Conceptualised psycho-medical footprint for health status outcomes and the potential impacts for early detection and prevention of chronic diseases in the context of 3P medicine

Background: The Suboptimal Health Status Questionnaire-25 (SHSQ-25) is a distinctive medical psychometric diagnostic tool designed for the early detection of chronic diseases. However, the synaptic connections between the 25 symptomatic items and their relevance in supporting the monitoring of suboptimal health outcomes, which are precursors for chronic diseases, have not been thoroughly evaluated within the framework of predictive, preventive, and personalised medicine (PPPM/3PM). This baseline study explores the internal structure of the SHSQ-25 and demonstrates its discriminatory power to predict optimal and suboptimal health status (SHS) and develop photogenic representations of their distinct relationship patterns. Methods: The cross-sectional study involved healthy Ghanaian participants (n = 217; aged 30–80 years; ~ 61% female), who responded to the SHSQ-25. The median SHS score was used to categorise the population into optimal and SHS. Graphical LASSO model and multi-dimensional scaling configuration methods were employed to describe the network structures for the two populations. Results: We observed differences in the structural, node placement and node distance of the synaptic networks for the optimal and suboptimal populations. A statistically significant variance in connectivity levels was noted between the optimal (58 non-zero edges) and suboptimal (43 non-zero edges) networks (p = 0.024). Fatigue emerged as a prominently central subclinical condition within the suboptimal population, whilst the cardiovascular system domain had the greatest relevance for the optimal population. The contrast in connectivity levels and the divergent prominence of specific subclinical conditions across domain networks shed light on potential health distinctions. Conclusions: We have demonstrated the feasibility of creating dynamic visualizers of the evolutionary trends in the relationships between the domains of SHSQ-25 relative to health status outcomes. This will provide in-depth comprehension of the conceptual model to inform personalised strategies to circumvent SHS. Additionally, the findings have implications for both health care and disease prevention because at-risk individuals can be predicted and prioritised for monitoring, and targeted intervention can begin before their symptoms reach an irreversible stage. We observed differences in the structural, node placement and node distance of the synaptic networks for the optimal and suboptimal populations. A statistically significant variance in connectivity levels was noted between the optimal (58 non-zero edges) and suboptimal (43 non-zero edges) networks (p = 0.024). Fatigue emerged as a prominently central subclinical condition within the suboptimal population, whilst the cardiovascular system domain had the greatest relevance for the optimal population. The contrast in connectivity levels and the divergent prominence of specific subclinical conditions across domain networks shed light on potential health distinctions

Radiolabelling an 18F biologic via facile IEDDA “click” chemistry on the GE FASTLab™ platform

The use of biologics in positron emission tomography (PET) imaging is an important area of radiopharmaceutical development and new automated methods are required to facilitate their production. We report an automated radiosynthesis method to produce a radiolabelled biologic via facile inverse electron demand Diels-Alder (IEDDA) “click” chemistry on a single GE FASTLab™ cassette. We exemplified the method by producing a fluorine-18 radiolabelled interleukin-2 (IL2) radioconjugate from a trans-cyclooctene (TCO) modified IL2 precursor. The radioconjugate was produced using a fully automated radiosynthesis on a single FASTLab™ cassette in a radiochemical yield (RCY) of 19.8 ± 2.6% in 110 min (from start of synthesis); the molar activity was 132.3 ± 14.6 GBq/μmol. The in vitro uptake of [18F]TTCO-IL2 correlated with the differential receptor expression (CD25, CD122, CD132) in PC3, NK-92 and activated human PBMCs. The automated method may be adapted for the radiosynthesis of any TCO-modified protein via IEDDA chemistry

A kit-based aluminium-[18F]fluoride approach to radiolabelled microbubbles

The production of 18F-labelled microbubbles (MBs) via the aluminium-[18F]fluoride ([18F]AlF) radiolabelling method and facile inverse-electron-demand Diels-Alder (IEDDA) ‘click’ chemistry is reported. An [18F]AlF-NODA-labelled tetrazine was synthesised in excellent radiochemical yield (>95% RCY) and efficiently conjugated to a trans¬-cyclooctene (TCO) functionalised phospholipid (40-50% RCY), which was incorporated into MBs (40-50% RCY). To demonstrate the potential of producing 18F-labelled MBs for clinical studies, we also describe a kit-based approach which is amenable for use in a hospital radiopharmacy setting

Minimally Invasive Pharmacokinetic and Pharmacodynamic Technologies in Hypothesis-Testing Clinical Trials of Innovative Therapies

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encourage