Demonstrating the use of population level data to investigate trends in the rate, radiation dose and cost of Computed Tomography across clinical groups: Are there any areas of concern?

INTRODUCTION: Increases in computed tomography (CT) use may not always reflect clinical need or improve outcomes. This study aimed to demonstrate how population level data can be used to identify variations in care between patient groups, by analysing system-level changes in CT use around the diagnosis of new conditions. METHODS: Retrospective repeated cross-sectional observational study using West Australian linked administrative records, including 504,723 adults diagnosed with different conditions in 2006, 2012 and 2015. For 90 days pre/post diagnosis, CT use (any and 2+ scans), effective dose (mSv), lifetime attributable risk (LAR) of cancer incidence and mortality from CT, and costs were assessed. RESULTS: CT use increased from 209.4 per 1000 new diagnoses in 2006 to 258.0 in 2015; increases were observed for all conditions except neoplasms. Healthcare system costs increased for all conditions but neoplasms and mental disorders. Effective dose increased substantially for respiratory (+2.5 mSv, +23.1%, P < 0.001) and circulatory conditions (+2.1 mSv, +15.4%, P < 0.001). The LAR of cancer incidence and mortality from CT increased for endocrine (incidence +23.4%, mortality +18.0%) and respiratory disorders (+21.7%, +23.3%). Mortality LAR increased for circulatory (+12.1%) and nervous system (+11.0%) disorders. The LAR of cancer incidence and mortality reduced for musculoskeletal system disorders, despite an increase in repeated CT in this group. CONCLUSIONS: Use and costs increased for most conditions except neoplasms and mental and behavioural disorders. More strategic CT use may have occurred in musculoskeletal conditions, while use and radiation burden increased for respiratory, circulatory and nervous system conditions. Using this high-level approach we flag areas requiring deeper investigation into appropriateness and value of care.

Assessing the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease: a European perspective.

Several countries have recently reassessed the international risk of variant Creutzfeldt-Jakob disease (vCJD) transmission through transfusion of blood and blood components (red blood cells, platelets and plasma) and relaxed donor deferrals based on geographic and transfusion exposure in countries formerly considered to be high risk, such as the UK. In this regard, the European Blood Alliance organised a consensus meeting of experts and involved professionals to discuss current knowledge, epidemiological data, prevention and various methods for assessing the risk of transfusion-transmitted vCJD, as well as to develop an appropriate position on possible approaches to address these challenges in Europe. Participants reached a consensus that the current risk of transfusion-transmitted vCJD associated with blood donors who either travelled to or received transfusions in the UK during the vCJD outbreak is minimal. In addressing such risks, it would be pragmatic that assessments and guidelines are developed by European expert bodies, rather than individual assessments by Member States. Regardless of the approach used, European or national, a qualitative risk assessment based on a review and analysis of available data, considering all the uncertainties and experiences of other countries, would provide crucial information to reassess blood donation strategies regarding the transfusion-associated vCJD risk.

Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

Nodal positivity in patients with clinically and radiologically node-negative breast cancer treated with neoadjuvant chemotherapy: multicentre collaborative study.

BACKGROUND: The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS: A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS: A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION: The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension due to septic emboli.

We present the case of a 28-year-old woman with a history of tricuspid valve endocarditis leading to chronic thromboembolic pulmonary hypertension (CTEPH) with multiple pulmonary artery chronic total occlusions (CTOs) due to septic emboli. Following a multidisciplinary care discussion, the patient was brought forward for balloon pulmonary angioplasty (BPA) with successful revascularization of all chronically occluded territories. This case highlights advances in pulmonary artery CTO interventions and demonstrates the feasibility of BPA for CTEPH patients with a history of septic emboli.

Premorbid weight in pulmonary arterial hypertension.

Relationships between obesity and outcomes in pulmonary arterial hypertension (PAH) are complex. Previous work suggested obesity, occurring alongside PAH, may be associated with better survival. In our work, we suggest obesity prior to PAH development is associated with worse survival. This may add a novel temporal element to the "obesity-paradox."

Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells.

Helicobacter pylori infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of H. pylori-induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations. We find using alkaline comet assay, single-molecule DNA fiber assays, and immunofluorescence microscopy of DNA repair foci that H. pylori induces transcription-dependent DNA damage in actively replicating, Leucine-rich-repeat containing G-Protein-Coupled Receptor 5 (Lgr5)-positive antral stem and progenitor cells and their Troy-positive corpus counterparts, but not in other gastric epithelial lineages. Infection-dependent DNA damage is aggravated by Apc inactivation, but not by Trp53 or Smad4 loss, or Erbb2 overexpression. Our data suggest that H. pylori induces DNA damage in stem and progenitor cells, especially in settings of hyperproliferation due to constitutively active Wnt signaling.

Use of CT, ED presentation and hospitalisations 12 months before and after a diagnosis of cancer in Western Australia: a population-based retrospective cohort study.

OBJECTIVE: To examine the use of CT, emergency department (ED)-presentation and hospitalisation and in 12 months before and after a diagnosis of cancer. DESIGN: Population-based retrospective cohort study. SETTING: West Australian linked administrative records at individual level. PARTICIPANTS: 104 009 adults newly diagnosed with cancer in 2004-2014. MAIN OUTCOME MEASURES: CT use, ED presentations, hospitalisations. RESULTS: As compared with the rates in the 12th month before diagnosis, the rate of CT scans started to increase from 2 months before diagnosis with an increase in both ED presentations and hospitalisation from 1 month before the diagnosis. These rates peaked in the month of diagnosis for CT scans (477 (95% CI 471 to 482) per 1000 patients), and for hospitalisations (910 (95% CI 902 to 919) per 1000 patients), and the month prior to diagnosis for ED (181 (95% CI 178 to 184) per 1000 patients) then rapidly reduced after diagnosis but remained high for the next 12 months. While the patterns of the health services used were similar between 2004 and 2014, the rate of the health services used during after diagnosis was higher in 2014 versus 2004 except for CT use in patients with lymphohaematopoietic cancer with a significant reduction. CONCLUSION: Our results showed an increase in demand for health services from 2 months before diagnosis of cancer. Increasing use of health services during and post cancer diagnosis may warrant further investigation to identify factors driving this change.

Regional Variation in Pulmonary Arterial Hypertension in the United States: The Pulmonary Hypertension Association Registry.

Rationale: Pulmonary arterial hypertension (PAH) is a heterogeneous disease within a complex diagnostic and treatment environment. Other complex heart and lung diseases have substantial regional variation in characteristics and outcomes; however, this has not been previously described in PAH. Objectives: To identify baseline differences between U.S. census regions in the characteristics and outcomes for participants in the Pulmonary Hypertension Association Registry (PHAR). Methods: Adults with PAH were divided into regional groups (Northeast, South, Midwest, and West), and baseline differences between census regions were presented. Kaplan-Meier survival analyses and Cox proportional hazards were used to estimate the association between region and mortality in unadjusted and adjusted models. Results: Substantial differences by census regions were seen in age, race, ethnicity, marital status, employment, insurance payor breakdown, active smoking, and current alcohol use. Differences were also seen in PAH etiology and baseline 6-minute walk distance test results. Treatment characteristics varied by census region, and mortality appeared to be lower in PHAR participants in the West (hazard ratio, 0.60; 95% confidence interval, 0.43-0.83, P = 0.005). This difference was not readily explained by differences in demographic characteristics, PAH etiology, baseline severity, baseline medication regimen, or disease prevalence. Conclusions: The present study suggests significant regional variation among participants at accredited pulmonary vascular disease centers in multiple baseline characteristics and mortality. This variation may have implications for clinical research planning and represent an important focus for further study to better understand whether there are remediable care aspects that can be addressed in the pursuit of providing equitable care in the United States.

Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma.

Background & Aims: Mcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1Δhep) on hepatocyte ploidy and cell cycle in murine liver in vivo and the possible implications on HCC. Methods: Livers of young Mcl-1Δhep and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, in situ chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression in vivo. Mcl-1Δhep tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing. Results: In young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1Δhep tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology. Conclusions: Our study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes in vivo. In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer. Impact and implications: Although Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes in vivo, whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation.

Plasma collection and supply in Europe: Proceedings of an International Plasma and Fractionation Association and European Blood Alliance symposium.

At the symposium organized by the International Plasma and Fractionation Association and European Blood Alliance, experts presented their views and experiences showing that the public sector and its blood establishments may strengthen the collection and increase the supply of plasma using the right strategies in plasma donor recruitment, retention and protection, scaling-up collection by increasing the number of donors within improved/new infrastructure, supportive funding, policies and legislation as well as harmonization of clinical guidelines and the collaboration of all stakeholders. Such approaches should contribute to increased plasma collection in Europe to meet patients' needs for plasma-derived medicinal products, notably immunoglobulins and avoid shortages. Overall, presentations and discussions confirmed that European non-profit transfusion institutions are committed to increasing the collection of plasma for fractionation from unpaid donors through dedicated programmes as well as novel strategies and research.

Patterns of computed tomography utilisation in injury management: latent classes approach using linked administrative data in Western Australia.

PURPOSE: Whilst computed tomography (CT) imaging has been a vital component of injury management, its increasing use has raised concern regarding ionising radiation exposure. This study aims to identify latent classes (underlying patterns) of CT use over a 3-year period following the incidence of injury and factors predicting the observed patterns. METHOD: A retrospective observational cohort study was conducted in 21,544 individuals aged 18 + years presenting to emergency departments (ED) of four tertiary public hospitals with new injury in Western Australia. Mixture modelling approach was used to identify latent classes of CT use over a 3-year period post injury. RESULTS: Amongst injured people with at least one CT scan, three latent classes of CT use were identified including a: temporarily high CT use (46.4%); consistently high CT use (2.6%); and low CT use class (51.1%). Being 65 + years or older, having 3 + comorbidities, history with 3 + hospitalisations and history of CT use before injury were associated with consistently high use of CT. Injury to the head, neck, thorax or abdomen, being admitted to hospital after the injury and arriving to ED by ambulance were predictors for the temporarily high use class. Living in areas of higher socio-economic disadvantage was a unique factor associated with the low CT use class. CONCLUSIONS: Instead of assuming a single pattern of CT use for all patients with injury, the advanced latent class modelling approach has provided more nuanced understanding of the underlying patterns of CT use that may be useful for developing targeted interventions.

Circulating fibrocyte percentage and neutrophil-lymphocyte ratio are accurate biomarkers of uncomplicated and complicated appendicitis: a prospective cohort study.

BACKGROUND: There is increasing evidence that uncomplicated appendicitis (UA) may be treated nonoperatively in cases of UA. This study aimed to evaluate and compare the diagnostic accuracy of circulating fibrocyte percentage (CFP), white blood cell count, C-reactive protein, and neutrophil-lymphocyte ratio (NLR) in diagnosing uncomplicated and complicated appendicitis. MATERIALS AND METHODS: Eighty consecutive adult patients presenting with suspected appendicitis were recruited in a cohort-based prospective study between June 2015 and February 2016 at University Hospital Limerick in Ireland. Peripheral venous samples were obtained at the presentation. Clinical, biochemical, radiological, and histopathological parameters were recorded. The CFP was determined by dual-staining for CD45 and collagen-I using flow cytometry analysis and correlated with histopathological diagnoses. RESULTS: Of the 46 patients who underwent appendicectomy, 34 (73.9%) had histologically proven acute appendicitis. A comparison of the diagnostic accuracy of biomarkers demonstrated the CFP had the highest diagnostic accuracy for UA (area under the curve=0.83, sensitivity=72.7%, specificity=83.3%, P=0.002). The NLR had the highest diagnostic accuracy in relation to complicated appendicitis (area under the curve=0.84, sensitivity=75.5%, specificity=83.3%, P=0.005). CONCLUSIONS: CFP and NLR are accurate biomarkers of UA and complicated appendicitis.

Western Australian women's expectations for expanded NIPT-An online survey regarding NIPT for single gene, recessive and chromosomal conditions.

Prenatal screening has evolved rapidly following the introduction of non-invasive prenatal testing (NIPT), with screening now available for an increasing number of conditions. We explored the attitudes and expectations of women within the context of using NIPT to detect multiple different single gene and chromosome conditions during pregnancy. An online survey was used to assess these issues with a sample of 219 women from Western Australia. In our study, the majority of women (96%) support of the concept of expanded NIPT for single gene and chromosome conditions provided the test involves no risk to the pregnancy and can provide the parents with relevant medical information about the fetus at any stage of pregnancy. 80% believed that expanded NIPT for single gene and chromosome conditions should be available at any stage during pregnancy and 68% of women indicated that test cost would be a factor in determining their participation in testing. Under half (43%) of the women favored an option to terminate a pregnancy at any stage if the fetus had a medical condition that would interfere with day to day functioning. The majority (78%) of women believed that testing for multiple genetic conditions would provide reassurance and lead to the delivery of a healthy child.

Transpulmonary amino acid metabolism in the sugen hypoxia model of pulmonary hypertension.

In pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation. In this study, we utilize the sugen/hypoxia (SuHx) rodent model of PAH to examine the RV, LV and MVEC intracellular metabolome (using targeted metabolomics) in normoxic and SuHx rats. We additionally validate key findings from our metabolomics experiments with data obtained from cell culture of normoxic and SuHx MVECs, as well as metabolomics of human serum samples from two different PAH patient cohorts. Taken together, our data, spanning rat serum, human serum and primary isolated rat MVECs reveal that: (1) key classes of amino acids (specifically, branched chain amino acids-BCAA) are lower in the pre-capillary (i.e., RV) serum of SuHx rats (and humans); (2) intracellular amino acid levels (in particular BCAAs) are increased in SuHx-MVECs; (3) there may be secretion rather than utilization of amino acids across the pulmonary microvasculature in PAH and (4) an oxidized glutathione gradient is present across the pulmonary vasculature, suggesting a novel fate for increased glutamine uptake (i.e., as a source of glutathione). in MVECs in PAH. In summary, these data reveal new insight into the shifts in amino acid metabolism occurring across the pulmonary circulation in PAH.