Proof Of Safety Research Articles

Dermo-cosmetic management of the periorbital complex

With the recent developments of highly technological dermo-cosmetics showing proofs of efficacy and safety, this category of products may be included in our recommendations to patients when they are concerned by skin aging and the appearance of their face. The periorbital complex is of particular relevance in this demand, as it is of major concern in the appearance of the whole face. Further, during the process of aging, the periorbital complex is often showing earlier signs of aging than other parts of the face. In this article, after a short summary about anatomy, we shall review the different signs of aging in this area, namely eyelid bags (EB), periorbital hyperpigmentation (POH), Crow’s Feet (CF) and finally eye lashes. Eyelid bags may have different aetiologies, and this is not only important to know them, but also to know how to distinguish them, in order to be able to bring the most convenient treatment and recommendations for their management. About POH, it also constitutes a frequent complaint in dermatology and aesthetic medicine. It can also have different aetiologies and for this reason, a strict classification was established for POH, both of them leading to differentiated treatments based on these data. Crow’s feet are also of importance, and often appear very early, being the first signs of face aging. To date exist efficient treatments for CF based on dermo-cosmetics, especially among the various bioactive peptides developed in the course of the last decade, but also vegetal active ingredients. Oral collagen may also be useful in this scope, when adequately prescribed. Finally, eye lashes, as they are considered an important aspect of the facial aesthetics, are the object of various beauty treatments to enhance them. They comprise the use of prostaglandins, efficient but accompanied by various side effects, and here also bioactive peptides, which represent a key stone in the dermo-cosmetic management of the periorbital complex.

Safety of a Smart Classes-Used Regression Test Selection Algorithm

Regression Test Selection (RTS) algorithms select which tests to rerun on revised code, reducing the time required to check for newly introduced errors. An RTS algorithm is considered safe if and only if all deselected tests would have unchanged results. In this paper, we present a formal proof of safety of an RTS algorithm based on that used by Ekstazi [Gligoric, M., L. Eloussi and D. Marinov, Practical regression test selection with dynamic file dependencies, in: Proceedings of the 2015 International Symposium on Software Testing and Analysis, ISSTA 2015 (2015), p. 211–222. URL https://doi.org/10.1145/2771783.2771784], a Java library for regression testing. Ekstazi's algorithm adds print statements to JVM code in order to collect the names of classes used by a test during its execution on a program. When the program is changed, tests are only rerun if a class they used changed. The main insight in their algorithm is that not all uses of classes must be noted, as many necessarily require previous uses, such as when using an object previously created. The algorithm we formally define and prove safe here uses an instrumented semantics to collect touched classes in an even smaller set of locations. We identify problems with Ekstazi's current collection location set that make it not safe, then present a modified set that will make it equivalent to our safe set. The theorems given in this paper have been formalized in the theorem prover Isabelle over JinjaDCI [Mansky, S. and E. L. Gunter, Dynamic class initialization semantics: A jinja extension, in: Proceedings of the 8th ACM SIGPLAN International Conference on Certified Programs and Proofs, CPP 2019 (2019), p. 209–221. URL https://doi.org/10.1145/3293880.3294104], a semantics for a subset of Java and JVM including dynamic class initialization and static field and methods. We instrumented JinjaDCI's JVM semantics by giving a general definition for Collection Semantics, small-step semantics instrumented to collect information during execution. We also give a formal general definition of RTS algorithms, including a definition of safety.

Epidemiology, pathophysiology and contemporary management of cardiogenic shock - a position statement from the Heart Failure Association of the European Society of Cardiology.

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus-driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high-quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in-hospital management.

Ten-Year Efficacy and Safety of Once-Daily Tacrolimus in Kidney Transplant: A Prospective Cohort Study

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney transplant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 ± 1.6 mL/min/1.73 m2) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 ± 2.2 mL/min/1.73 m2) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 ± 2.2 vs 48.0 ± 2.7 mL/min/1.73 m2 in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy-proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia.In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in patients with kidney transplantation.

Use compatibility intervals in regulatory toxicology

Recently it was recommended to avoid significance tests, in particular dichotomization into significant/non-significant on the basis of a p-value and a fixed 5% significance level (i.e. false positive rate). As an alternative, the interpretation of a suitable effect size and its compatibility interval is recommended, i.e. confidence intervals whose compatibility with the data, the assumptions, and the models is shown. This concept is used for the evaluation of assays in regulatory toxicology with special emphasis on the proof of hazard and proof of safety. Three case studies for multiple endpoints, multiple models and the consideration of historical controls illustrate the applicability of this concept. The corresponding software code for the open-source R project for statistical computing (www.r-project.org) is provided.

Partnerships and Collaborations: The Right Alliances for Clinical Trials in Africa.

Africa attracts < 1% of all trials conducted around the world. The implication is that proof of safety and efficacy in Africans is lacking for a lot of new therapies. The sizeable proportion of approximately 20% of the global population that Africa represents largely does not have empiric data to support use of new therapies in a population with a distinct genetic and racial profile. Beyond the imperative of evidence-based interventions, Africans carry a disproportionately heavy burden of certain diseases, including prostate cancer, sickle cell anemia, and malaria. It therefore provides opportunity for efficient recruitment of participants for trials for such diseases. However, this advantage has not convinced sponsors to carry out clinical trials in Africa. India and China each have roughly the same population size as Africa, but each presents just one regulatory jurisdiction for clinical trials. Africa has 54 countries, and a sponsor would theoretically need to file 54 different applications to cover the entire continent. Collaboration and partnership among all stakeholders in the clinical trial ecosystem will reduce the burden on sponsors and make Africa competitive as a destination for clinical trials. Collaboration among national regulatory agencies will enable Africa to be treated as one regulatory jurisdiction and reduce administrative burden. Sites and researchers can partner to improve quality, attain necessary certifications, and increase overall efficiency. Central to all of these are clinical research organizations that can coordinate and work across borders to make clinical trial projects seamless. Ultimately, patients will benefit as quality of clinical practice improves and access to new therapies is enhanced.

CRISPR-Cas13 as an Antiviral Strategy for Coronavirus Disease 2019.

CRISPR-Cas13 as an Antiviral Strategy for Coronavirus Disease 2019.

Potency and power

Building on a rich body of feminist scholarship on estrogen, this account interrogates how potent estrogenic cosmetics and consumer product labels emerged together, through the regulatory practices of scientists and lawyers, in mid-century Canada. Composed from archival and other primary sources, the story traces the development of Canada’s first cosmetic regulations – which applied only to cosmetic products containing estrogens. In 1944, “sex hormones” had been the first substances for which the Department of National Health and Welfare adopted labels in lieu of dose or potency standards under the Food and Drugs Act. With dose-response thresholds thus written out of the Sex Hormone Regulations, in 1949, regulators devised a new type of consumer product label that warned women to use estrogenic cosmetic products “with care”. Further regulatory amendments in 1950 appeared, on their face, to require positive proof of safety for estrogenic cosmetics, However, through varied administrative and enforcement practices that hinged upon “directions for use” in product labels, National Health officials quietly reintroduced dose-response logics back into estrogen regulation. As legal technologies for disciplining women consumers to regulate their own exposures, product labels were becoming instrumental. With labeling, estrogen catalyzed an early example of risk regulation in Canada.

Towards effective COVID‑19 vaccines: Updates, perspectives and challenges (Review).

In the current context of the pandemic triggered by SARS-COV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS-COV-2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a COVID-19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.

Оцінка програмного забезпечення систем залізничного транспорту станційного рівня на відповідність вимогам українських стандартів

The purpose of this article is to find effective methods for assessing and proving the functional safety of software at the station level railway control systems. Adaptation of experience and development of a common approach to the software verification process. Method. To achieve this purpose the analysis of current regulatory documents was conducted. An adaptation of the existing experience in performing the conformity assessment of information and control systems important for the safety of nuclear power plants was carried out. All this allowed to determine the general requirements and methods of evaluation of software for various purpose. Results. Based on the results of the analysis of the current normative documents, the procedure for evaluating the software of systems of various purposes has been implemented in the TCC of LTD RPI HARTRON-ARKOS. Scientific novelty. This article formulates proposals for the extension of the standards of DSTU 4178 in the part of the assessment and proof of functional safety of software at the station level railway control systems. At the same time, the general requirements and methods of evaluation of software for different purposes, given in the current standards, were taken into account. Practical importance. The proposed approach of railway system software evaluation greatly extends the requirements of DSTU 4178 and facilitates the development and implementation of new, more effective software verification methods.

Linagliptin: Cardiovascular and renal safety beyond doubt at a steep price

Dipeptidyl peptidase-IV inhibitors or “gliptins” are commonly used oral anti-diabetic drugs for Type 2 diabetes mellitus, preferred as add-on therapy after metformin. Various cardiovascular outcome trials (CVOTs) have established their cardiovascular safety. Approved later than other gliptins, linagliptin has unique pharmacokinetic profile. A literature review was performed by searching science databases, in addition to the Medline database via PubMed, for relevant articles. The search included meta-analyses, systematic reviews, review articles, and randomized and nonrandomized trials. Related publications in the English language were reviewed, and the most relevant papers were summarized. This review explores the potential of clinical use of this drug in light of the two recently reported CVOTs, and cost of therapy. Results of CAROLINA and CARMELINA, published in 2019 and 2018, respectively, provide robust proof of long-term CV and renal safety of linagliptin. Both trials are first of their kinds for including diabetes population with renal compromise and use of an active comparator, respectively. Physicians can confidently choose in subsets of adults with diabetes who have compromised renal or cardiac functions or who are at high risk without any dose adjustments. However, the price of the drug is very high, costlier than other oral drugs. Cost remains the biggest hurdle and is likely to remain so with the drug being patent protected for a considerable time in future. Thus, despite the promise of CV and renal safety, linagliptin is likely to remain out of reach for majority of the Indian population with diabetes.

Survey on Scenario-Based Safety Assessment of Automated Vehicles

When will automated vehicles come onto the market? This question has puzzled the automotive industry and society for years. The technology and its implementation have made rapid progress over the last decade, but the challenge of how to prove the safety of these systems has not yet been solved. Since a market launch without proof of safety would neither be accepted by society nor by legislators, much time and many resources have been invested into safety assessment in recent years in order to develop new approaches for an efficient assessment. This paper therefore provides an overview of various approaches, and gives a comprehensive survey of the so-called scenario-based approach. The scenario-based approach is a promising method, in which individual traffic situations are typically tested by means of virtual simulation. Since an infinite number of different scenarios can theoretically occur in real-world traffic, even the scenario-based approach leaves the question unanswered as to how to break these down into a finite set of scenarios, and find those which are representative in order to render testing more manageable. This paper provides a comprehensive literature review of related safety-assessment publications that deal precisely with this question. Therefore, this paper develops a novel taxonomy for the scenario-based approach, and classifies all literature sources. Based on this, the existing methods will be compared with each other and, as one conclusion, the alternative concept of formal verification will be combined with the scenario-based approach. Finally, future research priorities are derived.

Design, quality, safety and efficacy of extensively hydrolyzed formula for management of cow's milk protein allergy: What are the challenges?

Cow's milk protein allergy (CMPA) is one of the most common food allergies in infancy. Clinical food allergy guidelines recommend an extensively hydrolyzed formula (EHF) as the first-line treatment in nonbreastfed infants with CMPA. Designing and commercializing EHF poses both technical and regulatory challenges. Each manufacturing step, from sourcing of raw materials to release of the final product, needs to be managed in accordance with comprehensive quality systems. To avoid cross-contamination via externally sourced ingredients, suppliers should be carefully selected based on quality requirements. Strict zoning of the manufacturing areas according to contamination risk and air flow control are effective strategies to prevent accidental allergen contamination. Furthermore, dedicated manufacturing lines for hypoallergenic products are used to prevent potential cross-contamination from other products produced on the same line. The enzymatic hydrolysis, heat treatment and ultrafiltration used are specific to each manufacturer. Consequently, EHF are a heterogenous group of products with differences in the molecular weight profile of peptides, content of residual immunogenic cow's milk allergens, and residual in-vitro allergenicity. These differences are likely to affect clinical efficacy and safety. As not all commercialized EHF products have undergone formal testing in the laboratory and clinical trials, there is a need to develop guidelines for minimum technical and regulatory requirements for EHF products, including validated assays for ongoing quality control. Clinical trials assessing new EHF products for their hypoallergenicity and ability to support normal growth remain the definitive proof of efficacy and safety in infants and young children with CMPA.

A Blockchain Privacy Protection Scheme Based on Ring Signature

Blockchain is a point-to-point distributed ledger technology based on cryptographic algorithms. However, the open and transparent blockchain ledger supplemented by statistical methods such as sociological mining and data mining has caused users’ privacy to face major threats. Therefore, privacy protection has become a focus of current blockchain technology research. Ring signature technology is a commonly used encryption technology in the field of privacy protection. Therefore, this paper constructs a blockchain privacy protection scheme based on ring signature. This solution built a privacy data storage protocol based on the ring signature on the elliptic curve, and used the complete anonymity of the ring signature to ensure the security of data and user identity privacy in blockchain applications. The correctness and safety proof analysis of the proposed scheme were also carried out.

Reductions for safety proofs

Program reductions are used widely to simplify reasoning about the correctness of concurrent and distributed programs. In this paper, we propose a general approach to proof simplification of concurrent programs based on exploring generic classes of reductions. We introduce two classes of sound program reductions, study their theoretical properties, show how they can be effectively used in algorithmic verification, and demonstrate that they are very effective in producing proofs of a diverse class of programs without targeting specific syntactic properties of these programs. The most novel contribution of this paper is the introduction of the concept of context in the definition of program reductions. We demonstrate how commutativity of program steps in some program contexts can be used to define a generic class of sound reductions which can be used to automatically produce proofs for programs whose complete Floyd-Hoare style proofs are theoretically beyond the reach of automated verification technology of today.

Virtual Assessment of Automated Driving: Methodology, Challenges, and Lessons Learned

Automated driving as one of the most anticipated technologies is approaching its market release in the near future. Since several years, the research in the automotive industry is largely focused on its development and presents well-engineered prototypes. The many aspects of this development do not only concern the function and its components itself, but also the proof of safety and assessment for its market release. It is clear that previous methods used for the release of Advanced Driver Assistance Systems are not applicable. In contrast to already released systems, automated driving is not restricted to a certain field of application in terms of driving scenarios it has to take action in. This results in an infeasible amount of required testing and unforeseeable scenarios the function can face throughout its lifetime. In this article, we show a scenario-based approach that promises to overcome those challenges. In contrast to previous methods, it includes virtual test domains in a verified way to diminish the demand for real-world testing. Local verification of certain scenarios from real-world testing enables virtual variation in a local test space, and thus contributes to the test volume. The approach is implemented, evaluated, and shows first promising results. An intentional evaluation against a corner case-a scenario where the use of virtual test domains is challenged-from the set of scenarios reveals current weak spots. These are transformed into lessons learned, proposed solutions, and future work for enhancements. With the aid of these, the suggested methodology is a promising candidate to overcome the challenges of evaluating automated driving functions.

THE FUTURE OF BIOFEEDBACK: Four Important Questions from Biofeedback Pioneer Lilian Rosenbaum

THE FUTURE OF BIOFEEDBACK: Four Important Questions from Biofeedback Pioneer Lilian Rosenbaum

Cost reduction of solar thermal plants by advanced thermal-hydraulic design methods

Software programs for thermodynamic systems modelling and simulation, e.g. Polysun®, are well established and widely used. By comparison, there are few tools available for the dimensioning of pipe networks, pumps and expansion vessels. Furthermore, it has not been possible to prove operational safety numerically. This gap is closed by the software tools HYDRA and THD which are introduced in this article. HYDRA is used to design the pipe network of large thermal solar plants. THD allows the dimensioning of solar plants up to approximately 100 m2 collector area, including proof of venting capabilities and proof of stagnation safety.

Triboelectric nanogenerators for electro-assisted cell printing

Electro-assisted cell printing has been extensively applied to the biomedical field to generate cell-laden microspheres for tissue engineering, disease pathological studies, and treatment therapy development. Here we have developed a cell printing system driven by triboelectric nanogenerators (TENGs) along with a voltage multiplier rectifying circuit (VMRC) that provides a direct-current high-voltage (HV) output up to 5–8 kV. The microspheres generated by the system showed an adjustable diameter ranging among 200–400 μm, which is suitable for three dimensional (3-D) cell culture. Electrical analysis and multiple physical field simulations have been carried out to uncover the mechanisms of the triboelectric cell printing process. Additionally, two different experimental methods were utilized to measure the charge on each microsphere, which is around only 30 pC, a direct proof for the high safety of this method. Moreover, factor experiments were conducted to determine the practically appropriate parameters. Finally, HepaRG and HeLa cells were bioprinted with high cell viability (over 92%). These results proved that TENGs could be used a safe and efficient approach for electro-assisted cell printing as well as subsequent biomedical applications. In addition, the results reinforce the possibility of TENGs to be a simple and effective HV power source, giving a reference for more relevant research in the future.

Issues Meriting Further Study in Preventing Mother-to-Infant Transmission of Hepatitis B by Antiviral Therapy During Pregnancy

Abstract Mother-to-infant transmission of hepatitis B virus (HBV) is a main cause of chronic HBV infection. Maternal high HBV DNA level or positive hepatitis B e antigen (HBeAg) is the major risk factor for the transmission. With recommended passive and active immunoprophylaxis, the transmission occurs in nearly 0 and 4–12% of infants born to HBV-infected mothers with negative and positive HBeAg, respectively. Therefore, pregnant women with negative HBeAg appear not requiring antiviral therapy to prevent mother-to-infant transmission of HBV. Recent studies demonstrated that oral antivirals (lamivudine, telbivudine, or tenofovir) in pregnant women with high viral load or positive HBeAg, starting from 28–32 weeks of gestation, together with neonatal immunoprophylaxis, can almost completely prevent the transmission, indicating that it does not require antiviral therapy before 28 weeks of gestation. Accumulated evidence showed that the antivirals may be stopped upon delivery, and the infants may receive breast feeding after birth. However, these issues, as well as HBV DNA threshold for antiviral therapy during pregnancy, optimal timing for start and discontinuation of antivirals, and the drug safety of fetuses/infants, require further investigations to optimize the antiviral therapy during pregnancy. The proof of safety of fetal exposure to antivirals needs more evidence, which can be achieved from the real-world data analysis.