask system simulating the conditions in surface waters. The purpose of the study was to provide rate data for primary biodegradation in the scenario where antibiotics pollute surface waters as a result of run-off from arable land. The source of antibiotics may be application of manure as fertilizer or excreta of grazing animals. Assuming first-order degradation kinetics, ranges of half-lives for aerobic degradation of the four antibiotics studied were 4-8 days (OLA), 9.5-40 days (TYL), 14-104 days (MET) and 42-46 days (OTC). OLA and OTC were degraded with no initial lag phase whereas lag phases from 2 to 34 days (MET) and 31 to 40 days (TYL) were observed for other substances. The biodegradation behaviour was influenced by neither the concentrations of antibiotics nor the time of the year and location for sampling of surface water. Addition of 1 g/l of sediment or 3 mg/l of activated sludge from wastewater treatment increased the biodegradation potential which is believed to be the result of increased bacterial concentration in the test solution. Biodegradation was significantly slower in tests conducted in absence of oxygen. Assessments of the toxic properties of antibiotics by studying the influence on the biodegradation rates of 14C-aniline at different concentrations of antibiotics showed that no tests were conducted at toxic concentrations.

Shake-flask test for determination of biodegradation rates of (14)C-labeled chemicals at low concentrations in surface water systems.

A simple shake-flask surface water biodegradability die away test with (14)C-labeled chemicals added to microgram per liter concentrations (usually 1-100 microg/L) is described and evaluated. The aim was to provide information on biodegradation behavior and kinetic rates at environmental (low) concentrations in surface water systems. The basic principle of measurement was to determine evolved CO(2) indirectly from measurements of total organic activity in subsamples after stripping off their content of CO(2). Used with surface water alone the test simulates a pelagic environment and amended with sediments (0.1-1 dry weight/L) the test is intended to simulate a water environment with suspended solids (e.g., resuspended sediments). A protocol of the test used with the (14)C technique or with specific chemical analysis was recently developed by the International Organization for Standardization. Practical experience with the method is presented for a set of reference substances. These substances could be ranked in five groups of decreasing biodegradability: aniline>p-nitrophenol, 2, 4-dichlorophenoxyacetic acid>4-chloroaniline>maleic hydrazide, pentachlorophenol>atrazine. It was found that degradation rates and lag periods varied considerably among sampling sites and sometimes also among samples from the same site. No significant correlation could be established between degradation rates and microbial biomass estimates. Even small portions of added sediments greatly enhanced biodegradation of the absorbable compound pentachlorophenol, probably by providing sites for microbial attachment. Repeated tests indicated consistent degradation behavior for the readily degradable substances, whereas degradation sometimes stopped or failed with the more recalcitrant substances. A preadaptation step involving regular reinoculation with freshly collected surface water could, however, overcome the problems of false-negative results.

Influence of nitrogen status on the bioconcentration of hydrophobic organic compounds to Selenastrum capricornutum.

Changes in algal nitrogen status that increase algal lipid content also affect the bioconcentration of hydrophobic organic compounds (HOCs). Bioconcentration factors (BCFs) for several HOCs increased up to nine times as the total algal lipid content of the green algae Selenastrum carpricornutum increased from 17 to 44% of the algal dry weight as a consequence of nitrogen starvation. An increase in total lipid from 17 to 44% should theoretically increase the BCFs by a factor of 2.6. BCFs for PCB 31, PCB 49, PCB 153, and DDT increased with maximum lipid content by factors of 6.3, 8.9, 8.9, and 6.6, respectively, thus more than theoretically predicted from the lipid normalization of BCFs obtained at exponential growth phase (17% total lipid for S. carpricornutum), whereas BCFs for PCB 105, phenanthrene, and 4-chloroaniline increased at 44% lipid content, only by factors of 1.5, 1.5, and 2.5, respectively, and thus less than or equal to the theoretical prediction. Lipid-class normalization of BCFs did not reveal significant information beyond that available from normalizing to total lipid.

Correcting for toxic inhibition in quantification of genotoxic response in the umuC test.

An improved procedure for quantification of results from the umuC tests for genotoxicity is presented. The calculation method better separates toxic growth inhibition (cytotoxicity) from genotoxic effects than currently used methods and therefore, greatly extends the applicability of genotoxicity tests on environmental samples. The basic principle is to normalize the genotoxic response compensating for both decreasing biomass and growth rate reduction that results from cytotoxicity. The improved method and the currently used method was compared for umuC tests on the pure compounds: methylmethanesulfonate (MMS), N-methyl-N'-nitro-N-nitroguanidine (MNNG), sodium azide (NaN3), and 4-nitroquinoline-1-oxide (4-NQO). For compounds with no or low cytotoxicity, the two calculation methods gave practically identical results, while for highly cytotoxic compounds, the traditional method overestimated genotoxicity. umuC tests were also carried out on leachate polluted groundwater sampled downgradient of a landfill (Grindsted, Denmark). All polluted samples showed high cytotoxicity concomitant with high genotoxicity when the results were quantified in the traditional way. The new method showed that these results were in fact false positive, as the apparent genotoxicity was a result of cytotoxicity. Based on the mathematical analysis leading to the improved procedure for correction for cytotoxicity, it is suggested to alter the present test design of the umuC test in order to obtain well-defined exposure concentrations as well as mathematical consistency in the quantification of genotoxicity.

Estimation of kinetic rate constants for biodegradation of chemicals in activated sludge wastewater treatment plants using short term batch experiments and microgram/L range spiked concentrations.

Biodegradation rate constants that are believed to be predictive for activated sludge sewage treatment plants have been determined at microgram/L concentration levels using short term (hours) laboratory scale batch experiments with activated sludge. Rate constants were estimated for four model chemicals with widely different biodegradability characteristics, and experiments were conducted with sludges of various origin and treatment. Test substances were applied at concentrations ranging from a few microgram/L for deriving first order rate constants and up to several mg/L for full investigation of the kinetics. Model substances were acetate, aniline, 4-chloroaniline and pentachlorophenol and their biodegradation was assessed by means of 14C tracer technique. Some experiments included test concentrations equal to those prescribed in standard biodegradability tests (20 mg DOC/L). Sludge types investigated included adapted and non-adapted sludge from laboratory scale semicontinuous reactors as well as sludges collected from a pilot scale sewage treatment plant loaded with predominantly domestic sewage. At low chemical concentrations ( < approx. 100 micrograms/L) first order degradation rate constants were reasonably constant and varied only little with the applied concentration. With aniline, however, elimination rates increased at concentrations below about 20 micrograms/L, probably because transient sorption became significant. At higher concentrations absolute (linear) degradation rates could be described by saturation kinetics, and for aniline a half saturation constant, K(S), was estimated at 3 mg/L. "Best estimates" of average first order rate constants in the low concentration regime measured with 3 g SS/L and at 22 degrees C were: acetate, 8 h-1; aniline, 0.8 h-1, 4-chloroaniline, 0.15 h-1, and pentachlorophenol, 0.01 h-1 (non adapted sludge) or 0.02 h-1 (adapted sludge). These figures seem to agree well with standard or default biodegradation rate constants for sewage treatment plants suggested in a European Union technical guidance document for chemical risk assessment, which is currently under preparation.

Biodegradability simulation studies in semicontinuous activated sludge reactors with low (microgram/L range) and standard (ppm range) chemical concentrations.

The official OECD/EEC activated-sludge biodegradability simulation test has been criticised for providing a poor simulation of the biodegradability behaviour of industrial chemicals in municipal sewage treatment plants due to the high dosed concentration of test substance of approx. 20-40 mg/L necessitated by measuring compound removal by DOC-analysis. Realistic concentrations of industrial chemicals are more commonly in the microgram/L range. With increasing concentration both the kinetic regime of degradation and the adaptation behaviour can be expected to change. Results from a comparative study in semicontinuous reactors with high (20 mg DOC/L) and low (10 micrograms test substance/L) inlet concentrations of aniline, 4-chloroaniline, and pentachlorophenol, conducted by means of 14C-tracer technique, revealed large differences in biodegradation behaviour between the two concentration levels and led to the following tentative general conclusions: 1) the percentage of test compound removed by unadapted sludge tends to be higher with test compound dosed at trace concentrations than at standard (high) concentrations (20 mg/DOC/L); 2) by contrast, in successfully adapted systems, the removal percentage (and the "extent of adaptation") may be largest with high concentrations; 3) the use of real sewage instead of peptone synthetic sewage better safeguards against sludge deterioration, in particular at low sludge retention times, and tends to increase the adaptation potential of the sludge; 4) the use of synthetic sewage in combination with regular reinoculation of the reactor (in this study by replacing 10% of the sludge with freshly collected sludge once a week) may be a feasible alternative to using real sewage.

Screening methods for assessment of biodegradability of chemicals in seawater--results from a ring test.

An international ring test involving 14 laboratories was organized on behalf of the Commission of the European Economic Communities (EEC) with the purpose of evaluating two proposed screening methods for assessment of biodegradability in seawater: (a) a shake flask die-away test based primarily on analysis of dissolved organic carbon and (b) a closed bottle test based on determination of dissolved oxygen. Both tests are performed with nutrient-enriched natural seawater as the test medium and with no inoculum added other than the natural seawater microflora. The test methods are seawater versions of the modified OECD screening test and the closed bottle test, respectively, adopted by the Organization for Economic Cooperation and Development (OECD) and by the EEC as tests for "ready biodegradability." The following five chemicals were examined: sodium benzoate, aniline, diethylene glycol, pentaerythritol, and 4-nitrophenol. Sodium benzoate and aniline, which are known to be generally readily biodegradable consistently degraded in practically all tests, thus demonstrating the technical feasibility of the methods. Like in previous ring tests with freshwater screening methods variable results were obtained with the other three compounds, which is believed primarily to be due to site-specific differences between the microflora of the different seawater samples used and to some extent also to differences in the applied concentrations of test material. A positive result with the screening methods indicates that the test substance will most likely degrade relatively rapidly in seawater from the site of collection, while a negative test result does not preclude biodegradability under environmental conditions where the concentrations of chemicals are much lower than the concentrations applied for analytical reasons in screening tests. Nevertheless, the screening tests are considered useful and cost-effective tools for an initial assessment of biodegradability in marine environments.

A comparative study of test methods for assessment of the biodegradability of chemicals in seawater--screening tests and simulation tests.

A comparative study has been performed on test methods for assessing the biodegradability of chemicals in seawater environments. A simple shake flask die-away test with natural seawater and 14C-labeled chemicals added in microgram/liter concentrations is proposed as a "simulation" test. The analytical parameter used in this test is residual dissolved 14C activity. The performance of the simulation test has been compared with the performance of similar screening tests with dissolved organic carbon analysis and test compounds added in mg/liter concentrations to nutrient-enriched seawater. All chemicals investigated that passed the screening tests were also degradable in the simulation test and some results with simulation tests were positive; even screening tests were negative, while some compounds, including maleinhydrazide, known to be degradable in soil, remained undegraded in either type of test. Disappearance times after the ended lag time were smaller in screening tests than in simulation tests, but the rates of biodegradation cannot be meaningfully compared, as zero-order kinetics in combination with an exponentially growing population of degraders prevail in screening tests, while first-order kinetics and frequently a constant activity of degraders (cooxidation) prevail in simulation tests where the test material is a secondary substrate only. In screening tests, lag times are sometimes excessively long and highly variable. Whether the lag times could be decreased and their variability narrowed by supplementation with a cosubstrate (yeast extract) or by inoculation with seawater that had been preadapted to the test material was investigated. In most experiments such test modifications had no significant effect but in one experiment with 4-nitrophenol, inoculation with 1% preadapted seawater decreased the lag phase from greater than 35 to 9 days.

Biodegradation of 4-nitrophenol in standardized aquatic degradation tests.

During the years 1978-1981 both the European Economic Community (the EEC) and the Organization for Economic Cooperation and Development (the OECD) organized various interlaboratory comparison programs on standardized screening methods to study the biodegradability of chemicals in water. While the ring test results were generally rather heterogenous, one of the compounds studied, 4-nitrophenol, turned out to be particularly problematic as the compound was found either easily biodegradable or not biodegradable by various laboratories in various tests. This paper describes some more detailed studies on 4-nitrophenol degradation in two different tests, the modified OECD screening test (MOST test) and the Zahn-Wellens test, respectively. The test variables investigated include inoculum characteristics and pretreatment, test duration, and 4-nitrophenol concentration. The results are discussed in relation to toxicity and degradation pathways of 4-nitrophenol. It is concluded that in order to improve the comparability of results from standardized aquatic biodegradation tests, test strategies should allow the option of performing a test with a preadapted inoculum in the event of negative test results with freshly collected inocula. Increasing the inoculated concentration of microorganisms in some tests may also contribute to the attainment of more consistent test results.