The Nitrous Oxide Project: assessment of advocacy and national directives to deliver mitigation of anaesthetic nitrous oxide.

The environmental emissions attributed to anaesthetic nitrous oxide across the NHS are comparable to the carbon dioxide released by 135,000 flights from Frankfurt to New York. Much of these emissions are attributable to cumbersome and inadequately managed piped systems, resulting in excessive loss and waste. Since 2020, multiple hospital sites have been engaging with the Nitrous Oxide Project, a quality improvement method supporting a 'lean systems' approach to the provision of nitrous oxide. This review considers the frameworks supporting medical gas management in UK healthcare systems, and the impact of professional advocacy and medical gas stewardship to drive anaesthetic nitrous oxide mitigation in the NHS. Nitrous oxide mitigation efforts by grassroots and professional advocacy networks are enhanced through national centralised emission monitoring, distribution of data, technical information and provision of quality analysis. Given the climate harms of nitrous oxide, concerted efforts should be made to rationalise its use, and resources should be committed to supporting this at local, regional and national levels.

The evolving continuum of dysglycaemia: Non-diabetic hyperglycaemia in older adults.

Identifying non-diabetic hyperglycaemia (NDH) and intervening to halt the progression to type 2 diabetes has become an essential component of cardiovascular and cerebrovascular risk reduction. Diabetes prevention programs have been instigated to address the increasing prevalence of NDH and type 2 diabetes by targeting lifestyle modifications. Evidence suggests that the risk of progression from NDH to type 2 diabetes declines with age, and that a diagnosis of type 2 diabetes in older adults is not associated with the same risk of adverse consequences as it is in younger age groups. The current definition of NDH is not adjusted based on a person's age. Therefore, there is debate about the emphasis that should be placed upon a diagnosis of NDH in older adults. This article will explore the evidence and current clinical practice surrounding dysglycaemia through the spectrum of different age ranges, and the potential implications this has for older adults.

The current role for clinical and renal histological findings as predictor for outcome in Australian patients with lupus nephritis.

Objectives To investigate the current demographic, clinical and histological characteristics of patients with lupus nephritis (LN) in Western Australia (WA) with regards to their predictive value for patient and renal outcome. Methods Retrospective study of adult systemic lupus erythematosus (SLE) patients with a first renal biopsy demonstrating LN between 1997 and 2017 at a metropolitan tertiary hospital in WA. Clinical data were collected at baseline and last follow-up with renal biopsy findings classified by International Society of Nephrology (ISN) criteria. Annual incidence rates (AIRs)/100,000, Kaplan-Meyer curves and Cox regression hazard ratio for independent predictors for patient and renal survival were applied. Results The AIR was 3.3, 3.1 and 0.4 for Asian ( n = 29), Indigenous Australian (IA) ( n = 11) and Caucasian ( n = 43) patients, respectively ( p < 0.01). There was no significant subgroup difference regarding ISN class (proliferative 66%, membranous 19%, mesangial 15%), levels of proteinuria (median PCR 300 mg/mmol) or frequency of raised creatinine (31%), anti-dsDNA antibody (89%) or hypocomplementaemia (88%). Treatment included corticosteroids (91%), cyclophosphamide (30%), mycophenolate (67%) and antihypertensive drugs (67%). Five- (81%) and 10-year (70%) survival was lower for IAs than for Caucasians and Asians (95% each at both time points) ( p = 0.016). Five- and 10-year renal survival (endpoint renal replacement therapy (RRT)) was 86% and 64% for IA vs 100% for Asian, 100% and 96% for Caucasian patients ( p = 0.02). IA background was the only independent predictor for poor patient survival and together with male gender also for renal survival. Only 25% of all patients remained free of any organ damage with non-renal damage observed in 53% of survivors. Conclusions LN incidence in WA was 0.75/100,000 with the lowest rate observed in Caucasians. While Asian patients have the same favourable outlook as Caucasians, the outcome is much bleaker for IA patients. Other clinical and histological findings did not predict outcomes, and importantly more than half of all surviving patients accrued non-renal damage.

Management of sulfonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer.

The optimum treatment for HNF1A/HNF4A maturity-onset diabetes of the young and ATP-sensitive potassium (KATP ) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established that glibenclamide crosses the placenta and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A maturity-onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per conception either transfer to insulin before conception (at the risk of a short-term deterioration of glycaemic control) or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800-g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post-delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed.

Restless legs syndrome: an underappreciated and distressing problem for haemodialysis patients.

Restless legs syndrome is a distressing condition that is more common in patients with end-stage renal failure. Despite the significant impact it has on quality of life and the documented association between restless legs syndrome and increased mortality, limited data regarding the epidemiology of restless legs syndrome in Australian dialysis patients are available. We report a prospective study that assessed the prevalence and factors associated with restless legs syndrome in an in-centre haemodialysis population.

Antigen-specific T cell responses to BK polyomavirus antigens identify functional anti-viral immunity and may help to guide immunosuppression following renal transplantation.

Infection with the polyoma virus BK (BKV) is a major cause of morbidity following renal transplantation. Limited understanding of the anti-viral immune response has prevented the design of a strategy that balances treatment with the preservation of graft function. The proven utility of interferon-gamma enzyme-linked immunospot (ELISPOT) assays to measure T cell responses in immunocompetent hosts was the basis for trying to develop a rational approach to the management of BKV following renal transplantation. In a sample of transplant recipients and healthy controls, comparisons were made between T cell responses to the complete panel of BKV antigens, the Epstein-Barr virus (EBV) antigens, BZLF1 and EBNA1, and the mitogen phytohaemagglutinin (PHA). Correlations between responses to individual antigens and immunosuppressive regimens were also analysed. Antigen-specific T cell responses were a specific indicator of recent or ongoing recovery from BKV infection (P < 0·05), with responses to different BKV antigens being highly heterogeneous. Significant BKV immunity was undetectable in transplant patients with persistent viral replication or no history of BKV reactivation. Responses to EBV antigens and mitogen were reduced in patients with BKV reactivation, but these differences were not statistically significant. The T cell response to BKV antigens is a useful and specific guide to recovery from BKV reactivation in renal transplant recipients, provided that the full range of antigenic responses is measured.

Reliable test of clinicians' mastery in skin cancer diagnostics.

Differentiating between benign and malignant skin lesions can be very difficult and should only be done by sufficiently trained and skilled clinicians. To our knowledge there are no validated tests for reliable assessments of clinicians' ability to perform skin cancer diagnostics. To develop and gather validity evidence for a test in skin cancer diagnostics, a multiple-choice questionnaire (MCQ) was developed based on informal interviews with seven content experts from five skin cancer centers in Denmark. Validity evidence for the test was gathered from May until July 2019 using Messick's validity framework (content, response process, internal structure, relationship to other variables and consequences). Item content was revised through a Delphi-like review process and then piloted on 36 medical students and 136 doctors using a standardized response process. Results enabled an analysis of the internal structure and relationship to other variables of the test. Finally, the contrasting groups method was used to investigate the test's consequences (pass-fail standard). The initial 90-item MCQ was reduced to 40 items during the Delphi-like review process. Item analysis revealed that 25 of the 40 selected items were level I-III quality items with a high internal consistency (Cronbach's α = 0.83) and highly significant (P ≤ 0.0001) differences in test scores between participants with different occupations or levels of experience. A pass-fail standard of 12 (48%) correct answers was established using the contrasting groups' method. The skin cancer diagnostics MCQ developed in this study can be used for reliable assessments of clinicians' competencies.

One-day or two-day procedure for sentinel node biopsy in melanoma?

PURPOSE: We compared the outcome of a 1-day and a 2-day sentinel node (SN) biopsy procedure, evaluated in terms of lymphoscintigraphic, surgical and pathological findings. METHODS: We studied 476 patients with melanoma from two melanoma centres using static scintigraphy and blue dye. A proportional odds model was used for statistical analysis. RESULTS: The number of SNs visualized at scintigraphy increased significantly with time from injection to scintigraphy and activity left in the patient at scintigraphy, and depended on the melanoma location. The number of SNs removed at surgery increased with the number of SNs visualized at scintigraphy and time from injection to surgery. The frequency of nodal metastasis increased with increasing thickness and Clark level of the melanoma, and was highest for two SNs visualized at scintigraphy. CONCLUSION: This study showed that early vs. late imaging and surgery do make a difference on the outcome of the SN procedure and confirmed the importance of the scintigraphic visualization of all true SNs.

Sentinel node detection in melanomas using contrast-enhanced ultrasound.

BACKGROUND: Sentinel node (SN) biopsy has proven to be a useful clinical method based on the combination of radionuclide tracer principles and the dye technique. Contrast-enhanced ultrasound (CEUS) has been used successfully for detection of SN in animals, but the use of CEUS has not been reported in humans. PURPOSE: To investigate the possible use of CEUS in detecting SN in patients with malignant melanomas (MM), and to improve the method by using different concentrations of contrast agent and various positions of the extremity. MATERIAL AND METHODS: Ten patients with MM on an extremity and one healthy volunteer were included. One milliliter of a contrast agent (Sonovue; Bracco, Milan, Italy) was injected subcutaneously on both sides of the scar from the excised tumor. Contrast-enhanced lymph channels and lymph nodes (LNs) were searched for using low-mechanical-index CEUS and by stimulated acoustic emission. Afterward, lymphoscintigraphy was performed and the patient operated. During surgery, the SNs were located via scintigraphic findings, gamma-probe signals, and blue-dye visualization of lymph channels and LNs. Before the human study, a study of 10 mice was performed to exclude possible tissue damage, as the contrast agent was not registered for subcutaneous administration. RESULTS: In one patient, two contrast-enhanced inguinal LNs were visualized by CEUS, corresponding to two inguinal SNs found by scintigraphic imaging. No contrast-enhanced lymph channels or LNs were visualized in any other patients or in the volunteer. No tissue damage was observed in the 10 mice. CONCLUSION: This study does not support the use of CEUS for detection of SNs in humans. However, the application of CEUS for the investigation of SNs is still not fully explored in humans, and an alternative setup and/or contrast agent might provide better results.

Author Correction: Rapid susceptibility profiling of carbapenem-resistant Klebsiella pneumoniae.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Rapid susceptibility profiling of carbapenem-resistant Klebsiella pneumoniae.

The expanding global distribution of multi-resistant Klebsiella pneumoniae demands faster antimicrobial susceptibility testing (AST) to guide antibiotic treatment. Current ASTs rely on time-consuming differentiation of resistance and susceptibility after initial isolation of bacteria from a clinical specimen. Here we describe a flow cytometry workflow to determine carbapenem susceptibility from bacterial cell characteristics in an international K. pneumoniae isolate collection (n = 48), with a range of carbapenemases. Our flow cytometry-assisted susceptibility test (FAST) method combines rapid qualitative susceptible/non-susceptible classification and quantitative MIC measurement in a single process completed shortly after receipt of a primary isolate (54 and 158 minutes respectively). The qualitative FAST results and FAST-derived MIC (MICFAST) correspond closely with broth microdilution MIC (MICBMD, Matthew's correlation coefficient 0.887), align with the international AST standard (ISO 200776-1; 2006) and could be used for rapid determination of antimicrobial susceptibility in a wider range of Gram negative and Gram positive bacteria.

Radiation doses to staff involved in sentinel node operations for breast cancer.

BACKGROUND: The use of radioactive compounds for sentinel node biopsy is now a generally accepted part of the surgical treatment of breast cancer and melanoma, with the risk of radiation exposure to the operating team. The aim of this investigation was to study the levels of this exposure in relation to the permissible radiation dose limits. METHODS: The radiation exposure to the hands and bodies of the operating surgeons (the 'risk persons') was measured by thermoluminescent dosimeters in 79 operations and to the pathologists handling the specimens in 17 cases. Radioactivity and dose rate measurement from tumours and breast specimens were also performed. RESULTS: During an operation the mean skin dose (+/-SD) to the thermoluminescent dosimeters placed at the hand and the abdominal wall were 0.04 +/- 0.04 mSv (79 operations) and 0.01 +/- 0.02 mSv (67 operations) respectively. For the pathologist, the mean hand dose per operation was below the detection limit (17 operations). Correlation between the measured dose rate and the radioactive content of the tumours was 0.998. CONCLUSIONS: The radiation exposure to the staff involved in sentinel node (SN) biopsy for breast cancer using radioactive labelled tracers will be considerably below the permissible limits, even with high numbers of SN biopsy procedures. Pregnant staff members should participate in <100 SN operations.

Regulation of EGF-receptor expression by EGF and TGF alpha in epidermoid cancer cells is cell type-specific.

The epidermal growth factor receptor (EGF-R) and its major ligands EGF and transforming growth factor alpha (TGF alpha) play an important role in the development of multiple human tumors. However, little is known of the comparative effects of each ligand on the regulation of EGF-R expression. To investigate this issue we used two similar human epidermoid cancer cell lines that overexpress EGF-Rs (KB and A431). In KB cells, EGF and TGF alpha increased EGF-R mRNA and protein levels by 2-3 fold over 8 h, associated with a greater than 4-fold stabilization of EGF-R mRNA half-life. EGF and TGF alpha also increased transcription of EGF-R mRNA 2-3-fold in KB cells. In contrast, EGF and TGF alpha only minimally increased EGF-R mRNA and protein in A431 cells, without changing EGF-R mRNA half-life. Basal EGF-R mRNA half-life was 2 fold greater in A431 cells than in KB cells (6-7 h versus 2-3 h), whilst the half-life of a mutant 2.6 kb EGF-R mRNA present in A431 cells, which lacks the 3-untranslated region (3'-UTR), was 2 fold greater than the full-length EGF-R mRNA. RNA gel-shift studies demonstrated that KB and A431 cells contain cytoplasmic proteins that bind specifically to an AU-rich sequence from the 3'-UTR of EGF-R mRNA. Taken together, these results demonstrate that in KB cells EGF and TGF alpha upregulate EGF-R expression at both transcriptional and post-transcriptional levels. The identification of AU-rich EGF-R mRNA-specific RNA-binding proteins from epidermoid cancer cells that overexpress EGF-Rs suggests that regulated RNA-protein interactions involving this region may play a central role in modulating EGF-R mRNA stability.

Tumour response after hyperthermic isolated limb perfusion for locally advanced melanoma.

INTRODUCTION: The aim was to describe tumour response, complications, recurrence and survival after hyperthermic isolated limb perfusion (ILP) with melphalan or melphalan in combination with tumour necrosis factor-alpha in patients with melanoma metastases confined to an extremity. MATERIAL AND METHODS: A total of 84 perfusions were performed (53 women, 31 men, median age 63 years) from 1993 to 2010. 95% of the perfusions were administered to the lower limbs and 5% to the upper limbs. The inclusion criteria were recurrent and/or clinically apparent cutaneous/subcutaneous extremity in-transit melanoma metastases. RESULTS: The response rate after ILP was 85%; 42% had complete response (CR), 43% partial response (PR), 12% no change (NC) and 3% progression. Two- and five-year survival rates were 57% and 31%, respectively, and they were higher for patients with than without lymph node metastases. Time from ILP to recurrence was a median of seven months (range 1-37 months) for patients with CR or PR. Survival was longer for patients with CR or PR than for patients showing NC or progression. Several patients had mild or moderate local toxicity reactions, two patients developed severe local toxicity. CONCLUSION: ILP induces tumour regression in the vast majority of patients. One patient, i.e. 1% of the group, died from surgical complications. Otherwise, ILP treatment had an acceptable morbidity in this group of very sick patients. We are convinced that the treatment should be offered to improve local disease control in patients with multiple and/or recurrent melanoma confined to an extremity if surgical excision is not possible. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Immunolymphoscintigraphy for metastatic sentinel nodes: test of a model.

Aim. To develop a method and obtain proof-of-principle for immunolymphoscintigraphy for identification of metastatic sentinel nodes. Methods. We selected one of four tumour-specific antibodies against human breast cancer and investigated (1), in immune-deficient (nude) mice with xenograft human breast cancer expressing the antigen if specific binding of the intratumorally injected, radioactively labelled, monoclonal antibody could be scintigraphically visualized, and (2) transportation to and retention in regional lymph nodes of the radioactively labelled antibody after subcutaneous injection in healthy rabbits. Results and Conclusion. Our paper suggests the theoretical possibility of a model of dual isotope immuno-lymphoscintigraphy for noninvasive, preoperative, malignant sentinel node imaging.

A lucky fall? Case report.

Renal cell carcinomas (RCCs) account for 3% of all solid neoplasms, with an increased incidence after renal transplantation. In transplant recipients, RCCs predominantly occur in the patient's native kidneys. Herein is reported a case of a localized RCC of recipient origin that developed in the donor allograft and was detected 8 years after renal transplantation. Treatment with high-intensity focussed ultrasound followed by partial nephrectomy was successful, averting the need for dialysis therapy.

Radiation exposure to surgical staff during F-18-FDG-guided cancer surgery.

PURPOSE: High-energy gamma probes have recently become commercially available, developed for (18)F-FDG probe-guided surgery. The radiation received by the staff in the operating room might limit the use of it, but has never been determined. We therefore wanted to measure the absorbed staff doses at operations where patients had received a preoperative injection of (18)F-FDG. METHODS: Thirty-four patients with different cancers (breast cancer, melanoma, gastrointestinal cancers, respectively) were operated. At every operation the surgeon was monitored with a TLD tablet on his finger of the operating hand and a TLD tablet on the abdomen. The surgeon and anaesthesiologist were also monitored using electronic dosimeters placed in the trousers lining at 25 operations. RESULTS: The dose rate to the surgeon's abdominal wall varied between 7.5-13.2 microSv/h, depending on tumour location. The doses to the anaesthesiologists and the finger doses to the surgeon were much lower. About 350-400 MBq, i.e. ca. eight times higher activities than those used in the present study are supposed to be necessary for guiding surgery. It can be calculated from the body doses measured that a surgeon can perform between 150-260 h of surgery without exceeding permissible limits for professional workers. CONCLUSIONS: The radiation load to the operating staff will generally be so small that it does not present any limitation for FDG-guided surgery. However, it is recommended to monitor the surgical staff considering that the surgeon may be exposed to other radiation sources, and since the staff often includes women of child-bearing age.