The first biosimilar approved for the treatment of osteoporosis: results of a comparative pharmacokinetic/pharmacodynamic study.

To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the originator, a comparative pharmacokinetic trial was conducted. The study was successful in establishing bioequivalence. Marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency in 2017. INTRODUCTION: Teriparatide, the first bone anabolic agent, is the biologically active fragment of human parathyroid hormone. The imminent patent expiry of the originator will open the door for biosimilars to enter the osteology market, thereby improving access to a highly effective, yet prohibitively expensive therapy. METHODS: Subsequent to establishing comparability on the quality and non-clinical levels between RGB-10, a biosimilar teriparatide, and its reference product (Forsteo®), a randomised, double-blind, 2-way cross-over comparative study (duration: four days) was conducted in 54 healthy women (ages: 18 to 55 years) to demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence and comparable safety of these products. Extents of exposure (AUC0-tlast) and peak exposure (Cmax), as measured by means of ELISA, were evaluated as co-primary PK endpoints, and serum calcium levels, as measured using standard automated techniques, were assessed for PD effects. Safety was monitored throughout the study. RESULTS: The 94.12% CIs for the ratio of the test to the reference treatments, used due to the two-stage design (85.20-98.60% and 85.51-99.52% for AUC0-tlast and Cmax, respectively), fell within the 80.00-125.00% acceptance range. The calcium PD parameters were essentially identical with geometric mean ratios (GMRs) of 99.93% and 99.87% for AUC and Cmax, respectively. Analysis of the safety data did not reveal any differences between RGB-10 and its reference. CONCLUSION: Based on the high level of similarity in the preclinical data and the results of this clinical study, marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency (EMA) in 2017.

Enhancement of nutrient removal performance of activated sludge with a novel hybrid biofilm process.

The aim of this study was to investigate the efficacy of a hybrid biofilm pilot-scale treatment plant, designed with a novel configuration by the integration of a fixed-film system, to improve nitrogen removal. The pilot-scale system was established at a wastewater treatment plant in Istanbul and operated based on stream separation following a process consisting of Bio-P and primary sedimentation units in which carbonaceous compounds were entrapped/incorporated in settled biomass. The ammonia-rich supernatant was directed to a moving bed biofilm (MBBR) nitrification tank to obtain an efficient nitrification with the reduced organic loading after the primary sedimentation. The conventional activated sludge process, for which the net specific growth rate ([Formula: see text]) was measured to be 0.26 day-1 at 15 °C, exhibited a low nitrification capacity. However, the pilot-scale hybrid biofilm system secured nitrification performance up to 1.8 gN/m2/day ammonia loading, providing a competitive advantage over the conventional single sludge systems. The proposed hybrid configuration enables removal efficiencies of 80% and 85% for total nitrogen and phosphorus. It was possible to entrap organic matter by mixing 30% of return activated sludge (RAS) with raw wastewater. Simulation-based design study showed that the use of the hybrid biofilm system reduces the environmental footprint and aeration requirement of the nutrient removal by about 50% and 19%, respectively. Economic analyses highlighting the benefit of hybrid biofilm over conventional BNR system are illustrated.

Experimental Assessment of the Degradation of "Unbiodegradable" Organic Solids in Activated Sludge.

In current process models activated sludge consists of biodegradable and unbiodegradable organic fractions. Recent evidence suggests that this approach may not be accurate because some of this "unbiodegradable" material may indeed be degradable. To improve sludge production predictions, it is important to know to what extent the "unbiodegradable" organic fraction is degradable. Assuming that volatile suspended solids (VSS) is a measure of the sum of biodegradable and unbiodegradable organic solids and the integral of the oxygen uptake rate (OUR) is representative of the biodegradable organics, the combination of these measurements can be used to predict the change of unbiodegradable organic solids within an aerobic digestion batch experiment. This procedure was used to estimate degradation rates of "unbiodegradable" VSS between 0.006 to 0.029 d(-1). The advantage of the proposed method is that the degradation rate can be determined directly based on measurements and relies on a limited number of assumptions.

Vitamin D-neutralizing CYP24A1 expression, oncogenic mutation states and histological findings of human papillary thyroid cancer.

OBJECTIVE: The aims of the present study were to examine gene and protein expression of the vitamin D-inactivating 24-hyroxylase (CYP24A1) and the activating 1-alpha-hydroxylase (CYP27B1) enzyme in human papillary thyroid cancer (PTC), furthermore, to investigate the association between CYP24A1 expression and numerous clinical, histological parameters and somatic oncogene mutation status of thyroid tumor tissues. MATERIALS AND METHODS: Gene expression analysis was carried out in 100 Hungarian thyroid samples, both normal and papillary tumor tissue sections of the same patient. The specific mRNA to the selected genes was analyzed by TaqMan probe-based quantitative real-time RT-PCR. The somatic oncogene mutation states of BRAF, NRAS, HRAS and KRAS were also tested. RESULTS: CYP24A1 mRNA expression was markedly increased in 52 cases (52%) of the examined papillary cancers compared with that of normal thyroid tissue. There was a tendency toward difference in the distribution of high-level CYP24A1 in the PTC accompanied with somatic oncogene mutation. Positive correlation was seen between increased CYP24A1 expression rate and a group of variables reflecting tumor malignity (mainly vascular invasion, lymph node metastasis, tumor size, hypothyreosis) by principal components analysis. No significant alteration was seen in CYP27B1 gene expression between neoplastic and normal tissues. CONCLUSIONS: A definite alteration was seen in vitamin D3-inactivating CYP24A1 gene activity in PTC compared to their normal tissues on a relatively large patient population. Our findings raise the possibility that CYP24A1 may also directly be involved in thyroid carcinogenesis.

Report on a case of fibrogenesis imperfecta ossium and a possible new treatment option.

Fibrogenesis imperfecta is an extremely rare acquired progressive bone disorder of unknown etiology. In its course, normal bone architecture is replaced at sites by structurally unsound collagen-deficient tissue resulting in a disorganized bone structure and a skeleton that is radically susceptible to deformity and fracture. Herein, we report the case of a patient who had experienced constant bone pain and several spontaneous fractures since 1997. In 10 years' time with the sole exception of his skull, the disease affected the entire skeleton causing a significant decrease in height and progressive disablement. Laboratory findings included elevation of serum alkaline phosphatase and C-terminal telopeptide of type 1 collagen, with normal serum calcium, phosphate, 25-hydroxy-vitamin-D, and parathyroid hormone concentrations. Monoclonal gammopathy was present with no pathological plasma cells in bone marrow. Radiological and histological results were inconclusive suggesting either osteoporosis, osteomalacia, or Paget's disease and later on osteosclerosis. Treatment administered for the abovementioned conditions has proven to be of no effect. The findings eventually raised the possibility of fibrogenesis imperfecta ossium, which was confirmed by polarized light microscopy as well as transmission electron microscopy. The suggested therapy for the disease is melphalan that could not be initiated due to legal restrictions. Steroid monotherapy also reported to be moderately successful in one case resulted in no improvement. Paraproteinemia had been suggested not only to be a characteristic feature but also a possible etiological factor in this condition. In 2012, plasmapheresis was initiated monthly at the beginning, later on biweekly. In response, the patient's symptoms improved dramatically supporting the abovementioned theory.

Comparative statistical analysis of osteoporosis treatment based on Hungarian claims data and interpretation of the results in respect to cost-effectiveness.

UNLABELLED: The efficacy of interventions used in real life for the treatment of osteoporosis has not been evaluated on a national basis. We analysed the database of the single Hungarian health care provider between 2004 and 2010. A marked reduction in fracture incidence and hospitalization was seen, which also proved to be cost-effective. INTRODUCTION: Osteoporosis and its consequences place a significant burden on the health care systems of developed countries. Present therapeutic modalities are effective in reducing the risk of fractures caused by osteoporosis. However, we do not know whether the interventions introduced in the past 15 years have significantly reduced the number of osteoporotic fractures in real life, and if yes, how cost-effectively. METHODS: The database of the National Health Insurance Fund Administration in Hungary was analysed for the period between 2004 and 2010. Two specific patient groups were identified within the population. Patients, who were under osteoporosis treatment in more than 80% of the potential treatment days in three consecutive years (patients with high compliance), were compared with patients where this ratio was under 20% (patients with low compliance). Several statistical comparative models were implemented in order to capture a complete picture on the differences. Because of natural data heterogeneity of administration databases, propensity matching was applied as well. RESULTS: Comparing treated vs. control subjects, patients with high compliance showed a significant decrease in fracture risk and hospitalization, which was more robust after propensity adjustment. On the basis of the observed statistically significant differences, cost-effectiveness analysis was implemented. Utility loss due the observed fractures was compared with the total cost differences of the two arms based on modelling. Our calculations proved the cost-effectiveness of the long-term high compliance in real world settings. CONCLUSION: Our findings infer that the standardized and uniform health care of osteoporotic patients in a country may reduce general fracture incidence and hospitalization in a cost-effective way.

Anaerobic model for high-solids or high-temperature digestion - additional pathway of acetate oxidation.

Current anaerobic digestion models cannot properly simulate processes that are operated under high solids concentrations or high temperatures. A modification to existing models has been implemented by adding important missing degradation pathways, to accommodate these systems without artificially recalibrating the model parameters. Specifically, we implemented the alternate acetate oxidizing mechanism that is more tolerant to ammonia than the standard aceticlastic pathway. Inhibition values were estimated and an empirical function has been used to apply ammonia inhibition. The model also relates metabolic activity to un-ionised species such as undissociated acetic acid as substrate (although not obligatory for all organisms) and unionised ammonia as inhibitor. The model relies on an equilibrium chemistry module (e.g. including the phosphate buffer), resulting in more accurate pH predictions, which is crucial for proper modeling of CO2 and NH3 stripping. Calibration results from three case-studies modeling thermal hydrolysis and subsequent digestion of sludge are presented.

Instrumentation, control and automation in wastewater--from London 1973 to Narbonne 2013.

Key developments of instrumentation, control and automation (ICA) applications in wastewater systems during the past 40 years are highlighted in this paper. From the first ICA conference in 1973 through to today there has been a tremendous increase in the understanding of the processes, instrumentation, computer systems and control theory. However, many developments have not been addressed here, such as sewer control, drinking water treatment and water distribution control. It is hoped that this review can stimulate new attempts to more effectively apply control and automation in water systems in the coming years.

Analysis of activity structure in Szabolcs-Szatmár-Bereg County.

Agriculture has become multifunctional, its task is no longer only the production of healthy food, but it has also expanded with the functions of regional development, landscape management, environmental protection and tourism. This research seeks to explore the multifaceted nature of agriculture, extending beyond traditional food production, by investigating the interconnectedness of various functions, including energy conversion, utilization, and job creation, within the cohesive framework of rural development. According to another claim, agriculture cannot solve the problems of employment and job creation, but at the same time, it forms an economic basis for the quality of the cultural environment. Food production, energy conversion, use, and job creation systems form the unified structure of rural development. Their properties and characteristics, which are embodied in projects, can be interpreted in a system. This way of thinking prevails and strengthens even more when we examine spatial environments adjacent to borders since the connecting role and nature of development processes can be demonstrated for different social, economic and natural environments and its validity can be examined in adaptive solutions.

Going for mainstream deammonification from bench to full scale for maximized resource efficiency.

A three-pronged coordinated research effort was undertaken by cooperating utilities at three different experimental scales investigating bioaugmentation, enrichment and performance of anammox organisms in mainstream treatment. Two major technological components were applied: density-based sludge wasting by a selective cyclone to retain anammox granules and intermittent aeration to repress nitrite oxidizers. This paper evaluates process conditions and operation modes to direct more nitrogen to the resource-saving metabolic route of deammonification.

New approach to analyze genetic and clinical data in bisphosphonate-induced osteonecrosis of the jaw.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a major complication associated with long-term use of bisphosphonates (BP). We aimed to investigate the effect of CYP2C8 rs1934951 SNP and its relationship to a number of clinical and biochemical factors in 46 Hungarian subjects with bisphosphonate-induced ONJ. METHODS: Blood samples were collected from each subject and genomic DNA was extracted. SNP analysis of CYP2C8 gene was carried out by predesigned TaqMan primer/probe sets. The genetic data together with clinical and biochemical variables were evaluated by chi-square test, logistic regression, and principal component analysis (PCA). RESULTS: The risk of mandibular localization of ONJ was 19.2-fold higher in subjects with AG genotype than in normal GG genotype. PCA revealed strong positive correlations between maxillar localization of ONJ and a group of variables including intravenous BP application and serum lipid markers. Mandibular localization of ONJ was correlated positively with serum calcium, 25-hydroxy-vitamin D and PTH levels, oral BP application, and the length of BP therapy. The degree of the disease and the number of recurrences were correlated with the application of hormone-deprivation therapy for breast cancer patients. CONCLUSION: The statistical approach applying PCA to our data may contribute to the better understanding of factors playing role in the development of bisphosphonate-induced ONJ.

Activated sludge modelling: development and potential use of a practical applications database.

This study aims at synthesizing experiences in the practical application of ASM type models. The information is made easily accessible to model users by creating a database of modelling projects. This database includes answers to a questionnaire that was sent out to model users in 2008 to provide inputs for a Scientific and Technical Report of the IWA Task Group on Good Modelling Practice - Guidelines for use of activated sludge models, and a literature review on published modelling projects. The database is analysed to determine which biokinetic model parameters are usually changed by modellers, in which ranges, and what values are typically used for seven selected activated sludge models. These results should help model users in the calibration step, by providing typical parameter values as a starting point and ranges as a guide. However, the proposed values should be used with great care since they are the result of averaging practical experience and not taking into account specific parameter correlations.

Models for nitrification process design: one or two AOB populations?

Models for engineering design of nitrifying systems use one ammonia oxidizer biomass (AOB) state variable. A simple extension using two AOB populations allows a more accurate prediction of nitrification systems at switching process environments. These two AOB subpopulations are characterized by two different sets of kinetic parameters. Selection pressure and competition between the two functional AOB populations are determined by process conditions as demonstrated by three case studies: Case study I describes dynamics of two AOB populations showing different temperature sensitivities (modified Arrhenius term on growth and decay) when bioaugmented from the warm sidestream treatment environment to the cold mainstream and vice-versa. Case study II investigates competition between fast growing micro-strategists and k-strategists adjusted to low ammonia levels depending on the internal mixed liquor recycle rate (IMLR). Case study III shows that AOB transferred from the waste activated sludge of an SBR to the parallel continuous flow system with different decay kinetics can overgrow or coexist with the original population.

A systematic approach for model verification: application on seven published activated sludge models.

The quality of simulation results can be significantly affected by errors in the published model (typing, inconsistencies, gaps or conceptual errors) and/or in the underlying numerical model description. Seven of the most commonly used activated sludge models have been investigated to point out the typing errors, inconsistencies and gaps in the model publications: ASM1; ASM2d; ASM3; ASM3 + Bio-P; ASM2d + TUD; New General; UCTPHO+. A systematic approach to verify models by tracking typing errors and inconsistencies in model development and software implementation is proposed. Then, stoichiometry and kinetic rate expressions are checked for each model and the errors found are reported in detail. An attached spreadsheet (see http://www.iwaponline.com/wst/06104/0898.pdf) provides corrected matrices with the calculations of all stoichiometric coefficients for the discussed biokinetic models and gives an example of proper continuity checks.

Syntrophy of aerobic and anaerobic ammonia oxidisers.

Deammonification is known as an efficient and resource saving sidestream process option to remove the nitrogen load from sludge liquors. The transfer of the intermediate product nitrite between both syntrophic groups of organisms - aerobic and anaerobic ammonia oxidizers (AOB) - appears very sensitive to process conditions such as temperature, dissolved oxygen (DO) and operating nitrite level. Growth kinetics for aerobic and anaerobic AOBs differ by one order of magnitude and require an adequate selection of sludge retention time. This paper provides measurement- and model-based results on how selected sludge wasting impacts population dynamics in a suspended growth deammonification system. Anammox enrichment up to a doubled portion in mixed liquor solids can substantially improve process stability in difficult conditions. A case-study on low temperature operations outlines two possible strategies to balance syntrophic consumption of ammonium and nitrite.

New framework for standardized notation in wastewater treatment modelling.

Many unit process models are available in the field of wastewater treatment. All of these models use their own notation, causing problems for documentation, implementation and connection of different models (using different sets of state variables). The main goal of this paper is to propose a new notational framework which allows unique and systematic naming of state variables and parameters of biokinetic models in the wastewater treatment field. The symbols are based on one main letter that gives a general description of the state variable or parameter and several subscript levels that provide greater specification. Only those levels that make the name unique within the model context are needed in creating the symbol. The paper describes specific problems encountered with the currently used notation, presents the proposed framework and provides additional practical examples. The overall result is a framework that can be used in whole plant modelling, which consists of different fields such as activated sludge, anaerobic digestion, sidestream treatment, membrane bioreactors, metabolic approaches, fate of micropollutants and biofilm processes. The main objective of this consensus building paper is to establish a consistent set of rules that can be applied to existing and most importantly, future models. Applying the proposed notation should make it easier for everyone active in the wastewater treatment field to read, write and review documents describing modelling projects.

LCT 13910 C/T polymorphism, serum calcium, and bone mineral density in postmenopausal women.

SUMMARY: LCT 13910 CC genotype is associated with lactose intolerance, a condition often resulting in reduced milk intake. Women with the CC genotype were found to have decreased serum calcium and reduced bone mineral density. INTRODUCTION: The CC genotype of the 13910 C/T polymorphism of the LCT gene is linked to lactose intolerance and low calcium intake. METHODS: We studied 595 postmenopausal women, including 267 osteoporotic, 200 osteopenic, and 128 healthy subjects. Genotyping, osteodensitometry, and laboratory measurements were carried out. RESULTS: Frequency of aversion to milk consumption was 20% for CC genotype and 10% for TT + TC genotypes (p = 0.03). The albumin-adjusted serum calcium was 2.325 +/- 0.09 mmol/L for CC genotype and 2.360 +/- 0.16 mmol/L for TT + TC genotypes (p = 0.031). Bone mineral density (BMD; Z score) was lower in the CC than TT + TC genotypes, respectively, at the radius (0.105 +/- 1.42 vs 0.406 +/- 1.32; p = 0.038), at the total hip (-0.471 +/- 1.08 vs -0.170 +/- 1.09; p = 0.041), and at the Ward's triangle (-0.334 +/- 0.87 vs -0.123 +/- 0.82; p = 0.044). CONCLUSION: LCT 13910 C/T polymorphism is associated with decreased serum calcium level and lower BMD in postmenopausal women.

A comparative analysis of different approaches for integrated WWTP modelling.

In this paper a comparative analysis of the most important approaches for integrated WWTP modelling is presented. After an introductory presentation of the most important drawbacks and challenges for plant wide modelling, the fundamentals of three different approaches to construct integrated models are presented: "Interfaces" "Standard Supermodel" and "Tailored Supermodel". Afterwards, a comparative analysis of these approaches from different points of view (difficulties for the model end user, characterization of the process in the plant, flexibility or adaptability for each case of study, simulation platform requirements and computational costs) is carried out. From this comparison, some important conclusions about the suitability of each alternative depending on the simulation case study are extracted.

Balancing yield, kinetics and cost for three external carbon sources used for suspended growth post-denitrification.

Facilities across North America are designing plants to meet stringent limit of technology (LOT) treatment for nitrogen removal. In the Mid-Atlantic region of the United States, this is in response to the Chesapeake Bay Agreement, which limit effluent total nitrogen discharges from wastewater treatment plants to between 3-5 mg/L. Since denitrification is crucial for the removal of nitrogen, maximizing this process step will result in a decrease in nutrient load to the receiving waters. Of particular interest is the use of an alternate external carbon source to replace the most commonly used carbon, methanol. Three external carbon sources were evaluated in this study including: methanol, ethanol and acetate at 13 degrees C. The aim of this study was to evaluate the relative benefits and constraints for using these three carbon types. Laboratory scale Sequencing Batch Reactors (SBRs) were set up to grow and acclimate carbon free biomass to the specified substrate while in-situ Specific Denitrification Rates (SDNRs) were conducted concurrently. The results suggest that the SDNRs for acetate (31.0 + or - 4.6 mgNO(3)-N/gVSS/hr) and ethanol (29.6 + or - 5.6 mgNO(3)-N/gVSS/hr) are higher than that for methanol (10.1 + or - 2.5 mgNO(3)-N/gVSS/hr). The yield coefficients in g COD/g COD were observed to follow a similar trend with values of 0.45 + or - 0.05 for methanol, 0.53 + or - 0.06 for ethanol and 0.66 + or - 0.06 for acetate.

Activated sludge modelling in practice: an international survey.

The Good Modelling Practice Task Group (GMP-TG) of the International Water Association (IWA) is developing guidelines for the use of Activated Sludge Models (ASM). As part of this work the group created and sent out a questionnaire to current and potential activated sludge model users in 2007. The objectives of the questionnaire were (i) to better define the profile of ASM users, (ii) to identify the tools and procedures that are actually used and (iii) to highlight the main limitations while building and using ASM-type models. Ninety-six answers were received from all over the world, from several types of organisation. The results were analysed to identify the modellers' perceptions of models depending on their profile. The results also highlighted the main topics of interest for improving modelling procedures which are standardisation of the available modelling guidelines and better experience and knowledge transfer.