Container Closure Integrity Testing-Method Development for Freeze-Dried Products Using Laser-Based Headspace Oxygen Analysis.

The regulatory expectations introduced by the U.S. Food and Drug Administration in 1999, ICH Q5C, the revised draft of Annex 1, Eudralex volume 4 for consultation, and the recent update of USP general chapters 1207.1 and 1207.2 regarding container closure integrity (CCI) testing have created a need for further development of testing methods, although there are no universally accepted methods to test and evaluate the CCI of a biopharmaceutical drug product. Each testing method and principle has merits and demerits.This paper will present a simple approach to be used in method validation of CCI testing based on headspace oxygen analysis for freeze-dried biopharmaceutical drug products in vials, as well as a method for testing and verifying positive control vials. The model is based on Fick's law of diffusion and is empirically corrected to account for Knudsen diffusion in smaller defect sizes. The model considers storage conditions of the vials, allowing for testing of vials stored under anaerobic and near-sealing pressure conditions and different temperature conditions, as well as testing at different time points. Using this approach based on headspace oxygen analysis, the minimum timeframe for leak detection is dependent on the volume of the object tested, but standard vial sizes have shown that leak sizes of 0.2 µm can be detected within hours of vial stoppering with the model developed. CCI testing by headspace oxygen analysis using this approach can be done quickly and non-destructively. This method can prove its effectiveness in demonstration of a protective critical barrier (CCI) for a biopharmaceutical drug product during real-time situations of manufacturing, transportation, registered storage conditions, etc. (life-cycle approach).LAY ABSTRACT: The recent update of the guideline, USP general chapters 1207.1 and 1207.2, regarding container closure integrity (CCI) testing, has created a need for further development of testing methods. The new methods applied should be deterministic, i.e., describe predefined detection limits and objective quantitative data. Deterministic leak test methods are methods for which the leakage event being detected or measured is based on phenomena that follow a predictable chain of events.At present, there is no universally accepted method to test and evaluate the CCI of a biopharmaceutical drug product.This paper will present a simple model-based method based on headspace oxygen analysis for freeze-dried biopharmaceutical drug products in vials, as well as a method for testing and verifying positive control vials. Positive controls are vials with a known defect, e.g., an inserted micropipette.The model considers storage conditions of the vials, allowing for testing of vials stored under different pressure and temperature conditions, as well as testing at different time points. CCI testing by headspace oxygen analysis using the new approach can be done quickly and without destruction of the vials. This method can prove its effectiveness in demonstration of a protective critical barrier (CCI) for a biopharmaceutical drug product during real situations of manufacturing, transportation, registered storage conditions, etc.

Return to work after lumbar disc surgery is related to the length of preoperative sick leave.

INTRODUCTION: Lumbar disc herniation (LDH) is associated with high morbidity and significant socio-economic impact as the majority of the patients are of working age. The purpose of this study was to determine the impact of length of sick leave on the return-to-work rate after lumbar disc herniation surgery. METHODS: This was a single-centre study of LDH patients who underwent surgery from 18 May 2009 through 28 November 2014. Data were collected prospectively from the DaneSpine database. Questions in DaneSpine include preoperative length of sick leave and working status one year post-operatively. RESULTS: A total of 678 patients were included and 72% of the patients had returned to work one year after their surgery. The rate of patients returning to work decreases significantly with the length of preoperative sick leave. Among the patients who were on sick leave prior to their surgery, 83% returned to work if surgically treated within three months. In contrast, only 50% of those whose sick leave exceeded three months returned to work. CONCLUSION: The present analysis suggests that the return-to-work rate after lumbar disc herniation surgery is affected by the length of sick leave. FUNDING: none. TRIAL REGISTRATION: This study was registered with the Danish Data Protection Agency.

[Allergic rhinoconjunctivitis caused by occupational exposure to ginger]. / Allergisk rinokonjunktivitis pga. erhvervsmæssig udsættelse for ingefær.

We present a case report of occupational allergic rhinoconjunctivitis after exposure to dust from ginger-containing herbal medicine. The likelihood of an aetiological connection between exposure and the patient's symptoms was supported by a temporal association, positive specific IgE, positive histamine release test, positive prick test, and positive acoustic rhinometry test. Occupational allergy to ginger has rarely been reported. The cases described - including the one we present - suggest that work-related IgE-mediated allergy is associated with exposure to dry aerosols/dust.

Discovery of a Ni-Ga catalyst for carbon dioxide reduction to methanol.

The use of methanol as a fuel and chemical feedstock could become very important in the development of a more sustainable society if methanol could be efficiently obtained from the direct reduction of CO2 using solar-generated hydrogen. If hydrogen production is to be decentralized, small-scale CO2 reduction devices are required that operate at low pressures. Here, we report the discovery of a Ni-Ga catalyst that reduces CO2 to methanol at ambient pressure. The catalyst was identified through a descriptor-based analysis of the process and the use of computational methods to identify Ni-Ga intermetallic compounds as stable candidates with good activity. We synthesized and tested a series of catalysts and found that Ni5Ga3 is particularly active and selective. Comparison with conventional Cu/ZnO/Al2O3 catalysts revealed the same or better methanol synthesis activity, as well as considerably lower production of CO. We suggest that this is a first step towards the development of small-scale low-pressure devices for CO2 reduction to methanol.

Occupational asbestos exposure and lung cancer--a systematic review of the literature.

The objective of this study was to evaluate the scientific literature concerning asbestos and lung cancer, emphasizing low-level exposure. A literature search in PubMed and Embase resulted in 5,864 citations. Information from included studies was extracted using SIGN. Twenty-one statements were evidence graded. The results show that histology and location are not helpful in differentiating asbestos-related lung cancer. Pleural plaques, asbestos bodies, or asbestos fibers are useful as markers of asbestos exposure. The interaction between asbestos and smoking regarding lung cancer risk is between additive and multiplicative. The findings indicate that the association between asbestos exposure and lung cancer risk is basically linear, but may level off at very high exposures. The relative risk for lung cancer increases between 1% and 4% per fiber-year (f-y)/mL, corresponding to a doubling of risk at 25-100 f-y/mL. However, one high-quality case-control study showed a doubling at 4 f-y/mL.

Self-sustained carbon monoxide oxidation oscillations on size-selected platinum nanoparticles at atmospheric pressure.

High-quality mass spectrometry data of the oscillatory behavior of CO oxidation on SiO(2) supported Pt-nanoparticles at atmospheric pressure have been acquired as a function of pressure, coverage, gas composition and nanoparticle size. The oscillations are self-sustained for several days at constant temperature, pressure and CO/O(2) ratio. The frequency of the oscillations is very well defined and increases over time. The oscillation frequency is furthermore strongly temperature dependent with increasing temperature resulting in increasing frequency. A plausible mechanism for the oscillations is proposed based on an oxidation-reduction cycle of the nanoparticles which change the rate of CO oxidation on the particles.

Hydrogen production using a molybdenum sulfide catalyst on a titanium-protected n(+)p-silicon photocathode.

A low-cost substitute: A titanium protection layer on silicon made it possible to use silicon under highly oxidizing conditions without oxidation of the silicon. Molybdenum sulfide was electrodeposited on the Ti-protected n(+)p-silicon electrode. This electrode was applied as a photocathode for water splitting and showed a greatly enhanced efficiency.

Consequences of asthma on job absenteeism and job retention.

AIMS: Various social and economic effects are associated with asthma. This quantitative study describes the effects of current asthma on work life evaluated from the number of weeks receiving transfer incomes. METHODS: The study population comprised 7,241 persons answering the ECRHS II screening questionnaire, which was sent to a random age and gender stratified sample of 10,000 persons aged 20 to 44 years. Participants with current asthma were identified by positive answers to a set of validated questions. Transfer incomes for a five-year period were registered from a study-independent national database, which collects all public administered transfer incomes in Denmark. The numbers of weeks receiving unemployment, welfare, sick-leave and disability benefits were identified for each participant and differences between asthmatics and non-asthmatics were analyzed. RESULTS: Asthmatics had significantly more annual weeks receiving welfare (36.6 vs. 20.7, p=0.00), sick leave (9.2 vs. 6.6, p=0.00) and disability (19.3 vs. 11.4, p=0.00) benefits than non-asthmatics. Adult-onset asthmatics had increased prevalence rate ratios for disability of 2.40 (95% confidence interval 1.70-3.40). Blue collar work significantly increased the probability of all public transfer incomes. CONCLUSIONS: Current asthma makes it harder to keep a job. Adult-onset asthmatics and blue collar workers are particularly affected.

Effects of salinity on hard clam (Mercenaria mercenaria) defense parameters and QPX disease dynamics.

QPX (Quahog Parasite Unknown) is a protistan parasite affecting hard clams (Mercenaria mercenaria) along the Northeast coast of the United States. The fact that QPX disease epizootics are usually observed in field sites with high salinities led to the general assumption that salinity represents an important factor for disease distribution. This study was designed to investigate the effect of salinity on QPX disease development as well as constitutive and QPX-induced defense factors in M. mercenaria. Naïve and QPX-infected (both experimentally and naturally) clams were submitted to 17 and 30 psu for 4 months. Standard and QPX-specific cellular and humoral defense parameters were assessed after 2 and 4 months. These included total and differential hemocyte counts, reactive oxygen species production, phagocytic activity of hemocytes, lysozyme concentration in plasma, anti-QPX activity in plasma and resistance of hemocytes to cytotoxic QPX extracellular products. Results demonstrated higher QPX-associated mortality in naturally infected clams maintained at high salinity compared to those held at 17 psu. Our findings also showed an increase in mortality following experimental challenge with QPX in clams submitted to 30 psu but not in those held at 17 psu. Constitutive clam defense factors and the response to QPX challenge were also affected by salinity. QPX challenge caused significant but transitory changes in hemolymph parameters that were obvious at 2 months but disappeared at 4 months. Overall, our results show that salinity modulates clam immunity and the progress of QPX disease although its impact appears secondary as compared to findings we reported earlier for temperature.

The importance of surface morphology in controlling the selectivity of polycrystalline copper for CO2 electroreduction.

This communication examines the effect of the surface morphology of polycrystalline copper on electroreduction of CO(2). We find that a copper nanoparticle covered electrode shows better selectivity towards hydrocarbons compared with the two other studied surfaces, an electropolished copper electrode and an argon sputtered copper electrode. Density functional theory calculations provide insight into the surface morphology effect.

A general route for RuO2 deposition on metal oxides from RuO4.

A novel method for the deposition of RuO(2) from RuO(4)(g) on diverse metal oxides has been developed by grafting dopamine onto the otherwise un-reactive metal oxide surface. Oxygen evolution reaction on TiO(2) and the photoelectrochemical improvement of WO(3) by deposition of RuO(2) are just a few examples where this novel deposition method can be used.

Bioinspired molecular co-catalysts bonded to a silicon photocathode for solar hydrogen evolution.

The production of fuels from sunlight represents one of the main challenges in the development of a sustainable energy system. Hydrogen is the simplest fuel to produce and although platinum and other noble metals are efficient catalysts for photoelectrochemical hydrogen evolution, earth-abundant alternatives are needed for large-scale use. We show that bioinspired molecular clusters based on molybdenum and sulphur evolve hydrogen at rates comparable to that of platinum. The incomplete cubane-like clusters (Mo(3)S(4)) efficiently catalyse the evolution of hydrogen when coupled to a p-type Si semiconductor that harvests red photons in the solar spectrum. The current densities at the reversible potential match the requirement of a photoelectrochemical hydrogen production system with a solar-to-hydrogen efficiency in excess of 10%. The experimental observations are supported by density functional theory calculations of the Mo(3)S(4) clusters adsorbed on the hydrogen-terminated Si(100) surface, providing insights into the nature of the active site.

Effects of temperature on hard clam (Mercenaria mercenaria) immunity and QPX (Quahog Parasite Unknown) disease development: I. Dynamics of QPX disease.

Quahog Parasite Unknown (QPX) causes disease and mortality in hard clams, Mercenaria mercenaria. Seasonality of QPX disease prevalence in the field and changes in QPX growth and survival in vitro suggest a role of temperature in the hard clam-QPX interaction and disease development. This study specifically examined the effect of temperature on QPX disease development and dynamics. Naturally and experimentally infected clams were separately maintained in the laboratory at 13°C, 21°C, or 27°C for 4 months. Following this initial treatment, temperature was adjusted to 21°C for 5 additional months to simulate seasonal changes of temperature in the field and to investigate the effect of temperature variations on QPX disease dynamics. Mortality was continuously monitored during the experiment and clams were sampled at 2, 4 and 9 months for the assessment of QPX disease prevalence and intensity using our standard histological and quantitative PCR techniques. Results demonstrated significantly higher QPX disease prevalence and intensity, as well as higher mortality, in naturally-infected clams maintained at 13°C as compared to those held at 21°C or 27°C. Similarly, disease development was significantly higher in experimentally infected clams maintained at the colder temperature (70% prevalence after 4 months) as compared to those maintained under warmer conditions (<10%). Additionally, our results demonstrated an improvement in the condition of clams initially maintained at 13°C for 4 months after transfer to 21°C for 5 additional months, with a significant reduction of QPX prevalence (down to 19%). Interestingly, disease development or healing in clams maintained at different temperatures exhibited a strong relationship with clam defense status (jointly submitted paper) and highlighted the impact of temperature on clam activity and QPX disease dynamics. These findings should be taken into account for the timing of activities involving the monitoring, movement (e.g. relays, transplants) or grow out (e.g. commercial culture, municipal enhancement) of hard clams in enzootic areas.

Effects of temperature on hard clam (Mercenaria mercenaria) immunity and QPX (Quahog Parasite Unknown) disease development: II. Defense parameters.

Quahog Parasite Unknown (QPX) is a protistan parasite affecting hard clams Mercenaria mercenaria along the Northeastern coast of the United States. The geographic distribution and occurrence of disease epizootics suggests a primary role of temperature in disease development. This study was designed to investigate the effect of temperature on constitutive and QPX-induced defense factors in M. mercenaria. Control and QPX-challenged (both experimentally and naturally) clams were maintained at 13, 21 and 27°C for 4 months. Control and experimentally-infected clams originated from a southern broodstock (Florida, no prior reports of disease outbreak) while naturally-infected clams originated from a northern broodstock (Massachusetts, enzootic area). Standard and QPX-specific cellular and humoral defense parameters were assessed after 2 and 4 months. Measured parameters included total and differential hemocyte counts, reactive oxygen species production, phagocytic activity of hemocytes, lysozyme concentration in plasma, anti-QPX activity in plasma and resistance of hemocytes to cytotoxic QPX extracellular products. Results demonstrated a strong influence of temperature on constitutive clam defense factors with significant modulation of cellular and humoral parameters of control clams maintained at 13°C compared to 21 and 27°C. Similarly, clam response to QPX challenge was also affected by temperature. Challenged clams exhibited no difference from controls at 27°C whereas different responses were observed at 21°C and 13°C compared to controls. Despite differences in infection mode (experimentally or naturally infected) and clam origin (northern and southern broodstocks), similarities were observed at 13°C and 21°C between QPX infected clams from Florida and Massachusetts. Clam response to temperature and to QPX exhibited interesting relationship with QPX disease development highlighting major influence of temperature on disease development.

Direct observations of oxygen-induced platinum nanoparticle ripening studied by in situ TEM.

This study addresses the sintering mechanism of Pt nanoparticles dispersed on a planar, amorphous Al(2)O(3) support as a model system for a catalyst for automotive exhaust abatement. By means of in situ transmission electron microscopy (TEM), the model catalyst was monitored during the exposure to 10 mbar air at 650 degrees C. Time-resolved image series unequivocally reveal that the sintering of Pt nanoparticles was mediated by an Ostwald ripening process. A statistical analysis of an ensemble of Pt nanoparticles shows that the particle size distributions change shape from an initial Gaussian distribution via a log-normal distribution to a Lifshitz-Slyozov-Wagner (LSW) distribution. Furthermore, the time-dependency of the ensemble-averaged particle size and particle density is determined. A mean field kinetic description captures the main trends in the observed behavior. However, at the individual nanoparticle level, deviations from the model are observed suggesting in part that the local environment influences the atom exchange process.

Hospitalization for lifestyle related diseases in long haul drivers compared with other truck drivers and the working population at large.

Personal lifestyle and working conditions are closely linked for long haul truck drivers. We compare lifestyle related diseases in long haul drivers with other drivers of goods and the working population at large. Standardized hospital treatment ratios (SHR) for lifestyle related diseases were compared for long haul truck drivers and other truck drivers to the working population at large. The follow up group comprised of 2,175 long haul drivers and 15,060 other truck drivers. An increased risk was found for lifestyle related diseases among truck drivers except for alcohol related diseases. We identified a strong association between hospital treatment for obesity and working as a driver and an association between diabetes and working as a driver. No major differences in lifestyle related diseases were found in long haul drivers compared to other truck drivers with the exception of a significant lower risk for alcohol-related diseases and a possibly higher risk for lung cancer in long haul drivers. It is concluded that diseases related to excess caloric intake or lack of exercise may be a problem for truck drivers. This risk is preventable and of importance both in occupational medicine as in public health.

Truck drivers hours-of-service regulations and occupational health.

Major industrialised countries, like the United States, Canada, Australia and countries of the European Union (EU) have Hours-of-Service (HoS) regulations for truck drivers that stipulate duration of continuous driving and rest periods. The purported aim is the improvement of road safety by reducing fatigue and drowsiness, but the regulations can also have a strong impact on the working conditions for drivers. Better working conditions for truck drivers is one of the aims of the EU HoS regulations, but they do not seem to fully produce the desired benefits. Truck drivers continue to have a high prevalence of back disorders, which have been linked with the time spent driving. They also have a high incidence of heart disease, which might be due to stress factors at work. Stress levels can be affected by HoS regulations, that leave the driver little job control and lead to social isolation. HoS regulations could contribute more to the improvement of working conditions of truck drivers through counteracting irregular work schedules, night driving and social isolation. Moving the focus from simple control of time spent driving or not driving to fatigue management could improve job control and working conditions for truck drivers without loss of traffic safety.

Locomotor diseases among male long-haul truck drivers and other professional drivers.

OBJECTIVE: High risks for locomotor diseases have been reported for bus and truck drivers in general; however, little is known about the specific risks of long-haul truck drivers. METHODS: Standardised hospitalisation ratios (SHR) for different locomotor diseases of bus drivers, long-haul truck drivers and other truck drivers were compared with each other and with the general Danish working population. RESULTS: Intervertebral disc disorders were more common among professional drivers (SHR: 119, 95% CI: 114-125) and of similar magnitude for cervical and non-cervical disorders. Both long-haul truck drivers and bus drivers had higher SHR for intervertebral disc disorders (SHR: 133, 95% CI: 114-155/SHR: 141, 95% CI: 129-154, respectively) than other truck drivers (SHR: 109, 95% CI: 102-116). The SHR for carpal tunnel syndrome was high among long-haul drivers (SHR: 163, 95% CI: 101-249) and for other truck drivers (SHR: 130, 95% CI: 108-156) compared to bus drivers (SHR: 110, 95% CI: 79-149). All drivers had high SHR for lesions of the ulnar nerve (SHR: 159, 95% CI: 119-207), especially bus drivers (SHR: 197, 95% CI: 116-311). Long-haul truck drivers had high SHRs for synovitis and bursitis (SHR: 150, 95% CI: 105-207), in contrast to other truck drivers and bus drivers (SHR: 103, 95% CI: 89-120/SHR: 87, 95% CI: 66-112, respectively). CONCLUSION: All groups of professional drivers experience high risk of various disorders of the locomotor system but type of vehicle and specific working conditions are associated with different health effects on the locomotor system.