Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Synthesis and characterization of 2,6-bis-hydrazinopyridine, and its conversion to 2,6-bis-pyrazolylpyridines

2,6-Bis-hydrazinopyridine has been prepared and characterized for the first time. This material is useful for the preparation of a wide variety of 2,6-bis-pyrazolylpyridines. This approach represents the most efficient preparation to date of sterically crowded 2,6-bis-pyrazolylpyridines, and the only method for the preparation of pyrazolylpyridines containing unsymmetrically 3′,5′-disubstituted pyrazoles with the larger groups in the 5′ positions. © 2006 Elsevier Ltd. All rights reserved

Synthesis of 4-methoxy-3,5-dinitrobenzaldehyde: A correction to supposed tele nucleophilic aromatic substitution

1,3-Dinitro-5-trichloromethylbenzene (2) was reacted with sodium methoxide in an attempt to prepare 4-methoxy-3,5-dinitrobenzaldehyde (7) via a reported tele nucleophilic aromatic substitution. The product from this reaction was methyl 3,5-dinitrobenzoate (5) and not the methoxy aldehyde as had been reported. The desired product was prepared by conventional nitration methodology from 4-methoxy-3-nitrobenzaldehyde. © 2003 Elsevier Science Ltd. All rights reserved

Synthesis of methoxy and hydroxy containing tetralones: Versatile intermediates for the preparation of biologically relevant molecules

The synthesis of 5-hydroxy-6-methoxy-1-tetralone and the 7-hydroxy regioisomer along with the corresponding 5,7-dihyroxy analog has been achieved using an efficient directed metallation procedure followed by a regioselective methylene oxidation. This methodology represents a general synthetic route for the preparation of highly oxygenated tetralone analogs which are versatile building blocks for the construction of molecules of biological interest. © 2003 Elsevier Science Ltd. All rights reserved

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely fragile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage generates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular microscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations particularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research

Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan\u27s blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan\u27s blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies. © 2004 Wiley-Liss, Inc

Oxi4503, a novel vascular targeting agent: Effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate

Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel vascular targeting agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well- characterized vascular targeting agent already being evaluated in clinical trials. The potential for tumor vascular targeting by Oxi4503 was assessed in a mouse system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The vascular effects of Oxi4503 were assessed in the s.c. implanted MDA-MB-231 adenocarcinoma and the MHEC5-T hemangioendothelioma in SCID mice and in a range of normal tissues. Blood flow was measured by i.v. injection of fluorescence beads, while quantitative fluorescence microscopy was used to measure the spatial heterogeneity of blood flow in tumor sections. Oxi4503 induced the shutdown of tumor blood vessels in a dose-dependent pattern with an ED50 at 3 mg/kg in contrast to 43 mg/kg of CA4P. Quantitative fluorescence microscopy showed that Oxi4503 increased the spatial heterogeneity in tumor blood flow. Oxi4503 affected peripheral tumor regions less than central regions, although this was not as pronounced as seen with CA4P, where only central regions were affected. The vascular shutdown induced by administration of Oxi4503 at a dose of 6 mg/kg resulted in extensive cell loss 24 hours following treatment, which translated into a significant effect on tumor growth. Tumor growth was completely repressed at doses above 12.5 mg/kg of Oxi4503, while doses above 25 mg/kg showed tumor regression and even complete regression in some animals. These results are promising for the use of Oxi4503 as a tumor vascular targeting agent. Moreover the potent antitumor effect when administered as a single agent suggests a different activity profile than CA4P