Survey to identify research priorities for primary care in Scotland during and following the COVID-19 pandemic

OBJECTIVES: To identify research priorities for primary care in Scotland following the COVID-19 pandemic.DESIGN: Modified James Lind Alliance methodology; respondents completed an online survey to make research suggestions and rank research themes in order of priority.SETTING: Scotland primary care.PARTICIPANTS: Healthcare professionals in primary care in Scotland and members of primary care patient and public involvement groups. 512 respondents provided research suggestions; 8% (n=40) did not work in health or social care; of those who did work, 68.8% worked in primary care, 16.3% community care, 11.7% secondary care, 4.5% third sector, 4.2% university (respondents could select multiple options). Of those respondents who identified as healthcare professionals, 33% were in nursing and midwifery professions, 25% were in allied health professions (of whom 45% were occupational therapists and 35% were physiotherapists), 20% were in the medical profession and 10% were in the pharmacy profession.MAIN OUTCOMES: Suggestions for research for primary care made by respondents were categorised into themes and subthemes by researchers and ranked in order of priority by respondents.RESULTS: There were 1274 research suggestions which were categorised under 12 themes and 30 subthemes. The following five themes received the most suggestions for research: disease and illness (n=461 suggestions), access (n=202), workforce (n=164), multidisciplinary team (MDT; n=143) and integration (n=108). One hundred and three (20%) respondents to the survey participated in ranking the list of 12 themes in order of research priority. The five most highly ranked research priorities were disease and illness, health inequalities, access, workforce and MDTs. The disease and illness theme had the greatest number of suggestions for research and was scored the most highly in the ranking exercise. The subtheme ranked as the most important research priority in the disease and illness theme was ‘mental health’.CONCLUSIONS: The themes and subthemes identified in this study should inform research funders so that the direction of primary healthcare is informed by evidence

Survey to identify research priorities for primary care in Scotland during and following the COVID-19 pandemic.

Objectives To identify research priorities for primary care in Scotland following the COVID-19 pandemic. Design Modified James Lind Alliance methodology; respondents completed an online survey to make research suggestions and rank research themes in order of priority. Setting Scotland primary care. Participants Healthcare professionals in primary care in Scotland and members of primary care patient and public involvement groups. 512 respondents provided research suggestions; 8% (n=40) did not work in health or social care; of those who did work, 68.8% worked in primary care, 16.3% community care, 11.7% secondary care, 4.5% third sector, 4.2% university (respondents could select multiple options). Of those respondents who identified as healthcare professionals, 33% were in nursing and midwifery professions, 25% were in allied health professions (of whom 45% were occupational therapists and 35% were physiotherapists), 20% were in the medical profession and 10% were in the pharmacy profession. Main outcomes Suggestions for research for primary care made by respondents were categorised into themes and subthemes by researchers and ranked in order of priority by respondents. Results There were 1274 research suggestions which were categorised under 12 themes and 30 subthemes. The following five themes received the most suggestions for research: disease and illness (n=461 suggestions), access (n=202), workforce (n=164), multidisciplinary team (MDT; n=143) and integration (n=108). One hundred and three (20%) respondents to the survey participated in ranking the list of 12 themes in order of research priority. The five most highly ranked research priorities were disease and illness, health inequalities, access, workforce and MDTs. The disease and illness theme had the greatest number of suggestions for research and was scored the most highly in the ranking exercise. The subtheme ranked as the most important research priority in the disease and illness theme was 'mental health'. Conclusions The themes and subthemes identified in this study should inform research funders so that the direction of primary healthcare is informed by evidence

Cell-Penetrating Peptides as a Tool for the Cellular Uptake of a Genetically Modified Nitroreductase for use in Directed Enzyme Prodrug Therapy

Directed enzyme prodrug therapy (DEPT) involves the delivery of a prodrug-activating enzyme to a solid tumour site, followed by the subsequent activation of an administered prodrug. One of the most studied enzyme–prodrug combinations is the nitroreductase from Escherichia coli (NfnB) with the prodrug CB1954 [5-(aziridin-1-yl)-2,4-dinitro-benzamide]. One of the major issues faced by DEPT is the ability to successfully internalize the enzyme into the target cells. NfnB has previously been genetically modified to contain cysteine residues (NfnB-Cys) which bind to gold nanoparticles for a novel DEPT therapy called magnetic nanoparticle directed enzyme prodrug therapy (MNDEPT). One cellular internalisation method is the use of cell-penetrating peptides (CPPs), which aid cellular internalization of cargo. Here the cell-penetrating peptides: HR9 and Pep-1 were tested for their ability to conjugate with NfnB-Cys. The conjugates were further tested for their potential use in MNDEPT, as well as conjugating with the delivery vector intended for use in MNDEPT and tested for the vectors capability to penetrate into cells

Synthesis and characterisation of a nucleotide based pro-drug formulated with a peptide into a nano-chemotherapy for colorectal cancer

Recent studies in colorectal cancer patients (CRC) have shown that increased resistance to thymidylate synthase (TS) inhibitors such as 5-fluorouracil (5-FU), reduce the efficacy of standard of care (SoC) treatment regimens. The nucleotide pool cleanser dUTPase is highly expressed in CRC and is an attractive target for potentiating anticancer activity of chemotherapy. The purpose of the current work was to investigate the activity of P1, P4-di(2',5'-dideoxy-5'-selenouridinyl)-tetraphosphate (P4-SedU2), a selenium-modified symmetrically capped dinucleoside with prodrug capabilities that is specifically activated by dUTPase. Using mechanochemistry, P4-SedU2 and the corresponding selenothymidine analogue P4-SeT2 were prepared with a yield of 19% and 30% respectively. The phosphate functionality facilitated complexation with the amphipathic cell-penetrating peptide RALA to produce nanoparticles (NPs). These NPs were designed to deliver P4-SedU2 intracellularly and thereby maximise in vivo activity. The NPs demonstrated effective anti-cancer activity and selectivity in the HCT116 CRC cell line, a cell line that overexpresses dUTPase; compared to HT29 CRC cells and NCTC-929 fibroblast cells which have reduced levels of dUTPase expression. In vivo studies in BALB/c SCID mice revealed no significant toxicity with respect to weight or organ histology. Pharmacokinetic analysis of blood serum showed that RALA facilitates effective delivery and rapid internalisation into surrounding tissues with NPs eliciting lower plasma Cmax than the equivalent injection of free P4-SedU2, translating the in vitro findings. Tumour growth delay studies have demonstrated significant inhibition of growth dynamics with the tumour doubling time extended by &gt;2weeks. These studies demonstrate the functionality and action of a new pro-drug nucleotide for CRC. </p

Enhanced nanoparticle delivery exploiting tumour responsive formulations.

Abstract Nanoparticles can be used as drug carriers, contrast agents and radiosensitisers for the treatment of cancer. Nanoparticles can either passively accumulate within tumour sites, or be conjugated with targeting ligands to actively enable tumour deposition. With respect to passive accumulation, particles < 150 nm accumulate with higher efficiency within the tumour microenvironment, a consequence of the enhanced permeability and retention effect. Despite these favourable properties, clinical translation of nano-therapeutics is inhibited due to poor in vivo stability, biodistribution and target cell internalisation. Nano-therapeutics can be modified to exploit features of the tumour microenvironment such as elevated hypoxia, increased pH and a compromised extracellular matrix. This is in contrast to cytotoxic chemotherapies which generally do not exploit the characteristic pathological features of the tumour microenvironment, and as such are prone to debilitating systemic toxicities. This review examines strategies for tumour microenvironment targeting to improve nanoparticle delivery, with particular focus on the delivery of nucleic acids and gold nanoparticles. Evidence for key research areas and future technologies are presented and critically evaluated. Among the most promising technologies are the development of next-generation cell penetrating peptides and the incorporation of micro-environment responsive stealth molecules