Proof Of Safety Research Articles

QED as a many-body theory of worldlines. II. All-order S -matrix formalism

In arXiv:2206.04188, we developed a first-quantized worldline formalism for all-order computations of amplitudes in QED. In particular, we demonstrated in this framework an all-order proof of the infrared safety of the Faddeev-Kulish (FK) S-matrix for virtual exchanges in the scattering of charged fermions. In this work, we extend the worldline formalism for both the Dyson and FK S-matrix to consider further the emission and absorption of arbitrary numbers of photons. We show how Low's theorem follows in this framework and derive Weinberg's theorem for the exponentiation of IR divergences. In particular, we extend our all-order proof of the IR safety of the FK S-matrix to both virtual exchanges and real photon emissions. We argue that the worldline approach leads to a modern Wilsonian interpretation of the IR safety of the FK S-matrix and provides a novel template for the treatment of IR divergences in real-time problems. Using Grassmannian integration methods, we derive a simple and powerful result for N-th rank vacuum polarization tensors. Applications of these methods will be discussed in follow-up work.

A Non-perturbative Proof of the Asymptotic Safety of 4D Einstein Gravity, With or Without Matter

A Non-perturbative Proof of the Asymptotic Safety of 4D Einstein Gravity, With or Without Matter

Preventing Retinal Detachment: The Encircling Laser Retinopexy Technique.

Encircling (360 degree) retinal detachment prophylaxis using indirect ophthalmoscope laser delivery recently achieved strong proof of safety and effectiveness by preventing the development of peripheral retinal tears and detachments in the eyes of patients with Stickler syndrome (syndromic eyes). Untreated, Stickler syndrome patients have a 65% lifetime risk of retinal detachment (half by age 20, 80% bilateral). This report describes an optimal technique of encircling laser retinopexy to also prevent the more common retinal detachments seen in aging (non-syndromic) eyes that share with Stickler syndrome the common pathogenesis of peripheral retinal tears caused by vitreous traction.

The scenario of clinical research after the COVID-19 pandemic: assessment of regulatory aspects based on Anvisa

Clinical research is a study with human subjects to test the efficacy and safety of an intervention. The phase III study, as it has a larger number of participants and has more controls, is the main study to be presented as proof of efficacy and safety in registering products with Anvisa. With the advent of the global Covid-19 pandemic, it was possible to observe a significant increase in clinical studies being carried out worldwide. For this, this study was divided into three parts i. quantitative assessment of the attractiveness of studies in Brazil after the Covid-19 pandemic; ii. qualitative assessment of studies in Brazil after the Covid-19 pandemic, describing their main characteristics; iii. to assess whether the drugs registered in Brazil, for Covid-19, had their clinical trials carried out with an arm in Brazil. In this analysis, it was possible to identify that, in Brazil, the number of clinical trials increased, but not significantly. However, analyzes of DDCMs and DEECs, considering drugs indicated for Covid-19, by Anvisa, increased by more than 100%, reinforcing that clinical research carried out in Brazil, during this period, had the interest of registering drugs or changing their bulls.

Paraquat, Parkinson's Disease, and Agnotology.

Paraquat, Parkinson's Disease, and Agnotology.

The silent epidemic of substandard and falsified medicines in low- and middle-income countries: heed lessons from the tragic deaths of children in Indonesia

The silent epidemic of substandard and falsified medicines in low- and middle-income countries: heed lessons from the tragic deaths of children in Indonesia

In Vivo Proof of Biological Safety and Physiological Effects of Orally Ingested Water Containing H2-Filled Ultrafine Bubbles (UFBs).

Owing to their unique physicochemical properties and diverse biological effects, ultrafine bubbles (UFBs) have recently been expected to be utilized for industrial and biological purposes. Thus, this study investigated the biological safety of UFBs in water for living beings in drinking the water with a view to future use in health sciences. In this study, we used H2-filled UFBs (NanoGAS®) that can hold hydrogen in the aqueous phase for a long time. Mice were randomly assigned to one of three groups: those receiving NanoGAS® water, reverse osmosis water, or natural mineral water, and they ingested it ad libitum for one month or three months. As a result, subchronic drinking of NanoGAS® water does not affect either the common blood biochemical parameters or the health of the organs and mucosal membranes. Our results, for the first time, scientifically demonstrated the biological safety of H2-filled UFBs water for subchronic oral consumption.

A seasonality-adjusted sequential test for vaccine safety surveillance.

Post-market active safety monitoring is important for the timely capture of safety signals associated with exposure to a new vaccine or drug. The group sequential analysis is a common method employed in safety surveillance. Specifically, it compares the post-vaccination incidence of adverse event (AE) in a vaccinated population with a pre-specified reference level by sequentially conducting hypothesis testing during the surveillance. When the number of AEs is "too high", a safety signal is identified. If the null hypothesis is never rejected, the vaccine is considered safe. Such an approach does not account for either the variation in determining the reference risk from a control population or the seasonality effect. Furthermore, not rejecting the null could be due to a lack of power and cannot always be interpreted as proof of safety. In this paper, we proposed a new group sequential test procedure fully accounting for both seasonality and variation from the historical controls. More importantly, we proposed to construct a confidence interval for the relative AE risk between the exposed and control groups at the end of the study, which can be used to quantify the safety of the vaccine. The proposed method is illustrated via real-data examples on anaphylaxis and examined by extensive simulationstudies.

Formal Development of Safe Automated Driving Using Differential Dynamic Logic

The challenges in providing convincing arguments for safe and correct behavior of automated driving (AD) systems have so far hindered their widespread commercial deployment. Conventional development approaches such as testing and simulation are limited by non-exhaustive analysis, and can thus not guarantee safety in all possible scenarios. Formal methods can provide mathematical proofs that could be used to produce rigorous evidence to support the safety argument. This paper investigates the use of differential dynamic logic and the deductive verification tool KeYmaera X in the development of an AD feature. Specifically, this paper demonstrates how formal models and safety proofs of different design variants of a Decision & Control module can be used in the safety argument of an in-lane AD feature. In doing so, the assumptions and invariant conditions necessary to guarantee safety are identified, and the paper shows how such an analysis helps during the development process in requirement refinement and formulation of the operational design domain. Furthermore, it is shown how the performance of the different models is formally analyzed exhaustively, in <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">all</i> their allowed behaviors.

Reclassifying Fracture Critical Members (Non-Redundant Steel Tension Members) to System Redundant Members in a Steel Arch Bridge

The American Association of State Highway and Transportation Officials (AASHTO) Load and Resistance Factor Design Bridge Design Specifications define fracture critical members (FCMs) as steel primary members, which are subject to tension and whose failure would probably cause the collapse of a portion of or the entire bridge. FCMs not only lead to additional material procurement and fabrication quality requirements, but bridges with FCMs need to meet the requirements of special mandatory bi-annual hands-on inspections in additions to the routine planned bridge inspections per the National Bridge Inspection Standards. The special mandatory inspections for FCMs are a considerable budgetary constraint for asset owners while still not providing definite safety proofs within the period in between the inspections. Designation of FCMs should be carefully scrutinized in a new bridge constructed with high-quality materials and well-designed details. In 2012, the Federal Highway Administration published a memorandum introducing system redundant members (SRMs), which are identified through refined analysis and exempted from the inspection requirements for FCMs. A new AASHTO Guide Specification released in 2018 outlines a detailed procedure for the reclassification of FCMs as SRMs. This paper summarizes the analyses and results of a detailed FEA performed for a newly designed steel arch bridge. The analyses considered potential failure scenarios at the edge girder of the steel arch bridge and demonstrated the available redundancy in the system to distribute the loads by satisfying the performance criteria set forth in the AASHTO Guide Specification. Reclassification of the FCMs as SRMs could help the asset owner to reallocate their strained resources more efficiently.

A distributed simplex architecture for multi-agent systems

We present the Distributed Simplex Architecture (DSA), a new runtime assurance technique that provides safety guarantees for multi-agent systems (MASs). DSA is inspired by the Simplex control architecture of Sha et al., but with some significant differences. The traditional Simplex approach is limited to single-agent systems or a MAS with a centralized control scheme. DSA addresses this limitation by extending the scope of Simplex to include MASs under distributed control. In DSA, each agent runs a local instance of traditional Simplex such that the preservation of safety in the local instances implies safety for the entire MAS. Control Barrier Functions (CBFs) play a critical role. They are used to define DSA’s core components – the baseline controller and the decision module’s logic for switching between advanced and baseline control – and they provide the basis for the proof of safety. We present a general proof of safety for DSA, provided the CBF-related optimization problem solved by the baseline controller is feasible (has a solution) at each time step for which the baseline controller is in control. We also propose a novel extension to the switching logic designed to avoid states in which this optimization problem is infeasible. Finally, we present experimental results for several case studies, including flocking with collision avoidance, safe navigation of ground rovers through way-points, and safe operation of a microgrid.

Two Is Better Than One: Fetal Hemoglobin Reactivation and Alpha-Globin Downregulation to Correct the β-Hemoglobinopathy Phenotype through Base Editing

β-hemoglobinopathies are genetic anemias caused by a reduced or abnormal synthesis of the adult hemoglobin β-chain. In β-thalassemia, the reduced (β+) or absent (β0) production of β-chains causes α-globin precipitation and death of red blood cell (RBC) precursors. In sickle cell disease (SCD), a single amino acid change (β6Glu→Val) in the adult hemoglobin (Hb) βS-chain causes Hb polymerization with consequent RBC sickling, vaso-occlusive crises, organ damage and reduced life expectancy. Transplantation of autologous, genetically modified hematopoietic stem/progenitor cells (HSPCs) is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors or CRISPR/Cas9 nuclease are not equally effective in all the patients and/or raise safety concerns. Base editing (BE) allows the introduction of point mutations (C>T by cytidine base editors, CBEs; A>G by adenine base editors, ABEs) without generating dangerous double strand breaks, thus allowing the multiplexed editing of several targets. Mutations leading to elevated fetal Hb (HbF) or reduced α-globin expression are associated with a better clinical phenotype in both β-thalassemia and SCD patients. Fetal β-like γ-globin compensates for adult β-globin deficiency and reduced α-globin levels impairs its precipitation and inhibit Hb polymerization in SCD. In this study, we have developed BE strategies aiming to (i) reactivate HbF by down-regulating BCL11A, a master repressor of γ-globin expression though inactivation of its enhancers, and (ii) reduce the α-globin levels through targeting of the MCS-R2 enhancer of the α-globin genes (HBA1/2). First, we used CBEs and ABEs to target the GATA1 or ATF4 activator binding site (BS) within the erythroid-specific BCL11A enhancers (+58-kb and +55-kb regions) in SCD HSPCs through RNA delivery and achieved efficiencies of up to ~90%. A colony forming cell (CFC) assay showed no impact on progenitors' viability. RBCs derived from base-edited HSPCs exhibited high HbF expression levels that were sufficient to ameliorate the sickling phenotype. Samples carrying different mutations within the GATA1 or ATF4 BS were associated with different HbF levels, implying that some nucleotides are more essential for GATA1 and ATF4 binding and the consequent BCL11A gene activation. In parallel, we used CBEs and ABEs to target the GATA1 or NF-E2 activator BS within the MCS-R2 enhancer of HBA1/2. We screened single guide RNAs (sgRNAs) in an erythroid cell line (K562) that allowed editing of different nucleotides within the GATA1 and NF-E2 BS and we identified the most efficient sgRNAs diminishing α-globin expression. Next, selected sgRNAs were delivered to SCD HSPCs, achieving high editing efficiency (~85%). A CFC assay showed a good progenitor viability. RT-qPCR and Western Blot analyses in the erythroid progeny of edited SCD HSPCs confirmed α-globin downregulation at RNA and protein levels. Lastly, we combined both strategies using ABEs to target simultaneously BS within the BCL11A and MCS-R2 enhancers in SCD HSPCs. The concomitant usage of two sgRNAs did not affect editing efficiency at the different targeted sites, which was ~80% at both BCL11A and MCS-R2 enhancers. The erythroid progeny of edited SCD HSPCs harboring mutations in both BCL11A and MCS-R2 enhancers showed downregulation of α-globin and up-regulation of γ-globin at RNA and protein expression level. We expect that this combined strategy will efficiently rescue the pathological phenotype of RBCs derived from both SCD and β-thalassemic HSPCs. In conclusion, our study identified the core nucleotides of both the BCL11A and HBA1/2 MCS-R2 enhancers, which are crucial for regulating the expression of these genes and represent potential targets for scarless editing through BE to finely modulate globin expression. We also developed efficient BE strategies to simultaneously reactivate HbF and downregulate the α-globin expression in patient HSPCs. Validation of the above-described results in HSPCs in vivo will provide sufficient proof of efficacy and safety to enable the clinical development of base-edited HSPCs for the therapy of β-hemoglobinopathies.

Spreading the word: pediatric pain education from treatment to prevention

Pain affects everyone hence one can argue that it is in each individual’s interest to understand pain in order to hold correct and adaptive beliefs and attitudes about pain. In addition, chronic pain is reaching pandemic proportions and it is now well known that people living with chronic pain have a reduced life expectancy. To address and to prevent the growth of this public health disaster, we must start looking beyond adulthood. How children view pain has an impact on their behavioral coping responses which in turn predict persistent pain early in the lifespan. In addition, children who suffer from chronic pain and who are not (properly) treated for it before adolescence have an increased risk of having chronic pain during their adult life. Explaining pain to children and youth may have a tremendous impact not only on the individual child suffering from chronic pain but also on society, since the key to stop the pain pandemic may well lie in the first two decades of life. In order to facilitate the acquisition of adaptive behavioral coping responses, pain education aims to shift people’s view on pain from being an apparent threat towards being a compelling perceptual experience generated by the brain that will only arise whenever the conceivable proof of danger to the body is greater than the conceivable proof of safety to the body. Nowadays a lot of pain education material is available for adults, but it is not adapted to children’s developmental stage and therefore little or not suitable for them. An overview of the state-of-the-art pain education material for children and youth is provided here, along with its current and future areas of application as well as challenges to its development and delivery. Research on pediatric pain education is still in its infancy and many questions remain to be answered within this emerging field of investigation.

Study protocol for "MDMA-assisted therapy as a treatment for major depressive disorder: A proof of principle study".

Major depressive disorder (MDD) is a world-leading cause of disability. The available treatments are not effective in all patients, and there is a significant need for more effective treatment options. Here we present the protocol for an investigator-initiated and publicly funded trial of MDMA-assisted therapy (MDMA-AT) for MDD. This single-site, open-label study investigates the proof of principle and safety of MDMA-AT in participants with MDD and provides an initial impression of treatment effectiveness. A total of 12 participants [>18 years] with DSM-5 diagnosis of MDD will receive a flexible dose of MDMA in a therapeutic setting on two dosing days over a 4 week period preceded by three preparatory sessions. Each MDMA dosing session will be followed by three integration sessions. The primary outcome is change in MDD symptom severity, as measured by the mean change in MADRS scores from Baseline to 8 weeks after the second MDMA session. The secondary outcome is change in functional impairment, as evaluated by the mean change in Sheehan Disability Scale scores from Baseline to 8 weeks after the second MDMA session. Safety measures include vital signs, the incidence of Adverse Events and suicidality as measured by the Colombia-Suicide Severity Rating Scale. This proof of principle trial will inform the development of fully powered clinical trials, optimize the protocol for the administration of MDMA-AT in participants with MDD and explore uncertainties including barriers to recruitment, retention and acceptability of MDMA-AT as a treatment for MDD. EudraCT number 2021-000805-26.

Pain therapy within the ERAS concept – Creating objectivity in studies on personalized checkpoint acupuncture

Objectives: One of the key points within the ERAS concept is control of pain and PONV syndrome induced by abdominal surgical procedures. Acupuncture (AC) is widely accepted for pain and an FDA-approved therapy for nausea. To integrate AC in ERAS we set three preconditions: (1) rational access to the functional AC diagnostics the basis of ACpoint selection, (2) proof of efficacy and safety and (3) quality control. We are collecting first data to create a study design with enhanced objectivity, measurability and even double blinding in order to exclude suggestive and placebo-like effects.

NANOTECHNOLOGY: REFLECTIONS ON HEALTH BENEFITS AND RISKS

There is a constant increase in the demand for engineers who can transform nanotechnology from a scientific result into a commercial solution. However, new technologies often caused conflicts between those who want to exploit them as soon as possible and those who are waiting to receive absolute proof of safety. Certain types of nanoparticles are well studied and recommended for use in medicine, biology, chemistry, cosmetology, etc. Some nanoparticles are proven to be extremely toxic, with drastically different properties from the same volume compounds. The risks associated with using nanotechnologies and products containing nanoparticles cannot be minimized in the absence of regulations, which would allow adequate control to protect the environment and the population’s health. Companies are also extremely careful in investing in this field as long as there is no transparent regulation, as the ultimate goal is to protect the surrounding environment and society. In this paper, we present an overview of the benefits of nanotechnology in areas that affect human health, as well as the risks that may arise from the early use or ill-will of nanotechnologies.

Containerless Plurals: Separating Number from Type in Object-Oriented Programming

To let expressions evaluate to no or many objects, most object-oriented programming languages require the use of special constructs that encode these cases as single objects or values. While the requirement to treat these standard situations idiomatically seems to be broadly accepted, I argue that its alternative, letting expressions evaluate to any number of objects directly, has several advantages that make it worthy of consideration. As a proof of concept, I present a core object-oriented programming language, dubbed Num , which separates number from type so that the type of an expression is independent of the number of objects it may evaluate to, thus removing one major obstacle to using no, one, and many objects uniformly. Furthermore, Num abandons null references, replaces the nullability of reference types with the more general notion of countability, and allows methods to be invoked on any number of objects, including no object. To be able to adapt behavior to the actual number of receivers, Num complements instance methods with plural methods, that is, with methods that operate on a number of objects jointly and that replace static methods known from other languages. An implementation of Num in Prolog and accompanying type and number safety proofs are presented.

An Identity Authentication Scheme Based on SM2 Algorithm in UAV Communication Network

With the advancement of technology, the collaborative networking of multiple UAVs has become a mainstream trend. Due to the characteristics of UAV communication networks, there are many security issues with their communication networks. At present, the UAV communication network needs a secure and efficient authentication scheme. In this paper, we optimise an UAV authentication scheme based on the SM2 algorithm, design a two-way authentication mechanism to improve the security of the authentication scheme, and adopt the method of preshared secret information instead of digital signatures to improve the efficiency of authentication. Subsequently, the safety proof was based on the Dolev-Yao model. Finally, simulation experiments demonstrate that the scheme is more efficient in authentication compared to other similar authentication schemes and meets expectations.

No two classes of biosimilars: Urgent advice to the US Congress and the FDA.

The United States is the only country with legislation to approve two classes of biosimilars. One has "no clinically meaningful difference" from the reference product, and when it is tested for switching and alternating, it can receive an interchangeable status. The objective of this review is to establish whether it is possible from the switching and alternating studies to evaluate additional safety or efficacy. Analysed published data to ascertain if the testing with switching and alternating provide additional proof of safety or efficacy. Political and scientific rationale of creating a new class of biosimilars and how this affects the confidence in biosimilars. There is no safety or efficacy concern when switching or alternating biosimilars with the reference product. Unfortunately, the rationale for interchangeability is more political than scientific, and it has brought more confusion and mistrust in using biosimilars in the United States. The US Congress is requested to remove the interchangeability clause from the Biological Price and Competition Act to enable faster acceptance of biosimilars and remove the threat of lack of confidence in the safety of biosimilars.

Multivalent Vaccine Strategies against Polydrug Use in Opioid Use Disorders

The number of annual fatal drug overdoses reached more than 100,000 between April 2020 to 2021, of which the majority involved individual opioids or polydrug mixtures containing opioids. A series of conjugate vaccines targeting fentanyl, carfentanil, oxycodone, heroin, and their analogs or metabolites have shown preclinical proof of efficacy, selectivity, and safety. Individual vaccines consist of haptens, small molecules that mimic the structure of the targeted drug, conjugated to carrier proteins, such as detoxified diphtheria toxin (CRM) or keyhole limpet hemocyanin (KLH). These studies identified lead haptens based on fentanyl (Fen), carfentanil (Carf), oxycodone (Oxy), and heroin (Her). Preclinical studies showed the efficacy of each vaccine (Fen‐CRM, Carf‐CRM, Oxy‐KLH, and Her‐KLH) in blocking their respective target drug distribution to the brain and their behavioral effects in mice and rats. While multivalent vaccine formulations are commonly used as a safe and effective strategy against infectious diseases, multivalent vaccination strategies against polydrug use have not yet been fully explored at treating substance use disorders. In the current study, the balb/c mice were vaccinated with a combination of Fen‐CRM, Carf‐CRM, Oxy‐KLH, and Her‐KLH as a quadrivalent vaccine. ELISA showed that quadrivalent vaccine increased fentanyl‐, carfentanil‐, oxycodone‐, and heroin‐specific IgG titers in the immunized mice. Correspondingly, this simultaneous immunization prevented the distributions of fentanyl, carfentanil, oxycodone, and heroin to the brain when the mice were challenged by the mixture of these drugs. These data demonstrate that individual efficacy of monovalent vaccine was preserved in a multivalent formulation without interference. Amid opioid epidemics, multivalent vaccine strategies will provide a broad spectrum of protection against multiple opioids with a single vaccination.