Regulatory Demands Research Articles

Impact of the regulatory reserve and capacity demand on the process of justification of the generating sources in respect of the UES Russia management development

An analysis is made of the regulatory documents used to justify the capacity demand and one of its components - the normative capacity reserve. The methodological principles for considering energy availability at hydroelectric power stations from the standpoint of justification of reserve funds are justified. For the price zones of the UES Russia, retrospective information on the forecast values of maximum loads and power generation at hydroelectric power stations has been compared with their actual values. The article gives the practical results of influence of the identified regulatory documents inconsistencies and deviations of the maximum load forecasts and hydroelectric power generation from the actual power demand values and the justification of the generating sources to cover it under a competitive power selection procedure.

Streamlined downstream process for efficient and sustainable (Fab')2 antivenom preparation.

Background:Antivenoms are the only validated treatment against snakebite envenoming. Numerous drawbacks pertaining to their availability, safety and efficacy are becoming increasingly evident due to low sustainability of current productions. Technological innovation of procedures generating therapeutics of higher purity and better physicochemical characteristics at acceptable cost is necessary. The objective was to develop at laboratory scale a compact, feasible and economically viable platform for preparation of equine F(ab')2 antivenom against Vipera ammodytes ammodytes venom and to support it with efficiency data, to enable estimation of the process cost-effectiveness.Methods:The principle of simultaneous caprylic acid precipitation and pepsin digestion has been implemented into plasma downstream processing. Balance between incomplete IgG breakdown, F(ab')2 over-digestion and loss of the active drug's protective efficacy was achieved by adjusting pepsin to a 1:30 substrate ratio (w/w) and setting pH at 3.2. Precipitation and digestion co-performance required 2 h-long incubation at 21 °C. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography. In vivo neutralization potency of the F(ab')2 product against the venom's lethal toxicity was determined.Results:Only three consecutive steps, performed under finely tuned conditions, were sufficient for preservation of the highest process recovery with the overall yield of 74%, comparing favorably to others. At the same time, regulatory requirements were met. Final product was aggregate- and pepsin-free. Its composition profile was analyzed by mass spectrometry as a quality control check. Impurities, present in minor traces, were identified mostly as IgG/IgM fragments, contributing to active drug. Specific activity of the F(ab')2 preparation with respect to the plasma was increased 3.9-fold.Conclusion:A highly streamlined mode for production of equine F(ab')2 antivenom was engineered. In addition to preservation of the highest process yield and fulfillment of the regulatory demands, performance simplicity and rapidity in the laboratory setting were demonstrated. Suitability for large-scale manufacturing appears promising.

Are reinsurance companies overcapitalized?

The cost of insurance and reinsurance tends to follow the classic supply and demand dynamic – if there is too much supply relative to demand, prices will decline and vice versa. In reinsurance, we tend to measure supply in terms of capital, i.e. the money available to (re)insurers to support the risks that they accept from their policyholders. Demand is defined as the amount of premium a (re)insurer is receiving from their policyholders in exchange for taking on a part or all of one or several risks. Over the years the cost of reinsurance has declined to almost unsustainable levels due to an increase in capital relative to demand1.We believe that falling prices in the reinsurance industry due to the supply and demand argument are somewhat misguided. The cause for the increasing levels of (re)insurer capital over the past few years are mainly driven by the increasing demands of the rating agencies. High financial strength ratings as assigned by the rating agencies have become a necessity to (re)insurers in order to successfully compete in the market and significant amounts of capital, often far in excess of regulatory demands, tend to be required to achieve a high financial strength rating.

The feasibility of CO₂‐laser‐induced breakdown spectroscopy for fast lead determination in glass cullet

AbstractWith an overall collection and recycling rate of 74%, the material cycle for glass packaging is well established in the European Union. However, knowledge of the composition of the recycled glass cullet is necessary to avoid creeping accumulation of undesirable contaminants into the material cycle. Due to their toxic properties, this applies in particular for heavy metals, for example, lead. The state‐of‐the‐art technology for detection of lead in recycling glass sorting is X‐ray fluorescence (XRF). Due to lower regulatory demands, as well as increasingly economical hardware, laser‐based detection techniques, like Laser‐Induced Breakdown Spectroscopy (LIBS) may provide an alternate approach in industrial glass sorting to reach comparable detection limits and rates. In our work, CO2‐LIBS was investigated as an alternative tool for the determination of lead in glass cullet. Instead of usually utilized spectrometers, a combination of spectral filters and photodiode was employed to facilitate a fast detection rate. Glass samples with different lead content were investigated in two spectral ranges with respect to detection limits, detection speed, and accuracy. The results are compared to a commercial XRF‐sorting machine for glass cullet. It was found that comparable speeds and accuracies for lead detection in glasses can be reached.

Earth System Law for the Anthropocene

Law has failed to address the ever-deepening socio-ecological crisis of the Anthropocene. In the light of, and as a response to, law’s failures in this respect, this paper argues in support of developing a new legal paradigm for the Anthropocene epoch called Earth system law. It does so first by briefly describing the Anthropocene trope and the extent and dimensions of its socio-ecological crisis. The paper then specifically focuses on international environmental law as an example of how and why law has become incapable of, and inappropriate for, addressing this crisis, and for being unable to respond to the Anthropocene’s regulatory demands. By drawing on three Earth system-related regulatory implications of the Anthropocene trope (i.e., inclusivity, interdependencies and complexity), the final part of the paper makes out a case in support of reforming law and creating a new Earth system oriented legal paradigm that is fit for purpose in the Anthropocene epoch.

Bayesian Value-at-Risk Backtesting: The Case of Annuity Pricing

We propose new Unconditional, Independence and Conditional Coverage VaR-forecast backtests for the case of annuity pricing under a Bayesian framework that significantly minimise the direct and indirect effects of $p$-hacking or other biased outcomes in decision-making, in general. As a consequence of the global financial crisis during 2007--09, regulatory demands arising from Solvency II has required a stricter assessment setting for the internal financial risk models of insurance companies. To put our newly proposed backtesting technique into practice we employ linear and nonlinear Bayesianised variants of two typically used mortality models in the context of annuity pricing. In this regard, we explore whether the stressed longevity scenarios are enough to capture the experienced liability over the forecasted time horizon. Most importantly, we conclude that our Bayesian decision theoretic framework quantitatively produce a strength of evidence favouring one decision over the other.

The impact of different strategies for generation shift keys (GSKs) on the flow-based market coupling domain: A model-based analysis of Central Western Europe

The trading of electricity across zones relies on cross-border capacities, provided by transmission system operators. The target design of the European Union for capacity calculations is flow-based market coupling, a method that provides trading domains while taking into account grid restrictions. Flow-based market coupling heavily relies on Generation Shift Keys, an essential predictive parameter, translating zonal balance changes that originate from market coupling into nodal injections and consequent line flow changes. This analysis quantifies the effect of different Generation Shift Key strategies on the market coupling domains and individual network elements. A strategy entails suppositions regarding which generating units partake in market changes and to what extent. For this, a novel method for base case computations is proposed that relies on matching historical reference flows of network elements. The results show that different strategies substantially alter the shape and size of flow-based market coupling domains and have a statistically significant impact on individual network elements. For many lines, the average line flow sensitivity to market changes differs between 1% and 5% across strategies and up to 10% for a few lines. Furthermore, the analysis details how the n-1 security criterion influences the composition of domain constraints and to what extent network elements are affected by it. Particularly with regard to the planned geographical expansion of flow-based market coupling and changing regulatory demands for transmission system operators, this work attests to the importance of developing accurate and transparent flow-based market coupling parameters and model-based representations.

Driving the CAR to the Bone Marrow Transplant Program.

The US Food and Drug Administration (FDA) approved two commercially available chimeric antigen receptor (CAR) T cell therapies for the treatment of relapsed B cell acute lymphoblastic leukemia (B-ALL) children and young adults less than 25years of age and non-Hodgkin lymphoma in adults after promising results from early-phase single and multi-institutional clinical trials. In this review, we provide an overview of the practical aspects of a chimeric antigen T cell receptor (CAR-T) program development and the steps necessary for its successful implementation. CAR-T therapy is a complex process and poses significant challenges as institutions prepare to deliver this therapy as a standard of care for the eligible patients. It requires a rigorous infrastructure with specific clinical, administrative, and regulatory demands. Institutions that led the clinical trials for CAR-T have adopted various approaches to integrate commercial CAR-T products into their program. Delivering commercial CAR-T cells outside the scope of clinical trials requires careful planning, allocation of resources, and utilization of existing infrastructure. Institutions may need to adapt the existing recommendations and guidelines and tailor them to meet the needs of their program and ensure appropriate financial reimbursement for this expensive but promising immunotherapy.

Challenges and threats of investigator-initiated multicenter randomized controlled trials: the BACE trial experience

<p class="abstract"><strong>Background:</strong> Investigator-initiated clinical research has become a complex environment. Increasing administrative tasks and costs, imposed by stringent regulatory demands, risk to reduce this creative, independent and indispensable research field. The objective of the present study was to illustrate the burden of non-scientific challenges associated with an investigator-initiated multicentre randomized controlled trial, based on the Belgian trial with azithromycin for Chronic obstructive pulmonary disease (COPD) Exacerbations requiring hospitalization (BACE) trial experience.</p><p class="abstract"><strong>Methods:</strong> The trial enrolled 301 patients with COPD, hospitalized for an acute exacerbation between 2014-2017, and assessed the potential of azithromycin, an off-patent antibiotic. Key experienced challenges were complemented with registry data from the Clinical Trial Centre of the University Hospital Leuven to outline the local clinical respiratory research field, quotations for the trial protocol obtained from 3 pharmaceutical companies to provide insight into the budget restraints and a participation survey to capture the consortium’s perspective.</p><p class="abstract"><strong>Results:</strong> 60% of the required sample size was enrolled. Key challenges included trial implementation, study drug and database management. Industry-initiated trials dominated the local research field (61%), whereas investigator-initiated prospective interventional and multicenter trials accounted for 19% and 13%, respectively. The triple quotation revealed the BACE trial to require 1.6 to 2.1-fold the amount when executed by the pharmaceutical industry. The survey identified the lack of a local study team as an important obstacle for participation, along with inadequate financial compensation and excessive administrative workload.</p><p class="abstract"><strong>Conclusions: </strong>Without an adaptation of current regulatory and funding policies to overcome non-scientific challenges, investigator-initiated clinical research is risking to further decline.</p>

Innovative Lessons in Leadership

Innovative Lessons in Leadership

Senior manager decision-making and interactions with frontline staff in intellectual disability organisations: A Delphi study.

Very little is known of the activities of the most senior managers in organisations providing social care in the community to people with intellectual disabilities. Yet the importance of the focus and activities of senior managers in directing and supporting staff practice and staff experiences is likely to be central to an organisation's functioning and support provided for staff and service users. This study employed Delphi methodology with a panel of 11 senior managers, mostly chief executives, managing small to very large organisations providing support for people with intellectual disabilities, in the UK. Answering three rounds of questions, senior managers described their face-to-face and non-face-to-face contacts with staff and decision-making. Narrative data were subject to quantitative and thematic analysis. In the last round, themes were subject to quantitative analysis. Most contacts between senior managers and staff were in formal structured contexts and all managers used social media to promote the organisations' ambitionsregarding good practice. The panel focused upon accessing and understanding the informal aspects of their organisations and staff factors. Decisions were both short-term reactive and long-term strategic and an effort to link these was felt to improve organisational functioning. A framework for understanding senior managers' activities emerged showing two sources of demands and opportunity, extra-organisational focused upon meeting legal and regulatory demands and intra-organisational focused upon understanding and influencing informal staff practices/experiences and cultures within their organisations.

Design Variation of a Dual-Antigen Liposomal Vaccine Carrier System.

The enclosed work focuses on the construction variables associated with a dual-antigen liposomal carrier, delivering encapsulated polysaccharides and surface-localized proteins, which served as a vaccine delivery device effective against pneumococcal disease. Here, the goal was to better characterize and compare the carrier across a range of formulation steps and assessment metrics. Specifically, the vaccine carrier was subjected to new methods of liposomal formation, including alterations to the base components used for subsequent macromolecule encapsulation and surface attachment, with characterization spanning polysaccharide encapsulation, liposomal size and charge, and surface protein localization. Results demonstrate variations across the liposomal constructs comprised two means of surface-localizing proteins (either via metal or biological affinity). In general, final liposomal constructs demonstrated a size and zeta potential range of approximately 50 to 600 nm and −4 to −41 mV, respectively, while demonstrating at least 60% polysaccharide encapsulation efficiency and 60% protein surface localization for top-performing liposomal carrier constructs. The results, thus, indicate that multiple formulations could serve in support of vaccination studies, and that the selection of a suitable final delivery system would be dictated by preferences or requirements linked to target antigens and/or regulatory demands.

Safety evaluation of resveratrol as an active compound for drug-eluting cardiovascular implants

Abstract Resveratrol is a member of stilbenoids with promising anti-atherosclerotic properties. This hallmark makes it an extremely interesting candidate for local drug delivery to damaged tissue adjacent to the implant in order to reduce implant-related complications. For the regulatory approval drug-eluting medical devices have to be thoroughly tested for safety, efficacy and interactions with the surrounding tissue, including tests for sensitization among others. Studies for sensitization help to estimate the risk for an allergic reaction upon prolonged exposure to a chemical compound. Due to increased social and regulatory demand for replacement of animal experiments by in vitro approaches a number of reliable predictive non-animal tests have been developed. Here, we assessed the skin sensitization potential of resveratrol by the direct peptide reactivity assay (DPRA), one of the first non-animal tests adopted by the OECD.

Saccharomyces cerevisiae strains as bioindicators for titanium dioxide sunscreen photoprotective and photomutagenic assessment

Although several short-term assays are available for cosmetic photosafety assessment, cell models are usually highly sensitive to UV radiation, tending to overestimate both phototoxic and photomutagenic risks. In addition, these assays are performed with UV doses/fluences that do not correspond to actual environmental conditions. In this sense, Saccharomyces cerevisiae has already proved to be an interesting tool to predict photomutagenic potential of several compounds, including sunscreens. Yeast can support environmental UVB doses compatible with human daily sunlight exposure, allowing the use of irradiation sources to faithfully mimic the external conditions of ambient sunlight. Herein, we used a set of S. cerevisiae mutant strains sensitive to UVA, UVB and Solar Simulated Light sources in order to evaluate their potential as bioindicators for sunscreen development. The bioindicator potential of the strains was tested with the widely-used titanium dioxide inorganic sunscreen. The AWP001 (yno1) and LPW002 (ogg1yno1) strains obtained in this study stood out as promising experimental tools for the validation of this assay. Overall, our results evidenced a set of S. cerevisiae strains particularly useful for evaluating both photoprotective (efficacy) and photo/antiphotomutagenic (safety) potential of UV filters, meeting the industries and regulatory agencies demand for robust and efficient in vitro screening tests.

Interpersonal physiological regulation during couplesupport interactions: Examining the role of respiratory sinus arrhythmia and emotional support.

In times of need, people seek comfort and support from close others. Support provision is an integral component of attachment relationships, one that is linked with physical and psychological well-being. Successful support provision is believed to be grounded in transactions of sensitive, caring behavior between caregivers and support seekers and to serve a profound regulatory function. However, physiological processes underlying support transactions have not been previously studied. We assessed autonomic vagal regulation and coded spontaneous emotional support behaviors in N=100 heterosexual couples involved in a support interaction. We focused on cardiac vagal activation, operationalized as the increase in respiratory sinus arrhythmia (RSA) from baseline to interaction, as an indicator of regulatory efforts. Analyses revealed a negative association between caregivers' and support seekers' regulatory efforts, which was mediated by emotional support behaviors. We found that caregivers with greater increases in RSA from baseline to interaction provided more emotional support to their partners. Such emotional support was associated with smaller increases in support seekers' RSA and with support seekers' perceptions of their partners as being more sensitive to their needs. Finally, these links were only significant among dyads in which caregivers reported lower levels of attachment anxiety. We interpret these results in the framework of interpersonal regulatory processes, suggesting that provision of support may impose regulatory demands on the side of the caregivers, which in turn could result in attenuated regulatory efforts and positive partner perceptions for the support seekers.

Bribed into Cooperation: Subsidised Inter-municipal Cooperation in Slovenia

Due to the extreme heterogeneity of municipal sizes resulting in a number of small municipalities that are struggling to meet regulatory demands and standards, Slovenia should be the poster child for inter-municipal cooperation. This, coupled with the absence of a second level of local government, should make for flourishing inter-municipal cooperation. This article demonstrates how sound arguments for the establishment of inter-municipal cooperation do not always achieve favourable results – as in a vibrant and productive web of inter-municipal dialogue and cooperation. It was only after significant governmental subsidies were implemented in Slovenia that the municipalities initiated a cooperation process; however, that process only extended to subsidised tasks. The results of the empirical analyses show that a bottom-up process might take too long a time, while a local government (legal) framework may inhibit cooperation due to the fear of losing authority over municipal tasks.

Replacing Di(2-ethylhexyl) Terephthalate by Di(2-ethylhexyl) 2,5-Furandicarboxylate for PVC Plasticization: Synthesis, Materials Preparation and Characterization.

The worldwide regulatory demand for the elimination of non-phthalate compounds for poly(vinyl chloride) (PVC) plasticization has intensified the search for alternatives. Concomitantly, sustainability concerns have highlighted sugar-based 2,5-furandicarboxylic acid as one key renewable-chemical for the development of several products, namely di(2-ethylhexyl) 2,5-furandicarboxylate (DEHF) plasticizer. This study addresses the use of DEHF under a realistic scenario of the co-existence of both DEHF and entirely fossil-based plasticizers. More precisely, original PVC blends using mixtures of non-toxic DEHF and di(2-ethylhexyl) terephthalate ester (DEHT) were designed. The detailed structural, thermal, and mechanical characterization of these materials showed that they all have a set of interesting properties that are compatible with those of commercial DEHT, namely a low glass transition (19.2–23.8 °C) and enhanced elongation at break (up to 330%). Importantly, migration tests under different daily situations, such as for example exudation from food/beverages packages and medical blood bags, reveal very low weight loss percentages. For example, in both distilled water and phosphate buffered saline (PBS) solution, weight loss does not exceed ca. 0.3% and 0.2%, respectively. Viability tests show, for the first time, that up to 500 μM of DEHF, a promising cytotoxic profile is observed, as well as for DEHT. Overall, this study demonstrates that the combination of DEHF and DEHT plasticizers result in a noticeable plasticized PVC with an increased green content with promising cytotoxic results.

Qualitative formative implementation research to inform introduction of a new essential medicine.

The launch of novel pharmaceuticals in the developing world faces significant barriers that can delay or ultimately inhibit uptake. Implementation research can provide an understanding of factors influencing the introduction and scale up of a new product and thus can inform implementation strategy development. This study explored the factors likely to influence introduction of a novel oxytocin formulation for the prevention of postpartum hemorrhage in Ethiopia. Qualitative research methods were used to assess barriers and enablers associated with pre-determined domains: regulatory approval, pricing, supply and demand side advocacy, policy inclusion, end-user training and drug supply. Data were collected through focus group discussions and in-depth interviews with community members, healthcare providers and key informants. Verbatim transcripts were translated to English and analyzed using a thematic content framework. Approval from stringent regulatory bodies was an enabler for gaining national regulatory approval. Purchasers (government and patients) expressed price sensitivity but would be willing to pay a price comparable to or higher than current alternatives if improved quality is delivered. Endorsement from the World Health Organization was described as critical for national policy inclusion. Supply side advocacy should be directed towards the Ministry of Health, which is receptive to advice from reputable agencies with whom they have an existing relationship. Demand side advocacy should be delivered through existing health system channels such as Ministry of Health authorities (for healthcare workers) and community health workers (for community members). The requirement to purchase the product directly from a single manufacturer was highlighted as a potential barrier for entry into the local supply chain. This study highlighted several barriers and enablers associated with the introduction of a new drug product into the health system of Ethiopia. An advanced understanding of these influences can inform the design of locally-appropriate implementation strategies.

Ophthalmic surgery teaching

The outcomes of modern ophthalmic surgery, especially cataract surgery, continue to improve and patients now realistically expect an excellent and speedy outcome with good vision and few complications. Social and regulatory demands for greater transparency and accountability in medicine have increased, highlighting a fundamental ethical tension in medical education—balancing the needs of trainees (who have not yet mastered the technique) to gain experience by performing surgery, with patient safety and the needs of the public to be protected from risk. Patient safety and well-being are the paramount considerations in any training program and must be the first consideration in program design. A variety of different educational strategies, each implemented with the aim of improving operative skills assessment and teaching, has recently been described in the literature. Effective use of these educational tools, combined with a structured approach to teaching and providing meaningful feedback, could improve outcomes, decrease complications and improve the quality and efficiency of surgical training in ophthalmology. Supervisors must assess their teaching style and communication, as being a good surgeon does not necessarily make a good trainer. Open disclosure must be given to patients about who will be performing the surgery, and communication during surgery between supervisors and trainees must be clear, respectful and appropriate.

Studi Perilaku Wajib Pajak Usaha Mikro Kecil Menengah di Kabupaten Gorontalo Utara

This research was conducted to analyze the behavior of UMKM Taxpayers in North Gorontalo District. The results of this study are expected to provide input and develop research in the field of accounting, especially in the field of taxation and behavioral accounting. This research uses descriptive qualitative method. There are four informants who were selected based on the criteria of the researcher. Meanwhile, the data collection is completed by using the unstructured interview method. The results showed that the willingness of informants to register as taxpayers was driven by regulatory demands. In other side, the implementation of the Self Assessment System has not been fully implemented by the UMKM Taxpayer. This is not only by the lack of knowledge of taxpayers, as well as the condition of taxpayers living in North Gorontalo Regency which is The central of Tax office is quite far from Gorontalo City, it makes taxpayers take another account material that must be sacrificed rather than those issued to fulfill tax obligations.