Raman imaging of nanocarriers for drug delivery

The efficacy of pharmaceutical agents can be greatly improved through nanocarrier delivery. Encapsulation of pharmaceutical agents into a nanocarrier can enhance their bioavailability and biocompatibility, whilst also facilitating targeted drug delivery to specific locations within the body. However, detailed understanding of the in vivo activity of the nanocarrier-drug conjugate is required prior to regulatory approval as a safe and effective treatment strategy. A comprehensive understanding of how nanocarriers travel to, and interact with, the intended target is required in order to optimize the dosing strategy, reduce potential off-target effects, and unwanted toxic effects. Raman spectroscopy has received much interest as a mechanism for label-free, non-invasive imaging of nanocarrier modes of action in vivo. Advanced Raman imaging techniques, including coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS), are paving the way for rigorous evaluation of nanocarrier activity at the single-cell level. This review focuses on the development of Raman imaging techniques to study organic nanocarrier delivery in cells and tissues

Developing a competency-based approach to facilitate teaching and learning of antimicrobial stewardship as part of environmental sustainability in higher education.

The environmental impact of the inappropriate use of antimicrobials and antimicrobial resistance (AMR) is recognised by global organisations, such as the World Health Organisation and the European Union. Antimicrobial stewardship (AMS) is one strategy to promote appropriate use of antimicrobials to minimise AMR and is a priority for the NHS to ensure sustainable prescribing. It is therefore imperative to support and empower future health care professionals by providing them with the knowledge to be leaders in the field of AMS. National consensus-based competencies for teaching AMS to undergraduate healthcare professionals in the UK were launched in 2018. This generic framework includes competencies relating to specific aspects of antimicrobial prescribing and infection control, and also emphasizes the importance of collaborative interprofessional working. The aim of this project is to determine which AMS competencies are required to be met by student pharmacists. This pedagogic approach will provide a guiding tool for curricula development, and will allow identification of gaps and strengths within the undergraduate pharmacy curriculum. To enable the development of a UK-wide national AMS competency framework specifically for student pharmacists, a working group of academics and pharmacy practitioners with expertise in AMS was set up in September 2022. The diverse backgrounds of group members provide a healthy mix of ideas, with academics informing the group of what may be achievable within the constraints and professional requirements of the pharmacy curriculum, and pharmacy practitioners providing input into essential AMS competencies for early-career pharmacists. Student pharmacists from a national organisation are being invited to join the group to encourage co-designing of this curriculum. Considering the UN commitment to act on global antimicrobial resistance and the NHS Sustainable Development management plan, this project is timely and of great importance to support development of future pharmacists as leaders in environmental sustainability

Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1β p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Early Active Mobilization during Mechanical Ventilation in the ICU

Background Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability. Methods We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization. Results The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P=0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P=0.005). Conclusions Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.)