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Background and Aims: Six-monthly ultrasound surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis. Surveillance enhances early detection and improves survival. Yet, despite clear benefits, uptake remains low. We aim to identify and explore ways to overcome patient-related barriers to HCC surveillance with the aim of producing invitations for surveillance., Methods: Using the COM-B model of behaviour and a co-design process, we collaborated with patients, liver health charities and advocacy groups, to identify patient-related barriers to attending HCC surveillance. We performed qualitative thematic analysis of co-production workshops on HCC surveillance to develop information leaflets and surveillance invitations., Results: Twenty-eight participants attended five workshops. Fear of a serious diagnosis and stigma from healthcare professionals were highlighted as main patient-related barriers to attending surveillance appointments. Co-design was used to develop informative, user-friendly, non-judgemental invitations and information regarding HCC surveillance relevant to populations with cirrhosis., Conclusion: We identified potential patient barriers to surveillance uptake and developed patient facing material that directly addressed these barriers to be trialled in the clinic. Targeting patient-specific barriers may increase uptake of surveillance and therefore enhance early diagnosis., Competing Interests: RS received research funding (to institution) from AAA, Boston Scientific, Incyte pharmaceuticals; speaker fees from Esai. The authors report no other personal or financial conflicts of interest for this work., (© 2024 Qurashi et al.)

Objectives: To investigate the role of comorbid chronic obstructive pulmonary disease (COPD) and symptom type on general practitioners' (GP's) symptom attribution and clinical decision-making in relation to lung cancer diagnosis., Design: Vignette survey with a 2×2 mixed factorial design., Setting: A nationwide online survey exploring clinical decision-making in primary care., Participants: 109 GPs based in the United Kingdom (UK) who were registered as responders on Dynata (an online survey platform)., Interventions: GPs were presented with four vignettes which described a patient aged 75 with a smoking history presenting with worsening symptoms (either general or respiratory) and with or without a pre-existing diagnosis of COPD., Primary and Secondary Outcome Measures: GPs indicated the three most likely diagnoses (free-text) and selected four management approaches (20 pre-coded options). Attribution of symptoms to lung cancer and referral for urgent chest X-ray were primary outcomes. Alternative diagnoses and management approaches were explored as secondary outcomes. Multivariable mixed-effects logistic regression was used, including random intercepts for individual GPs., Results: 422 vignettes were completed. There was no evidence for COPD status as a predictor of lung cancer attribution (OR=1.1, 95% CI=0.5-2.4, p=0.914). There was no evidence for COPD status as a predictor of urgent chest X-ray referral (OR=0.6, 95% CI=0.3-1.2, p=0.12) or as a predictor when in combination with symptom type (OR=0.9, 95% CI=0.5-1.8, p=0.767)., Conclusions: Lung cancer was identified as a possible diagnosis for persistent respiratory by only one out of five GPs, irrespective of the patients' COPD status. Increasing awareness among GPs of the link between COPD and lung cancer may increase the propensity for performing chest X-rays and referral for diagnostic testing for symptomatic patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

While A2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A2B could be complementary and/or compensatory to A2A, simultaneous targeting of A2A and A2B ARs can provide higher potential for cancer immunotherapy. We developed M1069 - a highly selective dual antagonist of the A2A and A2B AR. In assays with primary human and murine immune cells, M1069 rescued IL 2 production from T cells (A2A dependent) and inhibited VEGF production by myeloid cells (A2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of secretion of pro tumorigenic cytokines CXCL1, CXCL5, and rescue of IL 12 secretion from adenosine differentiated dendritic cells compared to an A2A selective antagonist (A2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine differentiated human and murine dendritic cells treated with M1069 demonstrated superior T cell stimulatory activity compared to dendritic cells differentiated in presence of A2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced anti-tumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosinehi/CD73hi 4T1 breast tumor model, but not in the CD73 knockout (KO) 4T1 tumor model or in adenosinelow/CD73low MC38 murine colon carcinoma model. In summary, our dual A2A/A2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the anti-tumor activity of other agents, including BA and cisplatin.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Local Interpretability Model-agnostic Explanations (LIME) is a well-known post-hoc technique for explaining black-box models. While very useful, recent research highlights challenges around the explanations generated. In particular, there is a potential lack of stability, where the explanations provided vary over repeated runs of the algorithm, casting doubt on their reliability. This paper investigates the stability of LIME when applied to multivariate time series classification. We demonstrate that the traditional methods for generating neighbours used in LIME carry a high risk of creating 'fake' neighbours, which are out-of-distribution in respect to the trained model and far away from the input to be explained. This risk is particularly pronounced for time series data because of their substantial temporal dependencies. We discuss how these out-of-distribution neighbours contribute to unstable explanations. Furthermore, LIME weights neighbours based on user-defined hyperparameters which are problem-dependent and hard to tune. We show how unsuitable hyperparameters can impact the stability of explanations. We propose a two-fold approach to address these issues. First, a generative model is employed to approximate the distribution of the training data set, from which within-distribution samples and thus meaningful neighbours can be created for LIME. Second, an adaptive weighting method is designed in which the hyperparameters are easier to tune than those of the traditional method. Experiments on real-world data sets demonstrate the effectiveness of the proposed method in providing more stable explanations using the LIME framework. In addition, in-depth discussions are provided on the reasons behind these results., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Han Meng reports financial support was provided by China Scholarship Council. Han Meng reports financial support was provided by University of Nottingham. Isaac Triguero reports equipment, drugs, or supplies was provided by NVIDIA Corp., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Different training programs have been developed to improve trainee outcomes in urology. However, evidence on the optimal training methodology is sparse. Our aim was to provide a comprehensive description of the training programs available for urological robotic surgery and endourology, assess their validity, and highlight the fundamental elements of future training pathways., Methods: We systematically reviewed the literature using PubMed/Medline, Embase, and Web of Science databases. The validity of each training model was assessed. The methodological quality of studies on metrics and curricula was graded using the MERSQI scale. The level of evidence (LoE) and level of recommendation for surgical curricula were awarded using the educational Oxford Centre for Evidence-Based Medicine classification., Key Findings and Limitations: A total of 75 studies were identified. Many simulators have been developed to aid trainees in mastering skills required for both robotic and endourology procedures, but only four demonstrated predictive validity. For assessment of trainee proficiency, we identified 18 in robotics training and six in endourology training; however, the majority are Likert-type scales. Although proficiency-based progression (PBP) curricula demonstrated superior outcomes to traditional training in preclinical settings, only four of six (67%) in robotics and three of nine (33%) in endourology are PBP-based. Among these, the Fundamentals of Robotic Surgery and the SIMULATE curricula have the highest LoE (level 1b). The lack of a quantitative synthesis is the main limitation of our study., Conclusions and Clinical Implications: Training curricula that integrate simulators and PBP methodology have been introduced to standardize trainee outcomes in robotics and endourology. However, evidence regarding their educational impact remains restricted to preclinical studies. Efforts should be made to expand these training programs to different surgical procedures and assess their clinical impact., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases., Methods: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls ( n  = 9), neuroacanthocytosis syndrome patients ( n  = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients ( n  = 6), Huntington's disease patients (n = 5), and amyotrophic lateral sclerosis patients ( n  = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics., Results: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (O min ), maximal elongation index (EI max ), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (O hyper ), and the width of the curve close to the osmolality at maximal elongation index (O max -width)., Discussion: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only O hyper and O max -width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (O max ) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EI min ) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hernández, Peikert, Qiao, Darras, de Wilde, Bos, Leibowitz, Galea, Wagner, Rab, Walker, Hermann, van Beers, van Wijk and Kaestner.)

Red blood cells (RBC), the primary carriers of oxygen in the body, play a crucial role across several biomedical applications, while also being an essential model system of a deformable object in the microfluidics and soft matter fields. However, RBC behavior in viscoelastic liquids, which holds promise in enhancing microfluidic diagnostic applications, remains poorly studied. We here show that using viscoelastic polymer solutions as a suspending carrier causes changes in the clustering and shape of flowing RBC in microfluidic flows when compared to a standard Newtonian suspending liquid. Additionally, when the local RBC concentration increases to a point where hydrodynamic interactions take place, we observe the formation of equally-spaced RBC structures, resembling the viscoelasticity-driven ordered particles observed previously in the literature, thus providing the first experimental evidence of viscoelasticity-driven cell ordering. The observed RBC ordering, unaffected by polymer molecular architecture, persists as long as the surrounding medium exhibits shear-thinning, viscoelastic properties. Complementary numerical simulations reveal that viscoelasticity-induced repulsion between RBCs leads to equidistant structures, with shear-thinning modulating this effect. Our results open the way for the development of new biomedical technologies based on the use of viscoelastic liquids while also clarifying fundamental aspects related to multibody hydrodynamic interactions in viscoelastic microfluidic flows.

Introduction: Participation in bowel cancer screening is lower in regions where there is high ethnic diversity and/or socioeconomic deprivation. Interventions, such as text message reminders and patient navigation (PN), have the potential to increase participation in these areas. As such, there is interest in the comparative effectiveness of these interventions to increase bowel cancer screening participation, as well as their relative cost-effectiveness., Methods and Analysis: This study will use a three-arm randomised controlled trial design to compare the effectiveness and cost-effectiveness of text message reminders and PN to increase the uptake of bowel cancer screening in London. Participants will be individuals who have not returned a completed faecal immunochemical test kit within 13 weeks of receiving a routine invitation from the London bowel cancer screening hub. Participants will be randomised (in a 1:1:1 ratio) to receive either (1) usual care (ie, 'no intervention'), (2) a text message reminder at 13 weeks, followed by repeated text message reminders at 15, 17 and 19 weeks (in the event of non-response) or (3) a text message reminder at 13 weeks, followed by PN telephone calls at 15, 17 and 19 weeks in the event of non-response. The primary endpoint will be participation in bowel cancer screening, defined as 'the return of a completed kit by week 24'. Statistical analysis will use multivariate logistic regression and will incorporate pairwise comparisons of all three groups, adjusted for multiple testing., Ethics and Dissemination: Approvals to conduct the research have been obtained from University College London's Joint Research Office (Ref: 150666), the Screening Research, Innovation and Development Advisory Committee ('RIDAC', Ref: 2223 014 BCSP Kerrison), the Health Research Authority (Ref: 22/WM/0212) and the Confidentiality Advisory Group (Ref: 22/CAG/0140). Results will be conveyed to stakeholders, notably those managing the screening programme and published in peer-reviewed journals/presented at academic conferences., Trial Registration Number: ISRCTN17245519., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Blood is a highly complex fluid with rheological properties that have a significant impact on various flow phenomena. In particular, it exhibits a non-Newtonian elongational viscosity that is comparable to polymer solutions. In this study, we investigate the effect of three different anticoagulants, namely EDTA (ethylene diamine tetraacetic acid), heparin, and citrate, on the elongational properties of both human and swine blood. We observe a unique two stage thinning process and a strong dependency of the characteristic relaxation time on the chosen anticoagulant, with the longest relaxation time and thus the highest elongational viscosity being found for the case of citrate. Our findings for the latter are consistent with the physiological values obtained from a dripping droplet of human blood without any anticoagulant. Furthermore, our study resolves the discrepancy found in the literature regarding the reported range of characteristic relaxation times, confirming that the elongational viscosity must be taken into account for a full rheological characterization of blood. These results have important implications for understanding blood flow in various physiological, pathological and technological conditions.

Previously, our group established a surgical gesture classification system that deconstructs robotic tissue dissection into basic surgical maneuvers. Here, we evaluate gestures by correlating the metric with surgeon experience and technical skill assessment scores in the apical dissection (AD) of robotic-assisted radical prostatectomy (RARP). Additionally, we explore the association between AD performance and early continence recovery following RARP. 78 AD surgical videos from 2016 to 2018 across two international institutions were included. Surgeons were grouped by median robotic caseload (range 80-5,800 cases): less experienced group (< 475 cases) and more experienced (≥ 475 cases). Videos were decoded with gestures and assessed using Dissection Assessment for Robotic Technique (DART). Statistical findings revealed more experienced surgeons (n = 10) used greater proportions of cold cut (p = 0.008) and smaller proportions of peel/push, spread, and two-hand spread (p < 0.05) than less experienced surgeons (n = 10). Correlations between gestures and technical skills assessments ranged from - 0.397 to 0.316 (p < 0.05). Surgeons utilizing more retraction gestures had lower total DART scores (p < 0.01), suggesting less dissection proficiency. Those who used more gestures and spent more time per gesture had lower efficiency scores (p < 0.01). More coagulation and hook gestures were found in cases of patients with continence recovery compared to those with ongoing incontinence (p < 0.04). Gestures performed during AD vary based on surgeon experience level and patient continence recovery duration. Significant correlations were demonstrated between gestures and dissection technical skills. Gestures can serve as a novel method to objectively evaluate dissection performance and anticipate outcomes., (© 2024. The Author(s).)

Background: Cancer burden is higher and cancer screening participation is lower among individuals living in more socioeconomically deprived areas of England, contributing to worse health outcomes and shorter life expectancy. Owing to higher multi-cancer early detection (MCED) test sensitivity for poor-prognosis cancers and greater cancer burden in groups experiencing greater deprivation, MCED screening programmes may have greater relative benefits in these groups. We modelled potential differential benefits of MCED screening between deprivation groups in England at different levels of screening participation., Methods: We applied the interception multi-cancer screening model to cancer incidence and survival data made available by the National Cancer Registration and Analysis Service in England to estimate reductions in late-stage diagnoses and cancer mortality from an MCED screening programme by deprivation group across 24 cancer types. We assessed the impact of varying the proportion of people who participated in annual screening in each deprivation group on these estimates., Results: The modelled benefits of an MCED screening programme were substantial: reductions in late-stage diagnoses were 160 and 274 per 100 000 persons in the least and most deprived groups, respectively. Reductions in cancer mortality were 60 and 99 per 100 000 persons in the least and most deprived groups, respectively. Benefits were greatest in the most deprived group at every participation level and were attenuated with lower screening participation., Conclusions: For the greatest possible population benefit and to decrease health inequalities, an MCED implementation strategy should focus on enhancing equitable, informed participation, enabling equal participation across all socioeconomic deprivation groups., Trial Registration Number: NCT05611632., Competing Interests: Competing interests: RS and EH are employees of GRAIL, LLC and hold stock in Illumina. RS also has contingent value rights in GRAIL, LLC. EH is an inventor on multiple patents concerned with sequencing, microarrays and cancer detection. SLQ received payment from the Global Lung Cancer Coalition for authoring a context piece for their website and presenting this at their annual meeting, and receives grant funding for other projects from Cancer Research UK, University College London Hospitals NHS Trust, Yorkshire Cancer Research and NHS England. CvW receives grant funding for other projects from Cancer Research UK, National Institute for Health and Care Research and NHS England., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: As a local treatment for prostate cancer (PCa), robot-assisted radical prostatectomy (RARP) may have a quality of life (QoL) benefit over open surgery. Recent analyses revealed substantial between-country differences in the function and symptom scale scores for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), which is typically used to assess patient-reported QoL. Such differences could have implications for multinational studies in PCa., Objective: To examine whether nationality is significantly associated with patient-reported QoL., Design, Setting, and Participants: The study cohort comprised Dutch and German patients with PCa treated with RARP in a single high-volume prostate center from 2006 to 2018. Analyses were restricted to patients who were preoperatively continent with at least one follow-up time point., Outcome Measurements and Statistical Analysis: QoL was measured in terms of the global Quality of Life (QL) scale score and the overall summary score for the EORTC QLQ-C30. Linear mixed models for repeated-measures multivariable analyses (MVAs) were used to examine the association between nationality and both the global QL score and the summary score. MVAs were further adjusted for QLQ-C30 baseline values, age, Charlson comorbidity index, preoperative prostate-specific antigen, surgical expertise, pathological tumor and nodal stage, Gleason grade, degree of nerve-sparing, surgical margin status, 30-d Clavien-Dindo grade complications, urinary continence recovery, and biochemical recurrence/postoperative radiotherapy., Results and Limitations: For Dutch (n = 1938) versus German (n = 6410) men, the mean baseline scores were 82.8 versus 71.9 for the global QL scale score and 93.4 versus 89.7 for the QLQ-C30 summary score. Urinary continence recovery (QL: +8.9, 95% confidence interval [CI] 8.1-9.8; p < 0001) and Dutch nationality (QL: +6.9, 95% CI 6.1-7.6; p < 0001) were the strongest positive contributors to the global QL and summary scores, respectively. The main limitation is the retrospective study design. In addition, our Dutch cohort may not be representative of the general Dutch population and reporting bias cannot be ruled out., Conclusions: Our findings provide observational evidence under specific conditions involving the same setting for patients of two different nationalities suggesting that cross-national patient-reported QoL differences appear to be real and may need to be taken into consideration in multinational studies., Patient Summary: We observed differences in the quality-of-life scores reported by Dutch and German patients with prostate cancer after they underwent robot-assisted removal of the prostate. These findings should be taken into consideration in cross-national studies., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The ability to change shape is essential for the proper functioning of red blood cells (RBCs) within the microvasculature. The shape of RBCs significantly influences blood flow and has been employed in microfluidic lab-on-a-chip devices, serving as a diagnostic biomarker for specific pathologies and enabling the assessment of RBC deformability. While external flow conditions, such as the vessel size and the flow velocity, are known to impact microscale RBC flow, our comprehensive understanding of how their shape-adapting ability is influenced by channel confinement in biomedical applications remains incomplete. This study explores the impact of various rectangular and square channels, each with different confinement and aspect ratios, on the in vitro RBC flow behavior and characteristic shapes. We demonstrate that rectangular microchannels, with a height similar to the RBC diameter in combination with a confinement ratio exceeding 0.9, are required to generate distinctive well-defined croissant and slipper-like RBC shapes. These shapes are characterized by their equilibrium positions in the channel cross section, and we observe a strong elongation of both stable shapes in response to the shear rate across the different channels. Less confined channel configurations lead to the emergence of unstable other shape types that display rich shape dynamics. Our work establishes an experimental framework to understand the influence of channel size on the single-cell flow behavior of RBCs, providing valuable insights for the design of biomicrofluidic single-cell analysis applications., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

The discrete and charge-separated nature of matter - electrons and nuclei - results in local electrostatic fields that are ubiquitous in nanoscale structures and relevant in catalysis, nanoelectronics and quantum nanoscience. Surface-averaging techniques provide only limited experimental access to these potentials, which are determined by the shape, material, and environment of the nanostructure. Here, we image the potential over adatoms, chains, and clusters of Ag and Au atoms assembled on Ag(111) and quantify their surface dipole moments. By focusing on the total charge density, these data establish a benchmark for theory. Our density functional theory calculations show a very good agreement with experiment and allow a deeper analysis of the dipole formation mechanisms, their dependence on fundamental atomic properties and on the shape of the nanostructures. We formulate an intuitive picture of the basic mechanisms behind dipole formation, allowing better design choices for future nanoscale systems such as single-atom catalysts., (© 2024. The Author(s).)

Background: In recent years, the production of inclusion bodies that retain substantial catalytic activity was demonstrated. These catalytically active inclusion bodies (CatIBs) are formed by genetic fusion of an aggregation-inducing tag to a gene of interest via short linker polypeptides. The resulting CatIBs are known for their easy and cost-efficient production, recyclability as well as their improved stability. Recent studies have outlined the cooperative effects of linker and aggregation-inducing tag on CatIB activities. However, no a priori prediction is possible so far to indicate the best combination thereof. Consequently, extensive screening is required to find the best performing CatIB variant., Results: In this work, a semi-automated cloning workflow was implemented and used for fast generation of 63 CatIB variants with glucose dehydrogenase of Bacillus subtilis (BsGDH). Furthermore, the variant BsGDH-PT-CBDCell was used to develop, optimize and validate an automated CatIB screening workflow, enhancing the analysis of many CatIB candidates in parallel. Compared to previous studies with CatIBs, important optimization steps include the exclusion of plate position effects in the BioLector by changing the cultivation temperature. For the overall workflow including strain construction, the manual workload could be reduced from 59 to 7 h for 48 variants (88%). After demonstration of high reproducibility with 1.9% relative standard deviation across 42 biological replicates, the workflow was performed in combination with a Bayesian process model and Thompson sampling. While the process model is crucial to derive key performance indicators of CatIBs, Thompson sampling serves as a strategy to balance exploitation and exploration in screening procedures. Our methodology allowed analysis of 63 BsGDH-CatIB variants within only three batch experiments. Because of the high likelihood of TDoT-PT-BsGDH being the best CatIB performer, it was selected in 50 biological replicates during the three screening rounds, much more than other, low-performing variants., Conclusions: At the current state of knowledge, every new enzyme requires screening for different linker/aggregation-inducing tag combinations. For this purpose, the presented CatIB toolbox facilitates fast and simplified construction and screening procedures. The methodology thus assists in finding the best CatIB producer from large libraries in short time, rendering possible automated Design-Build-Test-Learn cycles to generate structure/function learnings., (© 2024. The Author(s).)

The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the abundance of the channels in RBCs. Furthermore, we utilize automated patch clamp, based on planar chips, to compare the activity of the two channels in reticulocytes and mature RBCs. In addition to this characterization, we performed membrane potential measurements to demonstrate the effect of channel activity and interplay on the RBC properties. Both the Gárdos channel and Piezo1, albeit their average copy number of activatable channels per cell is in the single-digit range, can be detected through transcriptome analysis of reticulocytes. Proteomics analysis of reticulocytes and mature RBCs could only detect Piezo1 but not the Gárdos channel. Furthermore, they can be reliably measured in the whole-cell configuration of the patch clamp method. While for the Gárdos channel, the activity in terms of ion currents is higher in reticulocytes compared to mature RBCs, for Piezo1, the tendency is the opposite. While the interplay between Piezo1 and Gárdos channel cannot be followed using the patch clamp measurements, it could be proved based on membrane potential measurements in populations of intact RBCs. We discuss the Gárdos channel and Piezo1 abundance, interdependencies and interactions in the context of their proposed physiological and pathophysiological functions, which are the passing of small constrictions, e.g., in the spleen, and their active participation in blood clot formation and thrombosis.

Erythrocyte sedimentation rate (ESR) is a clinical parameter used as a nonspecific marker for inflammation, and recent studies have shown that it is linked to the collapse of the gel formed by red blood cells (RBCs) at physiological hematocrits (i.e. RBC volume fraction). Previous research has suggested that the observation of a slower initial dynamics is related to the formation of fractures in the gel. Moreover, RBC gels present specific properties due to the anisotropic shape and flexibility of the RBCs. Namely, the onset of the collapse is reached earlier and the settling velocity of the gel increases with increasing attraction between the RBCs, while the gel of spherical particles shows the opposite trend. Here, we report experimental observations of the gel structure during the onset of the collapse. We suggest an equation modeling this initial process as fracturing of the gel. We demonstrate that this equation provides a model for the motion of the interface between blood plasma and the RBC gel, along the whole time span. We also observe that the increase in the attraction between the RBCs modifies the density of fractures in the gel, which explains why the gel displays an earlier onset when the aggregation energy between the RBCs increases. Our work uncovers the detailed physical mechanism underlying the ESR and provides insights into the fracture dynamics of an RBC gel. These results can improve the accuracy of clinical measurements., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Introduction: Parkinson's disease (PD) represents the fastest growing neurodegenerative disease with an increasing prevalence worldwide. It is characterised by complex motor and non-motor symptoms that lead to considerable disability. Specialised physiotherapy has been shown to benefit patients with PD. The Parkinson Netzwerk Therapie (PaNTher) was created to improve access to specialised physiotherapy tailored to care priorities of PD patients. This study aims to evaluate the effectiveness, acceptability and needs of the PaNTher network by neurologists and physiotherapists involved in the network in outpatient care., Methods and Analysis: This is a mixed-method, prospective, pragmatic non-randomised cohort study of parallel groups, with data collection taking place in Bavaria, Germany, between 2020 and 2024. Patients with PD insured by the Allgemeine Ortskrankenkasse Bayern (AOK Bayern) living in Bavaria will be recruited for study participation by network partners. Patients in the intervention group must reside in Munich or the surrounding area to ensure provision of specialised physiotherapy in close proximity to their place of residence. Controls receive care as usual. Six and 12 months after baseline, all patients receive a follow-up questionnaire. Mixed-effect regression models will be used to examine changes in impairment of activities of daily living and quality of life of patients with PD enrolled in the programme over time compared with usual care. Qualitative interviews will investigate the implementation processes and acceptability of the PaNTher network among neurologists and physiotherapists. The study is expected to show that the PaNTher network with an integrative care approach will improve the quality and effectiveness of the management and treatment of patients with PD., Ethics and Dissemination: The study has been approved by the ethics committee at the medical faculty of the Ludwig-Maximilians-University Munich (20-318). Results will be published in scientific, peer-reviewed journals and presented at national and international conferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Faecal occult blood testing (FOBT) and faecal immunochemical testing (FIT) are among the most used screening modalities for colorectal cancer (CRC). Colonoscopy is also widely used as a screening and diagnostic test for adults with a positive FOBT/FIT. Patient experience of colonoscopy is an important component for most CRC screening programmes. Individuals with negative experiences are less likely to engage with colonoscopy in the future and can deter others from attending colonoscopy when invited. This review synthesised data on patient experience with colonoscopy, following a positive result, to provide insights into how to improve patient experience within the English Bowel Cancer Screening Programme., Methods: MEDLINE, EMBASE and PsycINFO were searched for quantitative questionnaire studies evaluating patient-reported experience with colonoscopy, following a positive screening FOB/FIT result. The search was limited to studies published between 2000 and 2021 (ie, when the first FOBT/FIT screening programmes for CRC were introduced). Data-driven and narrative summary techniques were used to summarise the literature., Results: In total, six studies from the UK (n=4), Spain (n=1) and the Netherlands (n=1) were included in the review (total participants: 152 329; response rate: 68.0-79.3%). Patient experiences were categorised into three 'stages': 'pre-colonoscopy', 'during the test' and 'post-colonoscopy'. Overall, patients reported a positive experience in all six studies. Bowel preparation was the most frequently endorsed issue experienced pre-test (experienced by 10.0-41.0% of individuals, across all studies), pain and discomfort for during the test (experienced by 10.0-21.0% of participants) and abdominal pain and discomfort after the test (these were experienced by 14.8-22% of patients)., Conclusion: This review highlighted that patient-reported experiences associated with colonoscopy were generally positive. To improve the colonoscopy experience, bowel screening centres should investigate means to: make bowel preparation more acceptable, make colonoscopy less painful and reduce post-colonoscopy symptoms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bifurcations and branches in the microcirculation dramatically affect blood flow as they determine the spatiotemporal organization of red blood cells (RBCs). Such changes in vessel geometries can further influence the formation of a cell-free layer (CFL) close to the vessel walls. Biophysical cell properties, such as their deformability, which is impaired in various diseases, are often thought to impact blood flow and affect the distribution of flowing RBCs. This study investigates the flow behavior of healthy and artificially hardened RBCs in a bifurcating microfluidic T-junction. We determine the RBC distribution across the channel width at multiple positions before and after the bifurcation. Thus, we reveal distinct focusing profiles in the feeding mother channel for rigid and healthy RBCs that dramatically impact the cell organization in the successive daughter channels. Moreover, we experimentally show how the characteristic asymmetric CFLs in the daughter vessels develop along their flow direction. Complimentary numerical simulations indicate that the buildup of the CFL is faster for healthy than for rigid RBCs. Our results provide fundamental knowledge to understand the partitioning of rigid RBC as a model of cells with pathologically impaired deformability in complex in vitro networks.

The Biorelevant Gastrointestinal Transfer (BioGIT) system is a useful screening tool for assessing the impact of dose and/or formulation on early exposure after administration of immediate release or enabling drug products with a glass of water in the fasted state. The objective of this study was to investigate potential limitations. BioGIT experiments were performed with five low solubility active pharmaceutical ingredients with weakly alkaline characteristics: mebendazole (tablet and chewable tablet), Compound E (aqueous solutions, three doses), pazopanib-HCl (Votrient™ tablet, crushed Votrient™ tablet and aqueous suspension), Compound B-diHCl (hard gelatin capsule, three doses) and Compound C (hard gelatin capsule containing nanosized drug and hard gelatin capsule containing micronized drug). For all formulation or dose comparisons the ratio of mean BioGIT AUC 0-50   min values was not predictive of the ratio of mean plasma AUC 0-60   min values which became available after completion of BioGIT experiments. BioGIT experimental conditions have not been designed to simulate the gastrointestinal drug transfer process after administration of chewable tablets or aqueous solutions, therefore, BioGIT may not be useful for the assessment of intraluminal performance early after administration of such drug products. Also, based on this study, BioGIT may not be useful in investigating the impact of dose and/or formulation on early exposure when the dose is not administered with a glass of water to fasted healthy individuals or when BioGIT data are highly variable. Finally, the rapid dissolution of nanocrystals after administration of low solubility weak bases may require adjustment of the pH in the gastric compartment of BioGIT to slightly higher pH values. Limitations identified in this study for the BioGIT system may be also relevant to other in vitro systems proposed for similar evaluations., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the association between the quality of neurovascular bundle dissection and urinary continence recovery after robotic-assisted radical prostatectomy., Materials and Methods: Patients who underwent RARPs from 2016 to 2018 in two institutions with ≥1-year postoperative follow-up were included. The primary outcomes were time to urinary continence recovery. Surgical videos were independently assessed by 3 blinded raters using the validated Dissection Assessment for Robotic Technique (DART) tool after standardized training. Cox regression was used to test the association between DART scores and urinary continence recovery while adjusting for relevant patient features., Results: 121 RARP performed by 23 surgeons with various experience levels were included. The median follow-up was 24 months (95% CI 20 - 28 months). The median time to continence recovery was 7.3 months (95% CI 4.7 - 9.8 months). After adjusting for patient age, higher scores of certain DART domains, specifically tissue retraction and efficiency , were significantly associated with increased odds of continence recovery (p<0.05)., Conclusions: Technical skill scores of neurovascular bundle dissection vary among surgeons and correlate with urinary continence recovery. Unveiling the specific robotic dissection skillsets which impact patient outcomes has the potential to focus surgical training.

We report a study on granular matter with and without small additions of silicon oil, under low-frequency and large amplitude oscillatory shear strain under constant normal pressure, by running experiments with a rotational rheometer with a cup-and-plate geometry. We analysed the expansion with the Chebyshev polynomials of the orthogonal decomposition of stress-strain Lissajous-Bowditch loops. We found the onset of the strain amplitude for the yielding regime indicated a regime change from filament-like structures of grains to grain rearrangements for the dry granulate and from oscillations to the breaking and regeneration of liquid bridges for wet granulates. We have shown that this viscoelastic dynamics can be characterized by a noise temperature following Sollich et al. (Phys Rev Lett https://doi.org/10.1103/PhysRevLett.78.2020 , 1997). The analysis of the first harmonics of the Chebyshev expansion showed that the state of disorder of dry and wet granular matter in pre-yielding and yielding regimes involved ensembles of different inherent states; thus, each of them was governed by a different noise temperature. The higher-order harmonics of the Chebyshev expansion revealed a proportionality between the viscous nonlinearity and the variation in the elastic nonlinearity induced by the deformation, which shows the coupling between the elastic deformation and the viscous flow of mesoscopic-scale structures., (© 2023. The Author(s).)

A bold vision in nanofabrication is the assembly of functional molecular structures using a scanning probe microscope (SPM). This approach requires continuous monitoring of the molecular configuration during manipulation. Until now, this has been impossible because the SPM tip cannot simultaneously act as an actuator and an imaging probe. Here, we implement configuration monitoring using experimental data other than images collected during the manipulation process. We model the manipulation as a partially observable Markov decision process (POMDP) and approximate the actual configuration in real time using a particle filter. To achieve this, the models underlying the POMDP are precomputed and organized in the form of a finite-state automaton, allowing the use of complex atomistic simulations. We exemplify the configuration monitoring process and reveal structural motifs behind measured force gradients. The proposed methodology marks an important step toward the piece-by-piece creation of supramolecular structures in a robotic and possibly automated manner., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Studying inorganic/organic hybrid systems is a stepping stone towards the design of increasingly complex interfaces. A predictive understanding requires robust experimental and theoretical tools to foster trust in the obtained results. The adsorption energy is particularly challenging in this respect, since experimental methods are scarce and the results have large uncertainties even for the most widely studied systems. Here we combine temperature-programmed desorption (TPD), single-molecule atomic force microscopy (AFM), and nonlocal density-functional theory (DFT) calculations, to accurately characterize the stability of a widely studied interface consisting of perylene-tetracarboxylic dianhydride (PTCDA) molecules on Au(111). This network of methods lets us firmly establish the adsorption energy of PTCDA/Au(111) via TPD (1.74 ± 0.10 eV) and single-molecule AFM (2.00 ± 0.25 eV) experiments which agree within error bars, exemplifying how implicit replicability in a research design can benefit the investigation of complex materials properties., (© 2023. The Author(s).)

Current regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies. Information on repeated food effect studies is not common in the public domain. The goal of the work presented in this manuscript from the Food Effect PBPK IQ Working Group was to compile a dataset on these studies across pharmaceutical companies and provide recommendations on their conduct. Based on 54 studies collected, we report that most of the repeat food effect studies do not result in meaningful differences in the assessment of the food effect. Seldom changes observed were more than twofold. There was no clear relationship between the change in food effect and the formulation change, indicating that in most cases, once a compound is formulated appropriately within a specific formulation technology, the food effect is primarily driven by inherent compound properties. Representative examples of PBPK models demonstrate that following appropriate validation of the model with the initial food effect study, the models can be applied to future formulations. We recommend that repeat food effect studies should be approached on a case-by-case basis taking into account the totality of the evidence including the use of PBPK modeling., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The intraoperative activity of a surgeon has substantial impact on postoperative outcomes. However, for most surgical procedures, the details of intraoperative surgical actions, which can vary widely, are not well understood. Here we report a machine learning system leveraging a vision transformer and supervised contrastive learning for the decoding of elements of intraoperative surgical activity from videos commonly collected during robotic surgeries. The system accurately identified surgical steps, actions performed by the surgeon, the quality of these actions and the relative contribution of individual video frames to the decoding of the actions. Through extensive testing on data from three different hospitals located in two different continents, we show that the system generalizes across videos, surgeons, hospitals and surgical procedures, and that it can provide information on surgical gestures and skills from unannotated videos. Decoding intraoperative activity via accurate machine learning systems could be used to provide surgeons with feedback on their operating skills, and may allow for the identification of optimal surgical behaviour and for the study of relationships between intraoperative factors and postoperative outcomes., (© 2023. The Author(s).)

Blood flow in the microcirculatory system is crucially affected by intrinsic red blood cell (RBC) properties, such as their deformability. In the smallest vessels of this network, RBCs adapt their shapes to the flow conditions. Although it is known that the age of RBCs modifies their physical properties, such as increased cytosol viscosity and altered viscoelastic membrane properties, the evolution of their shape-adapting abilities during senescence remains unclear. In this study, we investigated the effect of RBC properties on the microcapillary in vitro flow behavior and their characteristic shapes in microfluidic channels. For this, we fractioned RBCs from healthy donors according to their age. Moreover, the membranes of fresh RBCs were chemically rigidified using diamide to study the effect of isolated graded-membrane rigidity. Our results show that a fraction of stable, asymmetric, off-centered slipper-like cells at high velocities decreases with increasing age or diamide concentration. However, while old cells form an enhanced number of stable symmetric croissants at the channel centerline, this shape class is suppressed for purely rigidified cells with diamide. Our study provides further knowledge about the distinct effects of age-related changes of intrinsic cell properties on the single-cell flow behavior of RBCs in confined flows due to inter-cellular age-related cell heterogeneity.

Background: "Artificial intelligence" and "big data" increasingly take the step from just being interesting concepts to being relevant or even part of our lives. This general statement holds also true for transfusion medicine. Besides all advancements in transfusion medicine, there is not yet an established red blood cell quality measure, which is generally applied., Summary: We highlight the usefulness of big data in transfusion medicine. Furthermore, we emphasize in the example of quality control of red blood cell units the application of artificial intelligence., Key Messages: A variety of concepts making use of big data and artificial intelligence are readily available but still await to be implemented into any clinical routine. For the quality control of red blood cell units, clinical validation is still required., Competing Interests: M.L. and S.Q. are employees of Cysmic GmbH, the manufacturer of Erysense, used for data generation presented in this study. In addition, S.R., G.S., S.Q., and L.K. are shareholders of Cysmic GmbH. H.E. and C.W. have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Lymphoceles (LC) occur in up to 60% after robot-assisted radical prostatectomy (RARP) and pelvic lymphadenectomy (PLND). In 2-10%, they are symptomatic and may cause complications and require treatment. Data on risk factors for the formation of lymphoceles after RARP and PNLD remain sparse in the urologic literature and are inconclusive to date. The underlying data of this secondary analysis were obtained from the prospective multi-center RCT ProLy. We performed a multivariate analysis to focus on the potential risk factors that may influence lymphocele formation. Patients with LC had a statistically significant higher BMI (27.8 vs. 26.3 kg/m 2 , p < 0.001; BMI ≥ 30 kg/m 2 : 31 vs. 17%, p = 0.002) and their surgical time was longer (180 vs. 160 min, p = 0.001) In multivariate analysis, the study group (control vs. peritoneal flap, p = 0.003), BMI (metric, p = 0.028), and surgical time (continuous, p = 0.007) were independent predictors. Patients with symptomatic lymphocele presented with higher BMI (29 vs. 26.6 kg/m 2 , p = 0.007; BMI ≥ 30 kg/m 2 : 39 vs. 20%, p = 0.023) and experienced higher intraoperative blood loss (200 vs. 150 mL, p = 0.032). In multivariate analysis, BMI ≥ 30 kg/m 2 vs. < 30 kg/m 2 was an independent predictor for the formation of a symptomatic lymphocele ( p = 0.02). High BMI and prolonged surgical time are general risk factors for the development of LC. Patients with a BMI ≥ 30 kg/m 2 had a higher risk for symptomatic lymphoceles., Competing Interests: Ubrig: Intuitive Surgery, Procept Biorobotics. Siemer: Intuitive Surgery. The other authors declare no conflicts of interest.

Objective: People from ethnic minority backgrounds are less likely to attend colonoscopy, following faecal immunochemical test screening, and are more likely to be diagnosed with colorectal cancer at an advanced stage as a result. The aim of this research was to explore the barriers and facilitators to attending colonoscopy, perceived by ethnic minority groups living in the United Kingdom., Methods: Semi-structured online and telephone interviews were conducted with thirty men and women of Black-African (n = 5), Black-Caribbean (n = 5), South Asian (n = 10) and White British (n = 10) descent. Participants were eligible for screening, but had not necessarily been invited for colonoscopy. All interviews were conducted in the participant's first language and were assessed using Framework-analysis, in line with a conceptual framework developed from previous interviews with healthcare professionals., Results: Five thematic groups of barriers and facilitators were developed: 'Locus of control', 'Cultural attitudes and beliefs', 'Individual beliefs, knowledge and personal experiences with colonoscopy and cancer', 'Reliance on family and friends' and 'Health concerns'. Differences were observed, between ethnic groups, for: 'Locus of control', 'Cultural attitudes and beliefs' and 'Reliance on family and friends'. Black and South Asian participants frequently described the decision to attend colonoscopy as lying with 'God' (Muslims, specifically), 'the doctor', or 'family' (Locus of control). Black and South Asian participants also reported relying on friends and family for 'language, transport and emotional support' (Reliance on family and friends). Black-African participants, specifically, described cancer as 'socially taboo' (Cultural attitudes and beliefs)., Conclusions: The results highlight several targets for culturally-tailored interventions to make colonoscopy more equitable., (© 2023 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

The distribution of red blood cells (RBCs) in the microcirculation determines the oxygen delivery and solute transport to tissues. This process relies on the partitioning of RBCs at successive bifurcations throughout the microvascular network, and it has been known since the last century that RBCs partition disproportionately to the fractional blood flow rate, therefore leading to heterogeneity of the hematocrit (i.e., volume fraction of RBCs in blood) in microvessels. Usually, downstream of a microvascular bifurcation, the vessel branch with a higher fraction of blood flow receives an even higher fraction of RBC flux. However, both temporal and time-average deviations from this phase-separation law have been observed in recent studies. Here, we quantify how the microscopic behavior of RBC lingering (i.e., RBCs temporarily residing near the bifurcation apex with diminished velocity) influences their partitioning, through combined in vivo experiments and in silico simulations. We developed an approach to quantify the cell lingering at highly confined capillary-level bifurcations and demonstrate that it correlates with deviations of the phase-separation process from established empirical predictions by Pries et al. Furthermore, we shed light on how the bifurcation geometry and cell membrane rigidity can affect the lingering behavior of RBCs; e.g., rigid cells tend to linger less than softer ones. Taken together, RBC lingering is an important mechanism that should be considered when studying how abnormal RBC rigidity in diseases such as malaria and sickle-cell disease could hinder the microcirculatory blood flow or how the vascular networks are altered under pathological conditions (e.g., thrombosis, tumors, aneurysm)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Internationally, colorectal cancer screening participation remains low despite the availability of home-based testing and numerous interventions to increase uptake. To be effective, interventions should be based on an understanding of what influences individuals' decisions about screening participation. This study investigates the association of defensive information processing (DIP) with fecal immunochemical test (FIT)-based colorectal cancer screening uptake., Methods: Regression modeling of data from a cross-sectional survey within a population-based FIT screening program was conducted. The survey included the seven subdomains of the McQueen DIP measure. The primary outcome variable was the uptake status (screening user or nonuser). Multivariable logistic regression was used to estimate the odds ratio (OR) for screening nonuse by DIP (sub)domain score, with adjustments made for sociodemographic and behavioral factors associated with uptake., Results: Higher scores (equating to greater defensiveness) on all DIP domains were significantly associated with lower uptake in the model adjusted for sociodemographic factors. In the model with additional adjustments for behavioral factors, the suppression subdomains of "deny immediacy to be tested" (OR, 0.53; 95% confidence interval [CI], 0.43-0.65; p < .001) and "self-exemption" (OR, 0.80; 95% CI, 0.68-0.96; p < .001) independently predicted nonuse of FIT-based screening., Conclusions: This is the first study outside the United States that has identified DIP as a barrier to colorectal cancer screening uptake, and it is the first focused specifically on FIT-based screening. The findings suggest that two suppression barriers, namely denying the immediacy to be tested and self-exempting oneself from screening, may be promising targets for future interventions to improve uptake., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Artificial intelligence (AI) systems can now reliably assess surgeon skills through videos of intraoperative surgical activity. With such systems informing future high-stakes decisions such as whether to credential surgeons and grant them the privilege to operate on patients, it is critical that they treat all surgeons fairly. However, it remains an open question whether surgical AI systems exhibit bias against surgeon sub-cohorts, and, if so, whether such bias can be mitigated. Here, we examine and mitigate the bias exhibited by a family of surgical AI systems-SAIS-deployed on videos of robotic surgeries from three geographically-diverse hospitals (USA and EU). We show that SAIS exhibits an underskilling bias, erroneously downgrading surgical performance, and an overskilling bias, erroneously upgrading surgical performance, at different rates across surgeon sub-cohorts. To mitigate such bias, we leverage a strategy -TWIX-which teaches an AI system to provide a visual explanation for its skill assessment that otherwise would have been provided by human experts. We show that whereas baseline strategies inconsistently mitigate algorithmic bias, TWIX can effectively mitigate the underskilling and overskilling bias while simultaneously improving the performance of these AI systems across hospitals. We discovered that these findings carry over to the training environment where we assess medical students' skills today. Our study is a critical prerequisite to the eventual implementation of AI-augmented global surgeon credentialing programs, ensuring that all surgeons are treated fairly., (© 2023. The Author(s).)

Background: Surgeons who receive reliable feedback on their performance quickly master the skills necessary for surgery. Such performance-based feedback can be provided by a recently-developed artificial intelligence (AI) system that assesses a surgeon's skills based on a surgical video while simultaneously highlighting aspects of the video most pertinent to the assessment. However, it remains an open question whether these highlights, or explanations, are equally reliable for all surgeons., Methods: Here, we systematically quantify the reliability of AI-based explanations on surgical videos from three hospitals across two continents by comparing them to explanations generated by humans experts. To improve the reliability of AI-based explanations, we propose the strategy of training with explanations -TWIX -which uses human explanations as supervision to explicitly teach an AI system to highlight important video frames., Results: We show that while AI-based explanations often align with human explanations, they are not equally reliable for different sub-cohorts of surgeons (e.g., novices vs. experts), a phenomenon we refer to as an explanation bias. We also show that TWIX enhances the reliability of AI-based explanations, mitigates the explanation bias, and improves the performance of AI systems across hospitals. These findings extend to a training environment where medical students can be provided with feedback today., Conclusions: Our study informs the impending implementation of AI-augmented surgical training and surgeon credentialing programs, and contributes to the safe and fair democratization of surgery., (© 2023. The Author(s).)

For some molecular players in red blood cells (RBCs), the functional indications and molecular evidence are discrepant. One such protein is transient receptor potential channel of canonical subfamily, member 6 (TRPC6). Transcriptome analysis of reticulocytes revealed the presence of TRPC6 in mouse RBCs and its absence in human RBCs. We transfused TRPC6 knockout RBCs into wild-type mice and performed functional tests. We observed the "rescue" of TRPC6 within 10 days; however, the "rescue" was slower in splenectomized mice. The latter finding led us to mimic the mechanical challenge with the cantilever of an atomic force microscope and simultaneously carry out imaging by confocal (3D) microscopy. We observed the strong interaction of RBCs with the opposed surface at around 200 pN and the formation of tethers. The results of both the transfusion experiments and the atomic force spectroscopy suggest mechanically stimulated protein transfer to RBCs as a protein source in the absence of the translational machinery. This protein transfer mechanism has the potential to be utilized in therapeutic contexts, especially for hereditary diseases involving RBCs, such as hereditary xerocytosis or Gárdos channelopathy., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Erythrocyte (or red blood cell) sedimentation rate (ESR) is a physical derived parameter of blood which is often used in routine health checks and medical diagnosis. For instance, in the case of inflammation, a higher ESR is observed due to the associated increase in fibrinogen and other plasma proteins. It was believed that this increase was due to the formation of larger aggregates of red blood cells (RBCs) caused by the increase in fibrinogen. Indeed, fibrinogen is an agent-fostering aggregation of RBCs and in the Stokes regime-assumed to be observed in blood-larger aggregates sediment faster. However, all models of ESR measurements based on this hypothesis require further specific physical assumptions, not required in any other system. Besides, modern studies in the field of colloidal suspensions have established that attractive particles form percolating aggregates (i.e. aggregates as wide as the container). The sedimentation of these colloids then follows a so-called "colloidal gel collapse". Recently, it has been shown that RBCs actually follow the same behavior. This hypothesis also allows to efficiently and analytically model the sedimentation curve of RBCs, from which robust and physically-meaningful descriptors can be extracted. This manuscript describes how to perform such an analysis, and discusses the benefits of this approach.

Objectives: Type 2 diabetes is associated with a higher risk of colorectal cancer (CRC) and advanced-stage cancer diagnosis. To help diagnose cancer earlier, this study aimed at examining whether diabetes might influence patient symptom attribution, help-seeking, and willingness to undergo investigations for possible CRC symptoms., Methods: A total of 1307 adults (340 with and 967 without diabetes) completed an online vignette survey. Participants were presented with vignettes describing new-onset red-flag CRC symptoms (rectal bleeding or a change in bowel habits), with or without additional symptoms of diabetic neuropathy. Following the vignettes, participants were asked questions on symptom attribution, intended help-seeking, and attitudes to investigations., Results: Diabetes was associated with greater than two-fold higher odds of attributing changes in bowel habits to medications (OR = 2.48; 95% Cl 1.32-4.66) and of prioritising diabetes-related symptoms over the change in bowel habits during medical encounters. Cancer was rarely mentioned as a possible explanation for the change in bowel habits, especially among diabetic participants (10% among diabetics versus 16% in nondiabetics; OR = 0.55; 95% CI 0.36-0.85). Among patients with diabetes, those not attending annual check-ups were less likely to seek help for red-flag cancer symptoms (OR = 0.23; 95% Cl 0.10-0.50)., Conclusions: Awareness of possible cancer symptoms was low overall. Patients with diabetes could benefit from targeted awareness campaigns emphasising the importance of discussing new symptoms such as changes in bowel habits with their doctor. Specific attention is warranted for individuals not regularly attending healthcare despite their chronic morbidity.

The objective of the present study was to confirm the usefulness of BioGIT data in the evaluation of the impact of dose and/or formulation on early exposure after oral administration of immediate release or enabling products of low solubility active pharmaceutical ingredients (APIs) with a glass of water in the fasted state. BioGIT experiments were performed with four APIs: Compound Α (tablet, three dose levels), Compound E (capsule PiC1, capsule PiC2 and tablet), fenofibrate (Lipidil® capsule and Lipidil 145 ONE® tablet) and Compound F (HP-β-CD aqueous solution and tablet). Based on mean plasma AUC 0-60min values which became available after completion of the BioGIT experiments, mean BioGIT AUC 0-50min values were useful for the evaluation of the impact of dose and/or formulation on early exposure. The log-transformed ratios of mean BioGIT AUC 0-50min values for two doses and/or two formulations estimated in this study and in a recent study for two diclofenac potassium products (Cataflam® tablet and Voltfast® sachet, same dose) vs. the corresponding log-transformed ratios of mean plasma AUC 0-60min values (n = 7 pairs of ratios), were included in a previously established correlation between log-transformed ratios of mean BioGIT AUC 0-50min values and log-transformed ratios of plasma AUC 0-60min values (n = 9 pairs of ratios). The correlation between log-transformed plasma AUC 0-60min ratios vs. log-transformed BioGIT AUC 0-50min ratios was confirmed (n = 16 pairs of ratios, R = 0.90). Compared with the previously established correlation the statistical characteristics were improved. Based on this study, the BioGIT system could be useful as a screening tool for assessing the impact of dose and/or formulation differences on early exposure, after administration of immediate release or enabling drug products of low solubility APIs with a glass of water in the fasted state, on an a priori basis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the WHO-5 tool in pediatric and young adult subjects with type 1 diabetes, and to analyse associations with demographic/psychological characteristics., Methods: We included 944 patients with type 1 diabetes 9-25 years of age, documented in the Diabetes Patient Follow-up Registry between 2018 and 2021. We used ROC curve analysis to determine optimal cut-off values for the WHO-5 scores to predict psychiatric comorbidity (ICD-10-diagnoses) and analysed associations with obesity, HbA 1c , therapy regimen, and lifestyle via logistic regression. All models were adjusted for age, sex, and diabetes duration., Results: In the total cohort (54.8% male), the median score was 17 [Q1-Q3: 13-20]. Adjusted for age, sex, and diabetes duration, the WHO-5 scores<13 were associated with psychiatric comorbidity, especially depression and ADHD, poor metabolic control, obesity, smoking, and less physical activity. There were no significant associations with therapy regimen, hypertension, dyslipidemia, or social deprivation. In subjects with any diagnosed psychiatric disorder (prevalence 12.2%), the odds ratio for conspicuous scores was 3.28 [2.16-4.97] compared to patients without mental disorders. Using ROC analysis, the optimal cut-off to anticipate any psychiatric comorbidity in our cohort was 15, and 14 for depression., Conclusions: The WHO-5 questionnaire is a useful tool to predict depression in adolescents with type 1 diabetes. ROC analysis suggests a slightly higher cut-off for conspicuous questionnaire results compared to previous reports. Due to the high rate of deviant results, adolescents and young adults with type-1 diabetes should be screened regularly for signs of psychiatric comorbidity., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Although the use of short implants is becoming more common for patients with atrophic alveolar ridges, their use is still quite limited. This is due to the lack of data of long-term survival compared to standard-length implants. The aim of this study was to determine the load in the bone and implant system with different superstructures., Methods: Three kinds of prosthetic restorations were created on short implants based on CT-Data. Two short implants with different macro-geometries were used. The implants were inserted in idealised posterior lower mandibular segments and afterwards restored with a crown, a double splinted crown, and a bridge., Results: The analysis was performed under load of 300 N either divided between a mesial and distal point or as a point load on the pontic/mesial crown. The different design of the implant systems had a noticeable influence on the stress in the cortical bone, in the implant system, and the displacement of the superstructure as well., Conclusions: Compared with implants of standard length, higher stresses were observed, which can lead early failure of the implant during the healing period or a late cervical bone resorption. Precise indications are essential for short implants to avoid the failure of short implants., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Low perceived risk of is associated with a low probability of engaging in risk preventive behaviours. Temporal framing has been suggested to make the risk seem higher, as narrower time frames appear to increase perceived risk and intentions to engage in risk-preventive behaviours. In two online experiments, we tested how manipulating risk information about colorectal cancer (CRC) influenced risk perception and preventive behaviours. 902 men and women aged 45-54 were recruited from an English online panel. Study 1 (N = 132) investigated how communicating CRC mortality instead of incidence rates influences risk perception, using both yearly and daily frames. In study 2 (N = 770), CRC incidence was described as occurring yearly, daily or hourly . The primary outcome measures were risk perception, intention to engage in preventive behaviours and whether participants chose to read information about ways to reduce CRC risk or skip it to finish the survey. Study 1 did not find a difference in intentions based on information about the risk of developing vs the risk of dying of CRC. Study 2 found that, while communicating CRC incidence occurring as every day increased information-seeking behaviour compared to every year and every hour (57.4% vs 45.9% vs 45.6%, p = 0.012), individuals in the daily condition were less likely to get all comprehension questions right (69.9% vs 78.2% vs 85.0%, respectively, p = 0.015). Temporal framing had no impact on perceived risk or intentions to engage in risk-reducing behaviours. While manipulating risk information in terms of temporal framing did not increase perceived risk, it may influence people's decision to engage with the information in the first place.

Background: Recent evidence suggests that faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) in symptomatic adults. To date, there has been little research exploring experiences of FIT for this population., Aim: To explore patient experience and satisfaction with FIT in an 'early adopter' site in England., Design: Explanatory sequential mixed-methods approach combining mailed quantitative surveys with semi-structured telephone interviews., Method: Multivariate logistic regression was used to analyse quantitative data. Thematic analysis was used to assess qualitative transcripts., Results: The survey had 260 responders, and it found that satisfaction with FIT was high (88.7%). Compared with test satisfaction, the proportion of responders satisfied with their GP consultation and how they received their results was lower (74.4% and 76.2%, respectively). Multivariate analysis showed that increased area-level deprivation and not receiving an explanation of the purpose of the test were associated with lower satisfaction with the GP consultation (both P -values <0.05), while increased area-level deprivation and not receiving results from the GP were associated with lower satisfaction with receiving results (both P -values <0.05). Interviews with responders ( n = 20) helped explain the quantitative results. They revealed that 'not knowing the purpose of the test' caused 'anxiety' and 'confusion', which led to dissatisfaction. 'Not receiving results from GP' was considered 'unacceptable', as this left patients with a 'niggling doubt' and lack of diagnosis or assurance that they did not have cancer., Conclusion: Patient satisfaction with symptomatic FIT is high. Efforts to improve satisfaction should focus on ensuring that patients understand the purpose of the test and always receive their test results., (© The Authors.)

Mobile game metrics have received attention since the emergence of big data technology and data-based decision-making. Among different metrics, the monthly active user number is usually significant because it shows the level of players' engagement and the profit of this game as a business. Therefore, the monthly active user number is valuable for researchers, analysts, and decision-makers interested in the mobile game industry. However, the actual monthly active user number data typically have the accuracy, accessibility, granularity, and cost problems. Therefore, a proxy to the monthly active user number would be helpful to facilitate the decision-making process. This paper proposes to capture user activity through the searches on the Internet from an information-seeking perspective. And the online search volume, wiki page view, social media posts and views are proposed as potential proxies. This paper proposes that the online search volume is an acceptable proxy for the monthly active user number in the context of Geo Augmented Reality (AR) mobile games through data analysis., Competing Interests: Competing interestsThe authors have no competing interests to declare that are relevant to the content of this article. Funding: The preparation of this manuscript was funded by the project “Opportunities in Contemporary Digital Game Design,” Start-up Grant for New Faculty, City University of Hong Kong., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The goal of our study was to examine the intention to get vaccinated using predictors from the 5C Model of vaccination attitudes, the Theory of Planned Behavior (TPB) and the Health Belief Model (HBM). Between August and November 2020, an online survey was delivered to 1428 participants in the UK and Germany (mean age = 40.6; 57% women), assessing socio-demographic and health factors, general vaccination attitudes, TBP and HBM variables, and COVID-19 vaccination intention. Vaccination intentions did not differ by country or survey period. Predictors of intention with the highest explanatory power in a relative weight analysis were confidence, collective responsibility (5C) perceived behavioral control, social norms, attitudes (especially negative affect & TPB cognitions), and perceived benefits (HBM). Women reported lower intention, although the effect size was small. Predictors from the TPB and HBM were effective to explain the intention to receive COVID-19 vaccines over and above socio-demographic variables, health-related factors and general vaccination attitudes. The results are interpreted in the context of current vaccination campaigns. Messages promoting sense of autonomy and control over the decision to get vaccinated, approval from significant others and reassurance that getting vaccinated will not be associated with fear or other negative feelings are important facilitators of vaccine uptake.

How well a surgery is performed impacts a patient's outcomes; however, objective quantification of performance remains an unsolved challenge. Deconstructing a procedure into discrete instrument-tissue "gestures" is a emerging way to understand surgery. To establish this paradigm in a procedure where performance is the most important factor for patient outcomes, we identify 34,323 individual gestures performed in 80 nerve-sparing robot-assisted radical prostatectomies from two international medical centers. Gestures are classified into nine distinct dissection gestures (e.g., hot cut) and four supporting gestures (e.g., retraction). Our primary outcome is to identify factors impacting a patient's 1-year erectile function (EF) recovery after radical prostatectomy. We find that less use of hot cut and more use of peel/push are statistically associated with better chance of 1-year EF recovery. Our results also show interactions between surgeon experience and gesture types-similar gesture selection resulted in different EF recovery rates dependent on surgeon experience. To further validate this framework, two teams independently constructe distinct machine learning models using gesture sequences vs. traditional clinical features to predict 1-year EF. In both models, gesture sequences are able to better predict 1-year EF (Team 1: AUC 0.77, 95% CI 0.73-0.81; Team 2: AUC 0.68, 95% CI 0.66-0.70) than traditional clinical features (Team 1: AUC 0.69, 95% CI 0.65-0.73; Team 2: AUC 0.65, 95% CI 0.62-0.68). Our results suggest that gestures provide a granular method to objectively indicate surgical performance and outcomes. Application of this methodology to other surgeries may lead to discoveries on methods to improve surgery., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases., Competing Interests: SR, GS, LK, SQ Though unrelated to the contents of this manuscript, the authors declare that SMR, GS, LK, and SQ are co-founders of Cysmic GmbH, ML Affiliated with Cysmic GmbH; the author has no financial interests to declare, FG, MD, PM, KZ, Av, CW No competing interests declared, AD Though unrelated to the contents of this manuscript, AD is a founder of Omix Technologies Inc and Altis Biosciences LLC, and a scientific advisory board member for Hemanext Inc and Forma Therapeutics, (© 2022, Recktenwald, Simionato et al.)