Riboflavin-Vancomycin Conjugate Enables Simultaneous Antibiotic Photo-Release and Photodynamic Killing against Resistant Gram-Positive Pathogens

Decades of antibiotic misuse have led to alarming levels of antimicrobial resistance, and the development of alternative diagnostic and therapeutic strategies to delineate and treat infections is a global priority. In particular, the nosocomial, multidrug-resistant "ESKAPE" pathogens such as Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp (VRE) urgently require alternative treatments. Here, we developed light-activated molecules based on the conjugation of the FDA-approved photosensitizer riboflavin to the Gram-positive specific ligand vancomycin to enable targeted antimicrobial photodynamic therapy. The riboflavin-vancomycin conjugate proved to be a potent and versatile antibacterial agent, enabling the rapid, light-mediated, killing of MRSA and VRE with no significant off-target effects. The attachment of riboflavin on vancomycin also led to an increase in antibiotic activity against S. aureus and VRE. Simultaneously, we evidenced for the first time that the flavin subunit undergoes an efficient photoinduced bond cleavage reaction to release vancomycin, thereby acting as a photoremovable protecting group with potential applications in drug delivery

Picosecond laser procedures to enhance the efficacy of tissue resection

The fundamental goal of this work was to develop an improved surgical modality in tissue, where minimising thermal damage is paramount, using an ultrashort pulse picosecond laser. Additionally, an investigation into flexibly delivering such pulses via a hollow core negative curvature fibre, in order to enable future minimally invasive endoscopic procedures, was conducted. Initially, the analysis of colon tissue resection in a porcine model based on plasma mediated laser ablation (at 1030 nm and 515 nm) using a scanning galvanometer is presented. A minimal thermally damaged region (<60 µm) and the ability to finely tune the depth of ablation using different scanning strategies, pulse repetition rate, pulse energy and laser fluences are demonstrated. These desirable surgical effects on the tissue were confirmed using surface profilometry and histological analysis. The picosecond laser ablation of healthy and cancerous lung tissue in an ovine model was also investigated. It has been observed that the ablation depth of cancerous tissue is approximately equal to half of the ablation depth of healthy tissue using the same laser parameters. This thesis also demonstrates that secondary effects of plasma formation such as shock wave induced mechanical damage, cavitation/gas bubble formation, can occur dependent on the parameters used. An appropriate scanning strategy (where there is little or no overlap between consecutive laser pulses) therefore needs to be implemented to minimise these detrimental effects. A laser scanning methodology (0% and 20% overlap with consecutive pulses) with enhanced reduction in thermal injury is presented using 20 kHz pulse repetition rate, 1030 nm wavelength and 13 J/cm2 laser fluence with a maximum ablation rate of 6 (0% Overlap) and 4 (20% overlap) mm3 /minute. The development of novel hollow core microstructured fibres has enabled the potential for delivery of ultrashort pulse picosecond laser radiation throughout the body. Therefore, in this thesis ultrashort laser pulses suitable for precision porcine colon resection were flexibly delivered via a hollow core negative curvature fibre. The fibre was manipulated via multi-axis robotic device to mimic movements expected during a practical surgical procedure. Again, a controllable change in ablation depth and with a minimum thermally damage region (< 85 µm) is observed. Furthermore, ablation depths are of comparable scale to that of early stage lesions/polyps in the inner lining of the colon and hence provide a level of control of resection suited to surgical application to thin walled structures such as the bowel.James Watt Scholarshi

Riboflavin-Vancomycin Conjugate Enables Simultaneous Antibiotic Photo-Release and Photodynamic Killing against Resistant Gram-Positive Pathogens

Decades of antibiotic misuse have led to alarming levels of antimicrobial resistance, and the development of alternative diagnostic and therapeutic strategies to delineate and treat infections is a global priority. In particular, the nosocomial, multi-drug resistant “ESKAPE” pathogens such as Gram-positive methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus spp (VRE) urgently require alternative treatments. Here, we developed light-activated molecules, based on conjugation of the FDA-approved photosensitizer riboflavin to the Gram-positive specific ligand vancomycin, to enable targeted antimicrobial photodynamic therapy. The riboflavin-vancomycin conjugate proved to be a potent and versatile antibacterial agent, enabling the rapid, light-mediated, killing of MRSA and VRE with no significant off-target effects. The attachment of riboflavin on vancomycin also led to an increased in antibiotic activity against S. aureus and VRE. Simultaneously, we evidenced for the first time that the flavin sub-unit undergoes an efficient photo-induced bond cleavage reaction to release vancomycin, thereby acting as a photo-removable protecting group for drug-delivery

Impact of COVID-19 on heart failure hospitalization and outcome in India – A cardiological society of India study (CSI–HF in COVID 19 times study – “The COVID C–HF study”)

Objectives: The presentation and outcomes of acute decompensated heart failure (ADHF) during COVID times (June 2020 to Dec 2020) were compared with the historical control during the same period in 2019. Methods: Data of 4806 consecutive patients of acute HF admitted in 22 centres in the country were collected during this period. The admission patterns, aetiology, outcomes, prescription of guideline-directed medical therapy (GDMT) and interventions were analysed in this retrospective study. Results: Admissions for acute heart failure during the pandemic period in 2020 decreased by 20% compared to the corresponding six-month period in 2019, with numbers dropping from 2675 to 2131. However, no difference in the epidemiology was seen. The mean age of presentation in 2019 was 61.75 (±13.7) years, and 59.97 (±14.6) years in 2020. There was a significant decrease in the mean age of presentation (p = 0.001). Also. the proportion of male patients decreased significantly from 68.67% to 65.84% (p = 0.037). The in-hospital mortality for acute heart failure did not differ significantly between 2019 and 2020 (4.19% and 4.,97%) respectively (p = 0.19). The proportion of patients with HFrEF did not change in 2020 compared to 2019 (76.82% vs 75.74%, respectively). The average duration of hospital stay was 6.5 days. Conclusion: The outcomes of ADHF patients admitted during the Covid pandemic did not differ significantly. The length of hospital stay remained the same. The study highlighted the sub-optimal use of GDMT, though slightly improving over the last few years