Are Repeat-Dose Toxicity Studies Informative for Safety Assessment of Vaccine Candidates? A Survey of Vaccine Developers.

A BioSafe-sponsored survey investigated how vaccine companies (n = 12) perceive the value of the repeat-dose toxicity studies for safety assessment of vaccine candidates. As all major vaccine developers were part of the survey, it was considered representative for the industry practices up to 2022. Vaccine developers indicated that they see scientific value in performing repeat-dose toxicity studies with vaccines, especially when novel components (e.

Off target toxicities and links with physicochemical properties of medicinal products, including antibiotics, oligonucleotides, lipid nanoparticles (with cationic and/or anionic charges). Data review suggests an emerging pattern.

Toxicology is an essential part of any drug development plan. Circumnavigating the risk of failure because of a toxicity issue can be a challenge, and failure in late development is extremely costly. To identify potential risks, it requires more than just understanding the biological target.

Preclinical proof of concept for VivoVec, a lentiviral-based platform for in vivo CAR T-cell engineering.

Background: Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence.

A qualitative study on stakeholder perceptions of digital prosthetic socket fabrication for transtibial amputations.

Background: Digital residual limb shape capture (three-dimensional [3D] scanning), computer-assisted design (CAD), and computer-assisted manufacturing with 3D printing technology show promise for a completely digital process of fabricating prosthetic sockets for patients with limb loss. The effectiveness and quality of digitally designed 3D-printed lower extremity prosthetic sockets is understudied, and there is lack of data on the patient and prosthetist experiences with this digital workflow.

Objective: To obtain stakeholder feedback on the feasibility and acceptability of using a completely digital prosthetic fabrication process consisting of 3D scanning, CAD, and 3D printing in a rehabilitation setting for adults with transtibial limb amputations.

Exploring the psychosocial needs of persons with lower extremity amputation and feasibility of internet cognitive behavioural therapy: a qualitative study.

Purpose: Following major lower extremity amputation (LEA), patients experience significant emotional distress and are at risk for anxiety and depression. There is a lack of mental health supports for this population, and internet-based cognitive behavioural therapy (iCBT) may be a useful resource to meet this need. The purpose of this study was to use a qualitative approach to explore the mental health needs of LEA patients and to gauge their attitudes of the use of iCBT to help them cope with their amputation.

Implementing patient navigator programmes within a hospital setting in Toronto, Canada: A qualitative interview study.

Objectives: This study sought to identify the organisation and system level barriers and facilitators influencing the implementation of patient navigator programmes in one acute care hospital system in Toronto, Canada.

Methods: A qualitative descriptive approach informed by the Consolidated Framework for Implementation Research. Data were collected using in-depth interviews and analysed thematically.

"We could be good partners if we work together": the perspectives of health and social service providers on the barriers to forming collaborative partnerships with social housing providers for older adults.

Background: Many older adults are aging-at-home in social housing. However, the lack of integration between housing and health services makes it difficult for older tenants to access needed supports. We examined barriers and facilitators health and social service providers face providing on-site services to older tenants.

Perceptions of Risk: Perspectives on Crime and Safety in Public Housing for Older Adults.

Background And Objectives: An increasing number of older adults are aging in place in public housing. Public housing is perceived to have higher rates of crime that have detrimental impacts on health and well-being. We used a qualitative approach to understand the experiences of safety and unsafety for older adults in public housing.

Assessing readiness to implement patient navigator programs in Toronto, Canada.

Objective: To explore factors influencing the implementation of patient navigator programs within a hospital for seniors with complex care needs.

Methods: A qualitative descriptive design using in-depth interviews was conducted. Participant interviews were conducted in Toronto, Ontario between September 2020 and February 2021.

Health care access and use among male and female Canadian Armed Forces veterans.

Background: Veterans are more likely than other Canadians to have chronic health conditions, making access to health care an important issue. However, little research has addressed health care access and use among veterans. This paper examines access and use among veterans compared with other Canadians.

Safety of vaccine adjuvants: focus on autoimmunity.

Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in relation to autoimmunity or autoimmune disease(s)/disorder(s) (AID). The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. The types of adjuvants considered included oil-in-water emulsions and toll-like receptor (TLR) agonists.

Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase.

Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS(-/-) mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo.

The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation.

The effects of valvular endothelial cell (VlvEC) paracrine signaling on VIC phenotype and nodule formation were tested using a co-culture platform with physiologically relevant matrix elasticities and diffusion distance. 100 μm thin poly(ethylene glycol) (PEG) hydrogels of 3-27 kPa Young's moduli were fabricated in transwell inserts. VICs were cultured on the gels, as VIC phenotype is known to change significantly within this range, while VlvECs lined the underside of the membrane.

Clickable, photodegradable hydrogels to dynamically modulate valvular interstitial cell phenotype.

Biophysical cues are widely recognized to influence cell phenotype. While this evidence was established using static substrates, there is growing interest in creating stimulus-responsive biomaterials that better recapitulate the dynamic extracellular matrix. Here, a clickable, photodegradable hydrogel substrate that allows the user to precisely control substrate elasticity and topography in situ is presented.

Role of cell-matrix interactions on VIC phenotype and tissue deposition in 3D PEG hydrogels.

Valvular interstitial cells (VICs) respond to 3D matrix interactions in a complex manner, but understanding these effects on VIC function better is important for applications ranging from valve tissue engineering to studying valve disease. Here, we encapsulated VICs in poly(ethylene glycol) (PEG) hydrogels modified with three different adhesive ligands, derived from fibronectin (RGDS), elastin (VGVAPG) and collagen-1 (P15). By day 14, VICs became significantly more elongated in RGDS-containing gels compared to VGVAPG or P15.

Hemodynamic and cellular response feedback in calcific aortic valve disease.

This review highlights aspects of calcific aortic valve disease that encompass the entire range of aortic valve disease progression from initial cellular changes to aortic valve sclerosis and stenosis, which can be initiated by changes in blood flow (hemodynamics) and pressure across the aortic valve. Appropriate hemodynamics is important for normal valve function and maintenance, but pathological blood velocities and pressure can have profound consequences at the macroscopic to microscopic scales. At the macroscopic scale, hemodynamic forces impart shear stresses on the surface of the valve leaflets and cause deformation of the leaflet tissue.

Small peptide functionalized thiol-ene hydrogels as culture substrates for understanding valvular interstitial cell activation and de novo tissue deposition.

A thiol-ene polymerization platform was used to synthesize peptide functionalized poly(ethylene glycol) hydrogels, which were initially characterized and compared to theoretical predictions of Young's modulus via a theoretical crosslinking density equation presented herein. After thorough characterization, this material system's utility for answering specific biological hypotheses was demonstrated with the culture and observation of aortic valvular interstitial cells (VICs). Specifically, these materials were used to better understand the role of substrate elasticity and biochemical functionality on VIC α-smooth muscle (αSMA) expression and secretory properties (i.

Histopathological lesions following intramuscular administration of saline in laboratory rodents and rabbits.

This review was undertaken to assess the nature and incidence of procedure-related changes in mice, rats and rabbits which received saline solution by intramuscular injection. Data were collected on the injection sites from 7 studies representing 152 animals. The original observations by the different study pathologists from both control and treated animals were evaluated in order to create a glossary of preferred terms to be used in toxicology studies.

Effect of pretreatment with atenolol and nifedipine on ZD6126-induced cardiac toxicity in rats.

Antivascular agents that act by destabilizing microtubules, such as ZD6126 (N-acetylcolchinol-O-phosphate), are associated with adverse cardiovascular effects, including transient hypertension, cardiac ischemia, myocardial infarction, and increases in circulating levels of markers of cardiac damage (e.g., troponins).

Biomarkers and mechanisms of drug-induced vascular injury in non-rodents.

In preclinical safety studies, drug-induced vascular injury can negatively impact candidate-drug selection because there are no obvious diagnostic markers for monitoring this pathology preclinically or clinically. Furthermore, our current understanding of the pathogenesis of this lesion is limited. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary target cells, smooth muscle (SMC) and endothelial cell (EC), are unknown.

2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD): a toxicology review.

2-Hydroxylpropyl-beta-cyclodextrin (HP-beta-CD) is an alternative to alpha-, beta- and gamma-cyclodextrin, with improved water solubility and may be more toxicologically benign. This paper reviews the toxicity of HP-beta-CD, using both literature information and novel data, and presents new information. In addition, it includes a brief review from studies of the metabolism and pharmacokinetics of HP-beta-CD in both humans and animals.

Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat.

The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats.