Safety Liability Research Articles

Medico-legal considerations in immediate loading implantology: risks, responsibilities, and best practices.

The field of immediate loading implantology has grown rapidly, offering quicker solutions for prosthetic rehabilitation. However, the complexity of this technique raises significant medico-legal concerns regarding patient safety, treatment planning, and professional liability. These issues are particularly relevant in elective procedures where failure could lead to litigation. A comprehensive review of current literature, including clinical studies, legal rulings, and malpractice claims, was conducted to assess the legal implications of immediate loading implantology. The analysis focused on professional liability, patient consent, and complications during treatment. The evidence indicates that a high standard of care, including detailed preoperative planning, risk assessment, and clear patient communication, is essential in minimizing legal risks. Malpractice claims often arise from inadequate patient information or failure to follow established protocols. Proper documentation of informed consent and adherence to evidence-based dentistry (EBD) guidelines are crucial to protect both patients and practitioners. Immediate loading implantology offers numerous benefits, but it requires meticulous planning and patient management to avoid medico-legal issues. Ensuring comprehensive patient consent and following evidence-based practices are key to reducing professional liability and improving outcomes. Further studies should explore standardized protocols for reducing complications and legal disputes in implantology.

P01-64 Approaches to mitigate known safety liabilities of immunomodulatory (IMiDs) drugs used in heterobifunctional degraders

P01-64 Approaches to mitigate known safety liabilities of immunomodulatory (IMiDs) drugs used in heterobifunctional degraders

An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.

Inhibitors of the transforming growth factor-β (TGF-β) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-β homologs has safety liabilities. TGF-β1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-β-binding proteins (LTBPs) present TGF-β1 in the extracellular matrix, and TGF-β1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-β1 presented by LTBPs but did not bind to TGF-β1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-β1 that is not accessible on GARP- or LRRC33-presented TGF-β1, explaining the antibody's selectivity for LTBP-complexed TGF-β1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-β1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-β inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-β1 as an approach for treating fibrosis.

Acceptance and demand of autonomous vehicles for long-distance recreational travel: An investigation based on a survey of visitors to US national parks

The study of anticipated changes in travel behavior that could be brought by autonomous vehicles (AVs) has been widespread for commuting and short-distance daily travel, yet little attention has been given to long-distance travel. To address this research gap, this paper presents an analytical model for estimating public preference towards the adoption and use (in terms of frequency and length of trips) of AVs, focusing on long-distance recreational travel (LDRT). The model considers socio-demographics, trip-specific characteristics, in-vehicle time use-related factors, and attitudinal latent variables (AV usefulness, AV concern, driving enjoyment) as potential influencers of AV acceptance and demand. To analyze the proposed model, data were collected from a survey of visitors to US national parks conducted in Summer 2022, and the structural equation modeling (SEM) technique was employed. The results indicate that the frequency and length of long-distance recreational trips will likely be higher in the AV era. This draws attention to tourism destination managers not only to manage the tourists’ demand at destinations but also to manage traffic on the roads leading to the destinations. Additionally, the results show that the LDRT demand will continue to rise with the increase in AV acceptance due to the usefulness and potential for several in-vehicle activities offered by vehicle automation, despite concerns about system safety, data privacy, and legal liability. The study also reveals that some travelers will likely miss manual driving enjoyment in AV driving, particularly in unique travel settings like tourism travel, and thus might opt for manual driving options. Based on these findings, we advocate for the timely consideration of induced LDRT, and tourism travel demand generated by AVs—such as provisioning sustainable public transport options to recreational and tourism destinations.

Legal Protection In Road Transportation: Safety, Passenger Rights And Carrier Liability

Legal Protection In Road Transportation: Safety, Passenger Rights And Carrier Liability

Subcutaneous administration of a novel TRPM8 antagonist reverses cold hypersensitivity while attenuating the drop in core body temperature.

We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin-induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT). Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin-induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry. VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose-dependently attenuated cold hypersensitivity in oxaliplatin-treated mice at 3, 10 and 30 mg·kg-1 (n = 7, P < 0.05). VBJ103 (30 mg·kg-1) antinociception was influenced by neither the TRPA1 antagonist HC-030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg-1, but not 100 or 300 mg·kg-1, n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg-1) dose-dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 μL; n = 5) did not alter CBT. We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target.

A Holistic Approach to Cybersecurity Integration in Autonomous Vehicles

The breakthrough of the self-driving car technology is a double-edged sword that gives us incredible opportunities and at the same time, it is the source of huge cybersecurity challenges. This paper champions the creation of a complete legal system and worldwide standards, like the ISO 26262, to regulate different parts of the autonomous vehicle (AV) operations, such as safety testing, liability, data privacy, and cybersecurity. By highlighting the significance of cybersecurity from the very start, the stakeholders and the automakers have to incorporate the practices like secure programming, routine updates, intrusion detection systems and encryption methods which will be the effective shield against the unauthorized access and data breaches. People should be informed and educated about the cybersecurity risks of AVs so that they can take the steps to protect themselves. Nevertheless, the integration of AVs with the Internet of Things (IoT) and other devices makes the cybersecurity landscape even more complicated, which means that there is a constant need for research and development to deal with problems like adversarial attacks. Presently, the deep learning-driven AV systems do not have the explainability which complicates the safety-critical applications, hence the need to increase the resilience training and deepen the deep learning models against attacks. The paper goes through all the literature on AV cybersecurity which stresses the need for functional safety standards and cybersecurity engineering guidelines. Collaboration between the governments, the industry, and the researchers is a must to set the legal foundations and the technical details for the AV cybersecurity across all levels of automation. Finally, solid cybersecurity is the key to the success of the autonomous vehicle revolution, hence the road to transformative safety, efficiency, and sustainability is paved. INDEX TERMS: Autonomous vehicles, Cybersecurity, ISO 26262, Encryption methods, ISO 21434, EU regulations, Security and Privacy.

Legal Issues of Fusion Technologies

Abstract A comprehensive regulatory framework for fusion must consider the unique characteristics and challenges of fusion technology, including safety, environmental protection, waste management, export/import control, and nuclear liability. The International Atomic Energy Agency (IAEA) has established safety standards and guidelines related to fusion, but more needs to be done to address the gaps in the existing legal frameworks. The article emphasizes the need for clear and predictable regulations to provide confidence for investors and promote the research, development, and deployment of this promising technology. Although significant progress has been made in recent years, commercial fusion power is still likely many years away from being a reality, but a legal framework is essential for its eventual success.

Milwaukee’s Swing Park: Guerrilla Urbanism at the Intersection of Public Space, Community, and Urban Planning

Guerrilla urbanism involves citizen-led bottom-up unsanctioned temporary efforts. This kind of temporary urbanism may offer unique opportunities not possible through traditional planning approaches. This paper is a case study of the Swing Park in Milwaukee, Wisconsin, USA. It began as an effort to temporarily enliven an area at one end of a pedestrian walkway – the Marsupial Bridge – suspended under a viaduct across the Milwaukee River. What started as an illegal temporary installation of swings made of used tires was embraced physically and emotionally as part of the everyday life of the pedestrian bridge by the local community who wanted the swings to stay. The guerrilla urbanism group found itself in conflict with the City’s Department of Public Works over concerns about safety and legal liability, aside from budgetary constraints on permanently upgrading and maintaining the swings. This paper conceptualizes the case study within a three-part framework of public space, community, and urban planning. It examines how the Swing Park has been seen to have both succeeded and failed, while problematizing it within the context of the interdisciplinary literature on temporary urbanism.

Digitalization of toxicology: improving preclinical to clinical translation.

Though the portfolio of medicines that are extending and improving the lives of patients continues to grow, drug discovery and development remains a challenging business on its best day. Safety liabilities are a significant contributor to development attrition where the costliest liabilities to both drug developers and patients emerge in late development or post-marketing. Animal studies are an important and influential contributor to the current drug discovery and development paradigm intending to provide evidence that a novel drug candidate can be used safely and effectively in human volunteers and patients. However, translational gaps-such as toxicity in patients not predicted by animal studies-have prompted efforts to improve their effectiveness, especially in safety assessment. More holistic monitoring and "digitalization" of animal studies has the potential to enrich study outcomes leading to datasets that are more computationally accessible, translationally relevant, replicable, and technically efficient. Continuous monitoring of animal behavior and physiology enables longitudinal assessment of drug effects, detection of effects during the animal's sleep and wake cycles and the opportunity to detect health or welfare events earlier. Automated measures can also mitigate human biases and reduce subjectivity. Reinventing a conservative, standardized, and traditional paradigm like drug safety assessment requires the collaboration and contributions of a broad and multi-disciplinary stakeholder group. In this perspective, we review the current state of the field and discuss opportunities to improve current approaches by more fully leveraging the power of sensor technologies, artificial intelligence (AI), and animal behavior in a home cage environment.

Autonomous Vehicles for All?

The traditional build-and-expand approach is not a viable solution to keep roadway traffic rolling safely, so technological solutions, such as autonomous vehicles (AVs), are favored. AVs have considerable potential to increase the carrying capacity of roads, ameliorate the chore of driving, improve safety, provide mobility for those who cannot drive, and help the environment. However, they also raise concerns over whether they are socially responsible, taking into account issues such as fairness, equity, and transparency. Regulatory bodies have focused on AV safety, cybersecurity, privacy, and legal liability issues, but have failed to adequately address social responsibility. Thus, existing AV developers do not have to embed social responsibility factors in their proprietary technology. Adverse bias may therefore occur in the development and deployment of AV technology. For instance, an artificial intelligence-based pedestrian detection application used in an AV may, in limited lighting conditions, be biased to detect pedestrians who belong to a particular racial demographic more efficiently compared to pedestrians from other racial demographics. Also, AV technologies tend to be costly, with a unique hardware and software setup which may be beyond the reach of lower-income people. In addition, data generated by AVs about their users may be misused by third parties such as corporations, criminals, or even foreign governments. AVs promise to dramatically impact labor markets, as many jobs that involve driving will be made redundant. We argue that the academic institutions, industry firms, and government agencies overseeing AV development and deployment must act proactively to ensure that AVs serve all and do not increase the digital divide in our society.

Evaluation of the translation of multiple cardiovascular regulatory mechanisms in the anesthetized dog

The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of “non-QT” cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects. The hemodynamic effects of 11 drugs (atropine, itraconazole, atenolol, ivabradine, milrinone, enalaprilat, fasudil, amlodipine, prazosin, amiloride, and hydrochlorothiazide) were profiled in an anesthetized dog cardiovascular model. Derived parameters included: heart rate, an index of left ventricular contractility, mean arterial pressure, systemic vascular resistance, and cardiac output. Species specific plasma protein data was generated (human, dog) and utilized to calculate free drug concentrations. Using the anesthetized dog cardiovascular model, 10 of the 11 drugs displayed the predicted changes in CV parameters based on their primary MoAs and corresponding clinically described effects. Interestingly but not unexpected, 1 of 11 failed to display their predicted CV pattern which is likely due to a delay in pharmacodynamic effect that is beyond the duration of the experimental model (hydrochlorothiazide). The analysis from the current study supports the strategic use of the anesthetized dog model early in the drug discovery process for a comprehensive cardiovascular evaluation with good translation to human.

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

Effects of public and private regulations on wholesale vendors' adoption of agrifood traceability to farms

AbstractAgrifood traceability of farms is extremely difficult owing to the small scale and dispersibility of farms. Fortunately, wholesale markets play an irreplaceable role in agrifood systems and in upstream traceability in many developing countries. This study first explores the mechanism of food safety liabilities related to the adoption of upstream traceability to farms. Then, the effects of public regulation by the government and private regulation by the market platform on wholesale vendors' adoption of traceability are investigated empirically. A unique panel dataset comprising 9287 food safety tests for 396 vendors from a wholesale market is used in the empirical analysis. The results show that vendors behave opportunistically by lowering their level of traceability when they expect a smaller possibility of being sampled. Given the same strength of regulation intensity, the effect of government regulation is larger than that of the market. The experience of failure in recent sampling tests motivates vendors to adopt higher levels of traceability. Recommendations regarding the frequency of food safety sampling tests conducted by the government and wholesale markets are proposed [EconLit Citations: Q18, L53].

A Study on the Perception of Safety Management in Middle School Physical Education Teachers

Purpose of the Study The purpose of this study is to establish a school safety culture through research on safety management as perceived by middle school physical education teachers. Research Method This study was conducted through in-depth interviews using a purposive sampling method from August 1 to September 30, 2024. Results: First, mandatory implementation of prevention education and safety education manuals and programs to increase prevention awareness. RAM is required. Second, regular facility and teaching management inspections are necessary and safety accidents can be prevented. Third, awareness of prevention and follow-up measures must improve a safe educational environment through institutional improvements in safety liability. Fourth, a safety training manual should be developed and unified and systematic training should be conducted. Conclusion Application to actual classroom environment. There is a need to develop a unified school safety education manual and systematic program.

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients.

Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome-coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically-based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed.

Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry

Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the on-target knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs.

Tern-701 (HS-10382) Is a Potent Inhibitor of BCR::ABL1 and Is Synergistic with Active Site Tyrosine Kinase Inhibitors

CONCLUSIONS Although tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 oncoprotein are effective therapeutics for chronic myeloid leukemia (CML), patients often develop drug resistance due to ATP-site mutations that inhibit drug binding. TERN-701 is a potent and highly selective inhibitor of BCR::ABL1 that is designed to bind the allosteric myristoyl site on the kinase, circumventing resistance to active site mutations, with potential for synergistic combination with active site TKIs. Competition binding screens were used to assess the selectivity of TERN-701 on more than 450 targets spanning the human kinome. The potency of TERN-701 against the proliferation of wild type and mutant CML cell lines, as well as a panel of 102 cancer cell lines, was assessed using CellTiter-Glo®. Synergy between TERN-701 and active site TKIs was assessed in vitro with interactions quantified using Bliss, combination, and curve-shift analyses. Prospective mutagenesis experiments were conducted by treating BaF/3 cells engineered to overexpress the BCR::ABL1 kinase with various concentrations of both TERN-701 and the TKI imatinib, followed by observation of clonal outgrowth of treated cells over time. We have previously shown that TERN-701 is a potent inhibitor of native CML cell lines such as K562. Here, we show that TERN-701 inhibited cell proliferation in various clinically relevant mutant CML cell lines (including T315I) with IC 50s ranging from 5 to 26 nM and 70 to 1200 nM against active site and myristoyl site mutations, respectively. TERN-701 was highly selective for BCR::ABL1, with no appreciable activity (&amp;gt;50%) against &amp;gt;450 purified kinase targets. Against a panel of cancer cell lines, TERN-701 was more selective than the comparator allosteric BCR::ABL1 inhibitor asciminib while maintaining similar potency. In vitro combination studies previously revealed that TERN-701 works synergistically with multiple TKIs in the non-mutant K562 cell line. Here, expanded studies using KCL22-s and BCR::ABL1-T315I mutant cell lines identified strong synergistic interactions between TERN-701 and active site TKIs, including ponatinib and dasatinib. Furthermore, prospective mutagenesis studies showed that the combination of TERN-701 and imatinib resulted in greater inhibition of the outgrowth of resistant clones relative to either compound alone. TERN-701 is a potent and highly selective allosteric inhibitor of BCR::ABL1 that can act synergistically with active site TKIs in vitro, even against the T315I gatekeeper mutation that confers resistance to all approved active site TKIs except ponatinib, which has known safety liabilities. These data support the continued development of TERN-701 for the treatment of CML using both monotherapy and combination approaches.

Compulsory liability insurance and excess cash holdings: Evidence from China

Our study examines how compulsory food safety liability insurance (CFSLI) relates to excess cash holdings. We use the implementation of CFSLI in different regions and at different times in China to identify its causal effects on the trust goods market using the difference-in-differences method. Our findings show that CFSLI significantly reduces excess cash holdings. Our results are robust to additional tests. The mechanisms that lead to this result are the mitigation of the precautionary motive arising from financing constraints and alleviation of the agency problem. Furthermore, we show that CFSLI plays a significant role in reducing excess cash holdings when there is considerable media coverage or a company is located in a region with a high level of marketization.

Use of cannabidiol (CBD) for the treatment of cognitive impairment in psychiatric and neurological illness: A narrative review.

Cannabidiol (CBD) is one of the major phytocannabinoids present in the cannabis plant, with no acute psychotropic effects and a favorable safety and abuse liability profile. Animal and limited controlled human studies have demonstrated CBD to have analgesic, anxiolytic, anti-inflammatory, antipsychotic, and anticonvulsant effects, to name a few possible indications. There is growing evidence for the use of CBD to treat neurological disorders such as epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. It has been suggested that CBD improves cognition and neurogenesis. Cognitive impairment is associated with numerous disorders and can involve deficits in learning, memory, executive functioning, and attention. The purpose of this review will be to evaluate the available preclinical and clinical data on CBD for the treatment of the cognitive impairment associated with several disorders including schizophrenia, epilepsy, Alzheimer's disease, and others. Preclinical, but not clinical, studies found evidence for an improvement in cognitive performance after treatment with CBD. More research is needed to determine whether CBD can be effectively used as a monotherapy to treat cognitive dysfunction. (PsycInfo Database Record (c) 2023 APA, all rights reserved).