Cost-effectiveness analysis of the use of immunotherapy in metastatic solid tumours in Austria by applying the ESMO-magnitude of clinical benefit scale (ESMO-MCBS) version 1.1

BACKGROUND: Immune checkpoint inhibitors (ICIs) treatment is a breakthrough in managing metastatic solid tumours, but its use is associated with a high financial burden for public health care systems. Validated tools such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) are frameworks that might help to better assess the clinical benefit of these novel innovative cancer drugs. METHODS: Here, we systematically analysed the number of European Medicines Agency-approved ICIs labels with an ESMO-MCBS grade <4 and the impact of the ICIs on incremental costs, gain of life years (LYs), quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio in the Austrian population. RESULTS: Of 23 ICIs treatment settings, we identified three clinical scenarios in metastatic solid cancers with an ESMO-MCBS grade <4 with no otherwise approved alternatives. In triple-negative breast cancer (TNBC), the addition of first-line atezolizumab increased QALYs by 0.33 compared with nab-paclitaxel only, with an incremental cost per QALY of €143 853. In small-cell lung cancer (SCLC), the addition of first-line atezolizumab increased the QALY by 0.09, with an incremental cost per QALY of €373 256, and the addition of first-line durvalumab increased the QALYs by 0.11, with an incremental cost per QALY of €589 527. CONCLUSIONS: Overall, most of the approved ICIs carry significant clinical benefit (≥4). Although TNBC and SCLC are challenging treatment scenarios, currently approved ICIs with an ESMO-MCBS grade <4 substantially increase the cost of medical treatment, and under a willingness-to-pay threshold of €100 000, they do not have a cost-effective comparative benefit

The antimutagenic and antioxidant potential of stercobilin and urobilin in the Ames Salmonella test

Das Ziel der vorliegenden Studie war die Abschätzung des antimutagenen bzw. antioxidativen Potentials von den beiden Gallenpigmenten Stercobilin und Urobilin im in vitro Ames Test. Für die Untersuchung wurden die Bakterienstämme Salmonella typhimurium TA98 und TA102 verwendet. Als mutagene Substanzen wurden 2, 4, 7- Trinitro-9-Fluorenon (TNFone), Aflatoxin B1 (AFB1), 2-Amino-1-methyl-6-phenylimidazo [4, 5,-b] Pyridin (PhiP) und tert-Butylhydroxyperoxide (t-BuOOH) herangezogen. Die Testkonzentrationen der Gallenfarbstoffe reichten von 0.001 bis 2 µmol/Platte (Urobilin) bzw. von 0.01 bis 2 µmol/Platte (Stercobilin). Um sicherzustellen, dass die beiden Gallenpigmente kein mutagenes Potential aufweisen, wurde dies in Mutagenitätstests überprüft. Die Tests wurden sowohl ohne (TNFone, t-BuOOH) als auch mit (PhiP, AFB1, t-BuOOH) metabolischer Aktivierung durchgeführt.The aim of the present study was to investigate the antimutagenic and antioxidant potential of the bile pigments, stercobilin and urobilin, in the Ames Salmonella test. The experiments in the bacterial system were designed with two Salmonella typhimurium tester strains, TA98 and TA102. Different mutagens including 2, 4, 7- trinitro-9-fluorenone (TNFone), aflatoxin B1 (AFB1), 2-amino-1-methyl-6-phenylimidazo [4, 5,-b] pyridine (PhiP) und tert-butylhydroxyperoxide (t-BuOOH) were used to confirm the formation of mutant revertants. Six doses of stercobilin (0.01, 0.05, 0.1, 0.5, 1 and 2 µmol/plate) and eight doses of urobilin (0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 and 2 µmol/plate) were screened. In order to ensure non-mutagenic potential of bile pigments, mutagenicity assays were performed. Tests were conducted without (TNFone, t-BuOOH) and with (PhiP, AFB1 and t-BuOOH) metabolic activation

Attitude is everything? The impact of workload, safety climate, and safety tools on medical errors: A study of intensive care units

Background: Hospitals face an increasing pressure towards efficiency and cost reduction while ensuring patient safety. This warrants a closer examination of the trade-off between production and protection posited in the literature for a high-risk hospital setting (intensive care). Purposes: Based on extant literature and concepts on both safety management and organizational/safety culture, this study investigates to which extent production pressure (i.e., increased staff workload and capacity utilization) and safety culture (consisting of safety climate among staff and safety tools implemented by management) influence the occurrence of medical errors and if/how safety climate and safety tools interact. Methodology / Approach: A prospective, observational, 48-hour cross-sectional study was conducted in 57 intensive care units. The dependent variable is the incidence of errors affecting those 378 patients treated throughout the entire observation period. Capacity utilization and workload were measured by indicators such as unit occupancy, nurse-/physician-to-patient ratios, levels of care, or NEMS scores. The safety tools considered include Critical Incidence Reporting Systems, audits, training, mission statements, SOPs/checklists and the use of barcodes. Safety climate was assessed using a psychometrically validated four-dimensional questionnaire. Linear regression was employed to identify the effects of the predictor variables on error rate, as well as interaction effects between safety tools and safety climate. Findings: Higher workload has a detrimental effect on safety while safety climate - unlike the examined safety tools - has a virtually equal opposite effect. Correlations between safety tools and safety climate as well as their interaction effects on error rate are mostly nonsignificant. Practice Implications: Increased workload and capacity utilization increase the occurrence of medical error; an effect that can be offset by a positive safety climate but not by formally implemented safety procedures and policies

Attitude is everything? The impact of workload, safety climate, and safety tools on medical errors: A study of intensive care units

Background: Hospitals face an increasing pressure towards efficiency and cost reduction while ensuring patient safety. This warrants a closer examination of the trade-off between production and protection posited in the literature for a high-risk hospital setting (intensive care). Purposes: Based on extant literature and concepts on both safety management and organizational/safety culture, this study investigates to which extent production pressure (i.e., increased staff workload and capacity utilization) and safety culture (consisting of safety climate among staff and safety tools implemented by management) influence the occurrence of medical errors and if/how safety climate and safety tools interact. Methodology / Approach: A prospective, observational, 48-hour cross-sectional study was conducted in 57 intensive care units. The dependent variable is the incidence of errors affecting those 378 patients treated throughout the entire observation period. Capacity utilization and workload were measured by indicators such as unit occupancy, nurse-/physician-to-patient ratios, levels of care, or NEMS scores. The safety tools considered include Critical Incidence Reporting Systems, audits, training, mission statements, SOPs/checklists and the use of barcodes. Safety climate was assessed using a psychometrically validated four-dimensional questionnaire. Linear regression was employed to identify the effects of the predictor variables on error rate, as well as interaction effects between safety tools and safety climate. Findings: Higher workload has a detrimental effect on safety while safety climate - unlike the examined safety tools - has a virtually equal opposite effect. Correlations between safety tools and safety climate as well as their interaction effects on error rate are mostly nonsignificant. Practice Implications: Increased workload and capacity utilization increase the occurrence of medical error; an effect that can be offset by a positive safety climate but not by formally implemented safety procedures and policies

Sinonasal meningioma in a Siberian tiger (Panthera tigris altaica)

Meningiomas are the most common primary brain tumour in dogs and cats. However, whilst there are numerous reports of extracranial (spinal, orbital and sinonasal) meningiomas in the dog, there have only been a few case reports of spinal meningiomas, and no post-mortem confirmed orbital or sinonasal meningiomas in cats. In this report, a 20-year-old captive tiger (Panthera tigris altaica) with a history of chronic ocular inflammation resulting in enucleation, spontaneously developed tetanic convulsions (epileptic seizures) that over a 2-year period resulted in a gradually worsening condition and the animal was eventually euthanized. At autopsy, a focal, expansile, neoplastic mass was found in the caudal nasal cavity midline, abutting the cribriform plate and slightly compressing the calvarium. Histological analysis revealed nasal turbinates attached to a wellcircumscribed expansile multi-lobular mass consisting of interlacing whorls and streams of neoplastic cells supported by a variably fibrous to microcystic collagenous matrix displaying rare psammoma bodies. The diagnosis was sinonasal transitional meningioma. This is the first report of a captive wild felid with an extracranial meningioma, specifically a tiger with a sinonasal transitional meningioma.The Wellcome Trust.https://www.mdpi.com/journal/vetsciam2023Centre for Veterinary Wildlife StudiesParaclinical Science

Markers of inflammation in free-living African elephants (Loxodonta africana) : reference intervals and diagnostic performance of acute phase reactants

INTRODUCTION: Acute phase reactants (APRs) have not been investigated in free-living African elephants (Loxodonta africana), and there is little information about negative APRs albumin and serum iron in elephants. OBJECTIVES: We aimed to generate reference intervals (RIs) for APRs for free-living African elephants, and to determine the diagnostic performance of APRs in apparently healthy elephants and elephants with inflammatory lesions. METHODS: Stored serum samples from 49 apparently healthy and 16 injured free-living elephants were used. The following APRs and methods were included: albumin, bromocresol green; haptoglobin, colorimetric assay; serum amyloid A (SAA), multispecies immunoturbidometric assay, and serum iron with ferrozine method. Reference intervals were generated using the nonparametric method. Indices of diagnostic accuracy were determined by receiver-operator characteristic (ROC) curve analysis. RESULTS: Reference intervals were: albumin 41-55 g/L, haptoglobin 0.16-3.51 g/L, SAA < 10 mg/L, and serum iron 8.60-16.99 μmol/L. Serum iron and albumin concentrations were lower and haptoglobin and SAA concentrations were higher in the injured group. Serum iron had the best ability to predict health or inflammation, followed by haptoglobin, SAA, and albumin, with the area under the ROC curve ranging from 0.88-0.93. CONCLUSIONS: SAA concentrations were lower in healthy African vs Asian elephants, and species-specific RIs should be used. Serum iron was determined to be a diagnostically useful negative APR which should be added to APR panels for elephants.University of Pretoriahttp://www.wileyonlinelibrary.com/journal/vcpdm2022Centre for Veterinary Wildlife StudiesCompanion Animal Clinical StudiesProduction Animal Studie

Comparison of three hematocrit measurement methods in the southern white rhinoceros (Ceratotherium simum simum)

BACKGROUND: Hematocrit (HCT) determination is an integral part of health and disease assessments in captive and wild white rhinoceroses. Several affordable automated hematology analyzers have been developed for in-clinic and field use and have the advantage of being able to measure a large number of additional measurands. However, the accuracy of these analyzers for rhinoceros HCT measurements has not yet been investigated. OBJECTIVES: We aimed to compare the HCT results generated by the EPOC portable analyzer system and the Abaxis VetScan HM5 with the gold standard of a manual packed cell volume (PCV) measured using the microhematocrit method. METHODS: Hematocrits were measured with the EPOC and the Abaxis VetScan HM5 (bovine setting) and compared with the PCVs of 69 white rhinoceros whole blood samples. Results were compared using Bland–Altman difference plots and PassingBablok regression analysis. A total allowable analytical error of 10% was set as the performance goal. RESULTS: A significant positive bias, with a mean of 7.7% for the EPOC and 17.9% for the Abaxis, was found compared with the manual PCV method. CONCLUSIONS: The allowable error goal of 10% was not exceeded with the EPOC analyzer. Although not analytically equivalent to the gold standard, the EPOC results could therefore be used as approximations in critical situations where manual measurements cannot be performed. The Abaxis exceeded this allowable error and overestimated HCTs in rhinoceroses. Therefore, method-specific reference intervals should be used.International Rhino Foundation; Veterinary Wildlife Services, Kruger National Park; Zebra Foundation for Veterinary Zoological Education; South African National Parks; University of Pretoriahttp://www.wileyonlinelibrary.com/journal/vcpdm2022Centre for Veterinary Wildlife StudiesCompanion Animal Clinical StudiesParaclinical Science

Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice

AIMS/HYPOTHESIS: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). METHODS: We studied metabolic adaptations in Lal (-/-) mice. RESULTS: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels. CONCLUSIONS/INTERPRETATION: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply