Potential Liability Research Articles

Benzylic Photobromination for the Synthesis of Belzutifan: Elucidation of Reaction Mechanisms Using In Situ LED-NMR.

A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two distinct mechanisms of overbromination, namely, the ionic and radical pathways, have been revealed by this study. The behavior of the major reaction species, including reactants, intermediates, products, and side products, has been elucidated. Comprehensive understanding of both pathways informed and enabled mitigation of a major process risk: a sudden product decomposition. Detailed knowledge of the processes occurring during the reaction and their potential liabilities enabled the development of a robust photochemical continuous flow process implemented for commercial manufacturing.

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.

Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

Drug-Induced Seizures: Considerations for Underlying Molecular Mechanisms.

A broad spectrum of chemical entities have been associated with drug-induced seizure (DIS), emphasizing the importance of this potential liability across various drug classes (e.g., antidepressants, antipsychotics, antibiotics, and analgesics among others). Despite its importance within drug safety testing, an understanding of the molecular mechanisms associated with DIS is often lacking. The etiology of DIS is understood to be a result of either a deficit in inhibitory (e.g., gamma aminobutyric acid) or an elevated excitatory (e.g., glutamate) signaling, leading to synchronous neuronal depolarization affecting various brain regions and impairing normal neurological functions. How this altered neuronal signaling occurs and how these changes interact with other non-brain receptor driven DIS-associated changes such as metabolic disturbances, electrolyte imbalances, altered drug metabolism, and withdrawal effects are poorly understood. Herein, we discuss important molecular mechanisms identified in DIS for several drugs and/or drug classes. With a better understanding of the molecular mechanisms associated with DIS, in vivo or in vitro models may be applied to characterize and mitigate DIS risk during drug development. Susceptibility stratification for DIS presents species differences in the following order beagle dogs > rodents and cynomolgus monkeys > Göttingen minipigs with a more than 2-fold difference between canines and minipigs, which is important to consider during non-clinical species selection. While clinical signs such as myoclonus, severe muscle jerks, or convulsions are often associated with abnormal epileptiform EEG activity, tremors are most of the time physiological and rarely observed with concurrent epileptiform EEG activity which need to be considered during DIS risk evaluation.

Determining the utility of an unmanned ground vehicle for weed control in specialty crop systems

Specialty crop herbicides are not a target for herbicide discovery programs, and many of these crops do not have access to relevant herbicides. High-value fruit and vegetable crops represent high potential liability in the case of herbicide-induced crop damage and low acres for revenue. Labour shortages and higher manual weeding costs are an issue for both conventional and organic specialty crop growers. Robotic weeders are promising new weed control tools for specialty crops because they are cheaper to develop and, with fewer environmental and human health risks, are less regulated than herbicides. However, many of the robotic weeders are too expensive for small growers to use. In the future, greater investment into robotic weeders for small-scale growers will be important. The Clearpath robotics platform Husky may provide a cheap and autonomous way to control weeds in small diversified specialty crop farms. Being able to work autonomously in multiple soil moisture environments is the driving factor behind optimizing the Husky platform for weed control. Research has been conducted to evaluate the impact of soil moisture and mechanical actuator on mobility and weed control. Though weed control was not commercially acceptable in these studies, future optimizations to the Husky robotics platform can achieve commercial success. Highlights - Specialty crop production is labor-intensive and vulnerable to rising labor expenses. - Robotic weeders are promising weed control tools, with fewer environmental and human health risks.

Spontaneous volunteer coordination during disasters and emergencies: Opportunities, challenges, and risks

During major disaster and emergency events, significant numbers of individuals known as Spontaneous Volunteers (SV) show up to provide help, often in an unplanned fashion. SV play a critical role in responding to major disasters when emergency management services are overwhelmed and require additional capacity. Despite many benefits that may accrue from their usage, there are also some s noteworthy potential challenges. Reviews conducted after some recent disaster events reveal that emergency management service personnel were uncertain as to how they should interact most effectively with these volunteers. Failure to effectively ‘coordinate’ and employ SV during disaster response can create additional complications and risks for already overburdened emergency organizations. This study examines spontaneous volunteer coordination challenges, opportunities, and risks during emergencies and disasters derived from aa survey of emergency managers in Ontario, Canada. A structured questionnaire consisting of five sections and 69 questions was completed by a sample of emergency managers in Ontario. The findings show that their usage of SV is common, however they perceive the SV relationship from a predominantly ‘managerial’ lens or perspective, focusing upon control, predictability and potential liability issues and obstacles regarding their recruitment, and utilization, etc. Lack of federal and provincial legal and legislative supports regarding the usage, liability, and safety of SV are among the main barriers to the more effective realization of their full potential. This paper presents detailed results and implications of this study.

Alone on an Island

Alone on an Island

Incentivizing Good Governance Beyond Regulatory Minimums: The Civil Nuclear Sector

The consequences from a blended cyber‐physical terrorist attack on a nuclear power plant are potentially catastrophic. Sabotage of the plant or theft and subsequent use of radiological materials can potentially lead to blackouts, deaths, and injuries and even a release of radiological materials. This threat continues to evolve in sophistication and complexity and is outpacing the ability and resources of governments to anticipate risks and to protect their critical infrastructure and the public from harm. Policymakers are working to keep up with the rapid onset of these threats to reinforce the resilience of critical infrastructure. Cyber vulnerabilities including insider threats are also evolving, with cyberattacks on nuclear facilities the tip of the iceberg as more sophisticated advanced persistent threats develop. This paper suggests governments look beyond regulations and policy directives to harness the power and energy of the market to incentivize operators to voluntarily adopt security measures beyond regulatory requirements.Good organizational governance is important and necessary to secure critical infrastructure including nuclear facilities and increasingly can be rewarded by the market. The definition of what is good organizational governance matters to investors, lenders, insurers, regulators, and the public. Is the organization going to be able to function effectively as an enterprise and provide a return to investors, pay back its loans, protect its workers and community, including the environment? In the nuclear field, the stakes can be high—with stakeholders depending on a stable baseload electric supply without safety or security incidents, especially of a radiological nature.This article documents findings from a multi‐year project to identify incentives for nuclear security beyond regulatory minimums, with a focus on nuclear power plants. We assessed the importance of standards and developed a “Good Governance Template” to support owners/managers in obtaining benefits and reducing potential liabilities. We found that market incentives are developing in areas such as insurance, credit, and other rating systems to support the development of good governance, including incentives for companies to demonstrate due care in the management of risks, especially cyber risks. Building a business case for nuclear security based on these incentives is an important step forward in securing our nuclear future, especially in terms of cyber risks.

The Scope of Exercising Public Authority in the Context of State (Treasury) Liability for Vaccinations Against COVID-19

Purpose: The purpose of this paper is to investigate the possibility of attributing liability to the State (State Treasury) for damages suffered by individuals who undergo voluntary vaccination against COVID-19, introduced in Poland from December 2020. Design/Methodology/Approach: The author employs a dogmatic method, analyzing the potential liability of the State on the assumption that there is currently no possibility to make a binding determination that the public authority's action in this regard can be judged as unlawful. Findings: With this assumption in mind, the study shows that the Polish Civil Code provisions make State liability possible only if it is established that the actions of public authorities are peremptory in nature. It then becomes possible to apply Article 4172 of the Civil Code, which constitues the liability of public authorities based on the principle of equity for the so-called legal damages. Practical implications: Conclusions can be applied in lawsuits in the event of vaccine-induced damages. Originality/value: The issue of tort liability for non-mandatory vaccinations, but administered by the State, has not been more widely analyzed by the Polish legislation so far.

Stable Positive Current Collectors for Li||Sb–Sn Liquid Metal Batteries

The corrosion of a liquid Sb–Sn alloy on a positive current collector (PCC) can seriously affect the performance of Li||Sb–Sn liquid metal batteries (LMBs) and hinder their industrial applications. This work systematically investigated Ti, Mo, and W as the PCCs of Li||Sb–Sn LMBs corrosion behaviors and electrochemical properties. The corrosion mechanism and cell performance recession reason are illuminated based on compatibility analysis and electrochemical measurements. Ti and Mo are more easily dissolved in the liquid Sb–Sn alloy than W, forming Ti–Sb–Sn and Mo–Sb–Sn corrosion products. The average corrosion rates of Ti, Mo, and W in the liquid Sb-Sn alloy are 0.105, 0.068, and 0.014 mm/a, respectively. These corrosion behaviors not only affect the cell voltage and capacity to varying degrees but also may cause potential security liability. Hence, W is an admirably stable PCC of Li||Sb–Sn LMBs, which can also serve as an electroconductive and corrosion-resistant protective coating to reduce cost and solve the forming problem.

Employers’ potential liability for family and domestic violence: An Australian overview

This article considers a range of legal issues that arise when family and domestic violence impacts upon the workplace. It examines the available data on the costs of family and domestic violence to employers and the community. It discusses the potential for employers to be affected by Australian State and Territory criminal and related laws that are intended to protect a person from family and domestic violence. Recent cases of discrimination arising from family and domestic violence are considered with some speculations as to other possible forms of liability for employers concerning work health and safety and workers compensation laws. The Australian Fair Work Commission’s determination of unpaid family domestic violence leave is also examined, as is the adoption of paid leave by some State and Territory governments and larger Australian employers. The article concludes with some reflections and speculations on how current laws may affect employers and what actions can be taken by employers to adopt supportive measures to protect employees. JEL Codes: K32, J28, L53

A Comparison of Acute Pharmacological Effects of Methylone and MDMA Administration in Humans and Oral Fluid Concentrations as Biomarkers of Exposure.

Simple SummaryMethylone is a synthetic cathinone that is usually used as a substitute for conventional psychostimulants, such as MDMA. Chemically, methylone is considered the β-keto analogue of MDMA, with which it presumably shares similar pharmacological effects. To date, the available data about the human pharmacology of methylone in humans are very scarce and are mainly derived from user experiences, published in internet forums or intoxication reports. Thus, an observational–naturalistic study was conducted to evaluate the acute pharmacological effects and determine biomarkers of exposure in oral fluid of methylone after oral self-administration in comparison to MDMA. Methylone induced the prototypical psychostimulant and empathogenic effects commonly associated with MDMA, although they were of lower intensity. Oral fluid concentrations of methylone can be considered a suitable biomarker of acute exposure, and oral fluid has been proven to be a useful biological matrix of detection.Considered the β-keto analogue of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-Methylenedioxymethcathinone (methylone) is a synthetic cathinone. Over the years, methylone has been used as a substitute for conventional psychostimulants, such as MDMA. To date, little is known about the human pharmacology of methylone; the only available information has been provided by surveys or published intoxication reports. In the present observational–naturalistic study, we evaluate the acute subjective and physiological effects of methylone after oral self-administration in comparison to MDMA in healthy poly-drug users. Fourteen participants (10 males, 4 females) selected their single oral doses of methylone from 100 to 300 mg (n = 8, mean dose 187.5 mg) or MDMA from 75 to 100 mg (n = 6, mean dose 87.5 mg) based on their experience. Study variables were assessed at 0, 1, 2, and 4 h (h) and included vital signs (non-invasive blood pressure, heart rate, cutaneous temperature) and subjective effects using visual analogue scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire. Additionally, oral fluid concentrations of methylone and MDMA were determined. Acute pharmacological effects produced by methylone followed the prototypical psychostimulant and empathogenic profile associated with MDMA, although they were less intense. Methylone concentrations in oral fluid can be considered a useful biomarker to detect acute exposure in oral fluid. Oral fluid concentrations of MDMA and methylone peaked at 2 h and concentrations of MDMA were in the range of those previously described in controlled studies. Our results demonstrate that the potential abuse liability of methylone is similar to that of MDMA in recreational subjects.

Right from the centre: The dramaturgy of right-wing politics in Chris Hannan’s What Shadows, Chris Bush’s The Assassination of Katie Hopkins, and Rob Drummond’s The Majority

ABSTRACT Reactionary retrenchment in UK society, including the resurgence of national chauvinism and anti-immigration sentiment, has recently stimulated explorations of right-wing politics in theatre. This article offers a reading of three recent productions that illuminate the way that reactionary politics is currently framed, explored and interrogated in UK theatre: What Shadows (2016) by Chris Hannan, Chris Bush’s The Assassination of Katie Hopkins (2018), and Rob Drummond’s The Majority (2017). The article argues that these pieces’ approach towards right-wing politics emerges from anxiety over ideological polarisation and a perceived breakdown in communication in political discourse. It suggests that this attempt to generate nuance, neutrality and complexity while dispensing criticism equally across both poles of left and right on the political spectrum implicitly works to authorise a ‘moderate’ centrist position. While the thesis of each play functions to validate a centrist position that is presumed to be automatically reasonable, the article considers the potential liabilities inherent in such dramaturgical framing in broaching topics relating to the far right and reactionary right.

Factors, Perceptions and Beliefs Associated with Inappropriate Antibiotic Prescribing in German Primary Dental Care: A Qualitative Study.

Dentists account for up to 10% of all prescribed antibiotics in primary care, with up to 80% being inappropriate. Targeted approaches to change prescription behavior are scarce. This study aimed at identifying specific barriers and facilitators for prudent antibiotic use in German dentistry by using qualitative methods. Nine in-depth interviews and two focus group discussions with another nine dentists were conducted and analyzed thematically. Dentists described being conflicted by the discordance of available treatment time and the necessity of thorough therapy. Lacking the opportunity of follow-up led to uncertainty. Dentists felt a lack of medical competency concerning prophylaxis for infectious endocarditis. A lack of empowerment to make therapeutic decisions interfered with guideline-conformity. The communication with fellow physicians is conflictual and improvement was wished for. In consequence, dentists felt pressure by potential medico-legal liability. Patients demanding quick and easy pain relief put extra strain on the interviewed dentists. Our hypotheses concord with preliminary data, mainly from the UK, but highlighted specifically medico-legal concerns and interprofessional communication as even greater barriers as described before. Tailored interventional concepts based on our findings may have the potential to lower antibiotic prescriptions in German primary dental care.

Three Delusions and a New Path: the Political Economy of the Chinese Food Traceability System

Unease about the numerous food safety incidents in China has unleashed public rage, outcry, and continuous discussion on new public alternatives and government measures. The Chinese government and Chinese technology giants stimulate the development of the food traceability system through unique identification codes attached to food packages that supposedly enable customers to know the whole life story of their food and to put their minds at ease. However, as a market-driven and technocratic approach, the food traceability system tends to carry three common delusions that government and corporate hype has embedded in their mechanisms. The first delusion is that the food traceability system is the optimum choice for solving China's food safety issues. It embodies a certainty machine (Zuboff, 2019) to supersede the necessity of trust and to construct the illusions of perfect information (Winseck, 2002) whereby the consumer is encouraged and incentivized to take on the role of screening and investigating their food to combat complex social and public health issues in China. Another delusion is that a highly integrated food traceability system can increase efficiency and convenience in Chinese society through a relentless automation system and AI-powered data analytics engine. The final delusion is that stiffened food traceability laws and regulations can cause technology giants to withdraw their business involvement in the food industry due to increased responsibility and potential financial liabilities. After critically examining several primary and secondary sources to decipher the multi-faceted relations between the Chinese government, Chinese citizens, foreign capitals, and three Chinese Internet giants (Alibaba, Tencent, and JD), this paper expounds on these three troubling delusions.

Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.

Liability for Damages Caused by COVID-19 Vaccination

Purpose: The article discusses the problem of liability for damages relating to optional COVID-19 vaccinations conducted in Poland. The author investigates instances of liability tied to particular entities involved in the vaccination process. First, the liability of the State Treasury based on Government officials promoting the vaccinations in the media. Second, liability of the Material Reserve Agency (now the Governmental Strategic Reserve Agency) for purchasing vaccines as aiding a tort. Third, that same agency held liable - as the importer - under product liability. Fourth, the National Health Fund, liable as the direct organizer of the vaccination. Fifth, the vaccine manufacturer in the context of dangerous product liability. Sixth, the treatment provider liable for the conduct of its personnel. Seventh, the European Union in its capacity as an importer of vaccines, for aiding a harmful effect on one’s health, but also for causing damage legally (in two alternative options). The study examines the possible implications of damages for mass vaccination against COVID-19, conducted in Poland from December 2020. Design/Methodology/Approach: The author applies a dogmatic method, examining potential liability due to the different categories of debtors involved in the organization and execution of the vaccination. Findings: Vaccination liability in tort is possible in the situations identified in the article. The main difficulty lies in the necessity of proving at least a condition sine qua non-type of causal connection between vaccination and bodily injury or a deterioration of health. Under this condition, liability may arise on the part of the National Health Fund, but also on the part of the vaccine manufacturer and the European Union. Practical Implications: The conclusions can be used in lawsuits in the event of vaccine-induced harm. Originality/Value: The issue of tort liability for vaccination that is not obligatory but organized by the State has not been extensively studied in the Polish legislation.

Human-induced pluripotent stem cell-derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs.

Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome‐3 (LQTS3) is caused by mutations in the Nav1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re‐engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient‐derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on‐target) and detrimental effects (off‐target) of mexiletine and synthetic analogs, respectively. The approach combined “drug discovery” and "hit to lead” refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22. Compared to mexiletine, compound 22 showed a 1.85‐fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P‐450, as previously shown, and by the flavin‐containing monooxygenase (FMO). Deuterated‐22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.

A hard fork in the road: developing an effective regulatory framework for public blockchains

ABSTRACT Over the past decade, public blockchains have emerged as innovative, technology platforms capable of highly secure and sophisticated peer-to-peer online transmission of data between unknown parties. However, public blockchains challenge traditional regulatory models that assume centralised, single points of control facilitated via established intermediaries. In such a context, the present paper analyses the potential liability attaching to blockchain participants and considers how privacy laws apply to blockchain transactions, given the immutable nature of blockchain records. The paper then recommends reforms to strengthen blockchain regulation, including statutory recognition of fiduciary obligations for elite developers with super-user access to allow recourse for loss resulting from hard forks. A ‘hard fork’ is a radical change to a network’s protocol that leads to formerly valid blocks and transactions becoming invalid or vice-versa. Finally, the paper considers changes to privacy laws to permit ongoing consent and cross-border disclosure of data to accommodate blockchain operations.

Organ Retention Litigation

The common practice of retaining organs and tissues after the autopsy dissection is a potential legal liability for forensic pathologists and the offices they work for. In 1988, a coroner and the coroner’s office were successfully sued for corneal procurements without the consent of the next of kin. That led to later lawsuits of forensic pathologists and medical examiner offices over the retention of brains for formalin fixation and neuropathologic examination without consent, although the autopsies were not consent based. National Association of Medical Examiners became involved in this ligation and filed numerous amicus briefs. These later lawsuits were not successful. After caselaw on the subject, such lawsuits have largely abated. Nonetheless, the threat of such lawsuits remains, and statutory language can be promulgated to mitigate the risk.

Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel.