Uncertainty-aware image classification on 3D CT lung.

Early detection is crucial for lung cancer to prolong the patient's survival. Existing model architectures used in such systems have shown promising results. However, they lack reliability and robustness in their predictions and the models are typically evaluated on a single dataset, making them overconfident when a new class is present. With the existence of uncertainty, uncertain images can be referred to medical experts for a second opinion. Thus, we propose an uncertainty-aware framework that includes three phases: data preprocessing and model selection and evaluation, uncertainty quantification (UQ), and uncertainty measurement and data referral for the classification of benign and malignant nodules using 3D CT images. To quantify the uncertainty, we employed three approaches; Monte Carlo Dropout (MCD), Deep Ensemble (DE), and Ensemble Monte Carlo Dropout (EMCD). We evaluated eight different deep learning models consisting of ResNet, DenseNet, and the Inception network family, all of which achieved average F1 scores above 0.832, and the highest average value of 0.845 was obtained using InceptionResNetV2. Furthermore, incorporating the UQ demonstrated significant improvement in the overall model performance. Upon evaluation of the uncertainty estimate, MCD outperforms the other UQ models except for the metric, URecall, where DE and EMCD excel, implying that they are better at identifying incorrect predictions with higher uncertainty levels, which is vital in the medical field. Finally, we show that using a threshold for data referral can greatly improve the performance further, increasing the accuracy up to 0.959.

ECMO simulation: How much, who to train, and a review of cost, fidelity and performance.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) is a high-risk, low-volume procedure requiring repetition, skill and multiple disciplines with fidelity of communication. Yet many barriers exist to maintain proficiency and skills with variable cost and fidelity. We designed and implemented a low-cost monthly ECMO simulation and hypothesized providers would have increased familiarity and improved teamwork. We also review some key elements of cost, fidelity and evaluation of effectiveness. METHODS: A structured, 1-hour ECMO simulation was performed on a customized mannikin on a monthly basis in 2022. Qualitative surveys were administered to each member post-simulation. Answers were categorized by theme, including satisfaction of patient care, evaluation of self and team dynamics, and areas for improvement. RESULTS: Most participants were satisfied with their ability to take care of the patient, with common themes of communication and coordination of roles. Identified areas of improvement were mostly limited to technical skills, and soft skills such as communication and teamwork. CONCLUSIONS: We designed and implemented a low-cost, monthly and multi-disciplinary ECMO simulation program with overall positive feedback and identified areas for improvement. There remains variability in cost, fidelity and evaluation of performance and retention. There may be a need to create guidelines for ECMO simulation training that can be applied at all institutions utilizing ECMO for patient care.

What are the information needs of people with dementia and their family caregivers when they are admitted to a mental health ward and do current ward patient information leaflets meet their needs?

INTRODUCTION: An admission to a mental health ward is an uncertain and unexpected part of a person's journey with dementia and consequently, families require information about what to expect and how to prepare. This study aimed to establish the information needs of people with dementia and their families at the point of admission to a mental health ward and to collate existing ward information leaflets to explore if they meet these information needs. METHODS: This research was conducted in two parts: (1) a qualitative study using focus groups, one with people with dementia and family carers with lived experience of such an admission (n = 6), and another with Admiral Nurses (n = 6) to explore information needs at the point of admission. (2) Each National Health Service (NHS) mental health trust (n = 67) was asked to provide a copy of their ward information shared at admission. A total of 30 leaflets were received from 15 NHS trusts; after removing duplicates, 22 were included. A content analysis was conducted to evaluate to what extent leaflets met the information needs identified by focus groups. RESULTS: Two main categories 'honest, accurate and up-to-date information' and 'who is the information for' and four subcategories were derived from focus group data. Participants felt that people with dementia and their families were likely to have different information needs. Material for people with dementia needed to be in an accessible format. Information should cover the aim of the admission, a timeline of what to expect and details about how families will be involved in care. Practical information about what to pack and ward facilities was valued. Participants spoke about the need to consider the tone of the information, given that people are likely to be distressed. The information leaflets reviewed did not meet the information needs identified by focus group participants. CONCLUSIONS: People with dementia and family carers have different information needs at the point of admission to a mental health ward. Information provided to people with dementia needs to be in an accessible format with content relevant to these needs. Wards should aim to co-create information to ensure that they meet people's information needs. PATIENT OR PUBLIC CONTRIBUTION: This research was supported by a patient and public involvement (PPI) group of people with dementia and carers who have experience in mental health wards. The idea for the study came from the group and was motivated by their experiences. The PPI group helped with the design of the study and took part in the focus groups. The information generated has been written up in this paper, and the knowledge generated has also been used to co-create a guide for wards on writing their information leaflets and to support the co-creation of a public information leaflet by Dementia UK about mental health admissions for people with dementia.

Application of a new approach methodology (NAM)-based strategy for genotoxicity assessment of data-poor compounds.

The conventional battery for genotoxicity testing is not well suited to assessing the large number of chemicals needing evaluation. Traditional in vitro tests lack throughput, provide little mechanistic information, and have poor specificity in predicting in vivo genotoxicity. New Approach Methodologies (NAMs) aim to accelerate the pace of hazard assessment and reduce reliance on in vivo tests that are time-consuming and resource-intensive. As such, high-throughput transcriptomic and flow cytometry-based assays have been developed for modernized in vitro genotoxicity assessment. This includes: the TGx-DDI transcriptomic biomarker (i.e., 64-gene expression signature to identify DNA damage-inducing (DDI) substances), the MicroFlow® assay (i.e., a flow cytometry-based micronucleus (MN) test), and the MultiFlow® assay (i.e., a multiplexed flow cytometry-based reporter assay that yields mode of action (MoA) information). The objective of this study was to investigate the utility of the TGx-DDI transcriptomic biomarker, multiplexed with the MicroFlow® and MultiFlow® assays, as an integrated NAM-based testing strategy for screening data-poor compounds prioritized by Health Canada's New Substances Assessment and Control Bureau. Human lymphoblastoid TK6 cells were exposed to 3 control and 10 data-poor substances, using a 6-point concentration range. Gene expression profiling was conducted using the targeted TempO-Seq™ assay, and the TGx-DDI classifier was applied to the dataset. Classifications were compared with those based on the MicroFlow® and MultiFlow® assays. Benchmark Concentration (BMC) modeling was used for potency ranking. The results of the integrated hazard calls indicate that five of the data-poor compounds were genotoxic in vitro, causing DNA damage via a clastogenic MoA, and one via a pan-genotoxic MoA. Two compounds were likely irrelevant positives in the MN test; two are considered possibly genotoxic causing DNA damage via an ambiguous MoA. BMC modeling revealed nearly identical potency rankings for each assay. This ranking was maintained when all endpoint BMCs were converted into a single score using the Toxicological Prioritization (ToxPi) approach. Overall, this study contributes to the establishment of a modernized approach for effective genotoxicity assessment and chemical prioritization for further regulatory scrutiny. We conclude that the integration of TGx-DDI, MicroFlow®, and MultiFlow® endpoints is an effective NAM-based strategy for genotoxicity assessment of data-poor compounds.

A systematic review of obesity as a barrier to accessing cancer screening services.

Introduction: Obesity is a known risk factor for the development of cancers, and a significant proportion of the population may be at risk of developing cancer owing to their weight status. There is acknowledged societal stigma towards people living with obesity, which can influence health behaviors and deter help seeking, such as cancer screening. Healthcare professionals' attitudes and views toward people living with obesity may adversely affect the patient-professional interface and treatment. Methods: A systematic review was carried out which aimed to explore the impact of living with obesity on the uptake of three main cancer-screening services: breast, cervical, and colorectal. Results: Ten studies were included in the review. Three main areas were identified from both a patient and healthcare professional perspective: barriers and challenges to screening, gender issues, and disparities in the population living with obesity. Conclusion: Further research is needed to improve uptake of cancer screening services, and for education on weight bias, which is often unconscious, to be considered for healthcare professionals working in cancer screening services. This may help to increase the incidence of early differential diagnosis of potential cancers and improve health outcomes for people living with obesity.

Division of Labor by the HELQ, BLM, and FANCM Helicases during Homologous Recombination Repair in Drosophila melanogaster.

Repair of DNA double-strand breaks by homologous recombination (HR) requires a carefully orchestrated sequence of events involving many proteins. One type of HR, synthesis-dependent strand annealing (SDSA), proceeds via the formation of a displacement loop (D-loop) when RAD51-coated single-stranded DNA invades a homologous template. The 3' end of the single-stranded DNA is extended by DNA synthesis. In SDSA, the D-loop is then disassembled prior to strand annealing. While many helicases can unwind D-loops in vitro, how their action is choreographed in vivo remains to be determined. To clarify the roles of various DNA helicases during SDSA, we used a double-strand gap repair assay to study the outcomes of homologous recombination repair in Drosophila melanogaster lacking the BLM, HELQ, and FANCM helicases. We found that the absence of any of these three helicases impairs gap repair. In addition, flies lacking both BLM and HELQ or HELQ and FANCM had more severe SDSA defects than the corresponding single mutants. In the absence of BLM, a large percentage of repair events were accompanied by flanking deletions. Strikingly, these deletions were mostly abolished in the blm helq and blm fancm double mutants. Our results suggest that the BLM, HELQ, and FANCM helicases play distinct roles during SDSA, with HELQ and FANCM acting early to promote the formation of recombination intermediates that are then processed by BLM to prevent repair by deletion-prone mechanisms.

A novel phonetic approach to continuous flow left ventricular assist device auscultation.

BACKGROUND: The dominant sound generated by continuous flow left ventricular assist devices (cf-LVADs) has generically been referred to as a "hum". This term, however, implies that despite distinct engineering designs, all cf-LVADs generate the same quality of sound. Furthermore, no structured method for auscultation of cf-LVADs exists. We hereby report a novel and simple phonetic approach to device auscultation, the aims of which are to improve recognition, understanding, and teaching of sound produced by normally functioning cf-LVADs. We sought to evaluate whether clinically relevant pump or person related events can produce changes in the expected audio fingerprint of a particular cf-LVAD, and whether these changes in sound can be identified by auscultation and translated phonetically. METHODS: Sound recordings were made on 7 people implanted with one of 3 U.S. Food and Drug Administration (FDA) approved cf-LVADs. Of the 7, 3 were considered to have normal device function and stable condition. The remaining 4 people had a clinically relevant pump or person related event. Recordings were made with a stethoscope attachment that allows digital recording of sound and provides a real time phonocardiogram. RESULTS: The main findings were the following: 1.) each cf-LVAD generates a unique audio fingerprint 2.) the audio fingerprint can be phonetically translated in a simple manner. 3.) pump or patient related events result in changes in device sound, that can be appreciated phonetically. CONCLUSIONS: Phonetics offer a novel and easily reproducible method for evaluation and teaching normal cf-LVAD sounds by auscultation. Additionally, clinically relevant pump or person related events can produce changes in the expected audio fingerprint of a particular cf-LVAD. These changes in sound can be identified by auscultation and translated phonetically. Auscultation is an important component of the physical examination of people supported with cf-LVADs.

Digital breast tomosynthesis: sensitivity for cancer in younger symptomatic women.

OBJECTIVE: Full-field digital mammography (FFDM) has limited sensitivity for cancer in younger women with denser breasts. Digital breast tomosynthesis (DBT) can reduce the risk of cancer being obscured by overlying tissue. The primary study aim was to compare the sensitivity of FFDM, DBT and FFDM-plus-DBT in women under 60 years old with clinical suspicion of breast cancer. METHODS: This multicentre study recruited 446 patients from UK breast clinics. Participants underwent both standard FFDM and DBT. A blinded retrospective multireader study involving 12 readers and 300 mammograms (152 malignant and 148 benign cases) was conducted. RESULTS: Sensitivity for cancer was 86.6% with FFDM [95% CI (85.2-88.0%)], 89.1% with DBT [95% CI (88.2-90%)], and 91.7% with FFDM+DBT [95% CI (90.7-92.6%)]. In the densest breasts, the maximum sensitivity increment with FFDM +DBT over FFDM alone was 10.3%, varying by density measurement method. Overall specificity was 81.4% with FFDM [95% CI (80.5-82.3%)], 84.6% with DBT [95% CI (83.9-85.3%)], and 79.6% with FFDM +DBT [95% CI (79.0-80.2%)]. No differences were detected in accuracy of tumour measurement in unifocal cases. CONCLUSIONS: Where available, DBT merits first-line use in the under 60 age group in symptomatic breast clinics, particularly in women known to have very dense breasts. ADVANCES IN KNOWLEDGE: This study is one of very few to address the accuracy of DBT in symptomatic rather than screening patients. It quantifies the diagnostic gains of DBT in direct comparison with standard digital mammography, supporting informed decisions on appropriate use of DBT in this population.

LIN28B promotes neuroblastoma metastasis and regulates PDZ binding kinase.

Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, decreases self-renewal and migration. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and self-renewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7i and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B. Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.

Saved by the VAC: Minimally Invasive Removal of a Surely Fatal Right Heart Thrombus in a Patient with Advanced Heart Failure.

Intracardiac thrombi are associated with an increased morbidity and mortality due to their unpredictability and embolic potential. Right heart thrombus is infrequently encountered in clinical practice outside the scenario of acute pulmonary embolism with hemodynamic compromise, and even more uncommon is the presence of a massive right heart thrombus. Embolic potential is high, and historically, management has revolved around open surgical removal or systemic thrombolysis. We hereby present a case of a massive right heart thrombus in a high surgical risk patient, which was successfully removed using a percutaneous aspiration device.

Acute Isolated Coronary Artery Dissection Causing Massive Acute Myocardial Infarction and Leading to Unsuccessful Coronary Bypass, Extracorporeal Life Support, and Successful Cardiac Transplantation.

Described herein is a 42-year-old woman who suddenly developed a spontaneous isolated coronary arterial dissection which led to massive acute myocardial infarction with shock, unsuccessful coronary artery bypass grafting, transiently successful extracorporeal life support, and finally successful heart transplant. Such a sequence of events is exceedingly rare for patients with coronary dissection and prompted this report.

In vitro mutagenicity of selected environmental carcinogens and their metabolites in MutaMouse FE1 lung epithelial cells.

Chemicals in commerce or under development must be assessed for genotoxicity; assessment is generally conducted using validated assays (e.g. Tk mouse lymphoma assay) as part of a regulatory process. Currently, the MutaMouse FE1 cell mutagenicity assay is undergoing validation for eventual use as a standard in vitro mammalian mutagenicity assay. FE1 cells have been shown to be metabolically competent with respect to some cytochrome P450 (CYP) isozymes; for instance, they can convert the human carcinogen benzo[a]pyrene into its proximate mutagenic metabolite. However, some contradictory results have been noted for other genotoxic carcinogens that require two-step metabolic activation (e.g. 2-acetylaminofluorene and 2-amino-3-methylimidazo[4,5-f]quinoxaline). Here, we examined three known or suspected human carcinogens, namely acrylamide, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 4-aminobiphenyl (4-ABP), together with their proximate metabolites (i.e. glycidamide, N-OH-PhIP and N-OH-4-ABP), to aid in the validation of the FE1 cell mutagenicity assay. Assessments of the parent compounds were conducted both in the presence and absence of an exogenous metabolic activation mixture S9; assessments of the metabolites were in the absence of S9. The most potent compound was N-OH-PhIP -S9, which elicited a mutant frequency (MF) level 5.3-fold over background at 5 µM. There was a 4.3-fold increase for PhIP +S9 at 5 µM, a 1.7-fold increase for glycidamide -S9 at 3.5 mM and a 1.5-fold increase for acrylamide +S9 at 4 mM. Acrylamide -S9 elicited a marginal 1.4-fold MF increase at 8 mM. Treatment with PhIP -S9, 4-ABP ±S9 and N-OH-4-ABP -S9 failed to elicit significant increases in lacZ MF with any of the treatment conditions tested. Gene expression of key CYP isozymes was quantified by RT-qPCR. Cyp1a1, 1a2 and 1b1 are required to metabolise PhIP and 4-ABP. Results showed that treatment with both compounds induced expression of Cyp1a1 and Cyp1b1 but not Cyp1a2. Cyp2e1, which catalyses the bioactivation of acrylamide to glycidamide, was not induced after acrylamide treatment. Overall, our results confirm that the FE1 cell mutagenicity assay has the potential for use alongside other, more traditional in vitro mutagenicity assays.

Radiology and patient communication: if not now, then when?

KEY POINTS: • Communication with patients in radiology is, in general, indirect using the referrer as a conduit. • Direct patient communication may be beneficial for radiology departments and radiologists to improve patient awareness about the nature of our role and also to provide correct and measured information about the nature and frequency of discrepancies in radiology.

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

In vitro mammalian cell mutation assays based on transgenic reporters: A report of the International Workshop on Genotoxicity Testing (IWGT).

Chemical safety evaluations require assessment of genetic toxicity. Transgenic rodent (TGR) assays permit enumeration of mutations in chromosomally-integrated targets contained in shuttle vectors. In order to improve in vitro mutagenicity assessment, and to substantially reduce animal use, in vitro assays using transgenic reporters have been developed. These assays are based on cells derived from TGRs, or cells transfected with transgenic shuttle vectors containing a mutation target. As part of the 7th International Workshop on Genotoxicity Testing, an In Vitro Mammalian Cell Gene Mutation Assay working group reviewed all published information pertaining to in vitro transgene mutagenicity assays; the utility, advantages and disadvantages of the assays were evaluated and discussed. The review revealed that over 20 TGR-based in vitro assays have been used to assess the mutagenic activity of over 150 agents. Overall, the Working Group considered in vitro transgene mutagenicity assays pragmatic tools for the safety evaluation of new and existing substances. A formal SWOT (strengths, weaknesses, opportunities, threats) analysis revealed advantages including the use of established scoring protocols, avoidance of laborious clone isolation and enumeration, ability to use metabolically competent primary cells, ability to detect different types of genetic damage, large dynamic range, and complementarity to in vivo TGR endpoints. Disadvantages include lack of validation and little consistency in protocols, the use of specialised reagents, the time and effort required for mutant enumeration, the use of some cell lines that lack metabolic capacity, and the need for multiple assays to cover all mutational mechanisms. Several assays have been partially validated, indicating promising reliability, reproducibility and applicability domain. Once in vitro transgene mutagenicity assays have been more thoroughly validated, they are well placed to augment or replace existing in vitro mammalian cell mutagenicity assays, particularly in cases where the in vivo TGR mutation assay is intended for follow-up.