Critical evaluation of artificial intelligence as a digital twin of pathologists for prostate cancer pathology.

Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.

Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations reside in spatially segregated micro-environmental niches with conserved cellular compositions that are repeated across healthy and diseased tissue. We show that IL4I1+ macrophages phagocytose dying cells in areas with high cell turnover and predict good outcome in colon cancer. In contrast, SPP1+ macrophages are enriched in hypoxic and necrotic tumor regions and portend worse outcome in colon cancer. A subset of FOLR2+ macrophages is embedded in plasma cell niches. NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors. Our findings indicate that a limited number of unique human macrophage niches function as fundamental building blocks in tissue.

Development and external validation of the eFalls tool: a multivariable prediction model for the risk of ED attendance or hospitalisation with a fall or fracture in older adults.

BACKGROUND: Falls are common in older adults and can devastate personal independence through injury such as fracture and fear of future falls. Methods to identify people for falls prevention interventions are currently limited, with high risks of bias in published prediction models. We have developed and externally validated the eFalls prediction model using routinely collected primary care electronic health records (EHR) to predict risk of emergency department attendance/hospitalisation with fall or fracture within 1 year. METHODS: Data comprised two independent, retrospective cohorts of adults aged ≥65 years: the population of Wales, from the Secure Anonymised Information Linkage Databank (model development); the population of Bradford and Airedale, England, from Connected Bradford (external validation). Predictors included electronic frailty index components, supplemented with variables informed by literature reviews and clinical expertise. Fall/fracture risk was modelled using multivariable logistic regression with a Least Absolute Shrinkage and Selection Operator penalty. Predictive performance was assessed through calibration, discrimination and clinical utility. Apparent, internal-external cross-validation and external validation performance were assessed across general practices and in clinically relevant subgroups. RESULTS: The model's discrimination performance (c-statistic) was 0.72 (95% confidence interval, CI: 0.68 to 0.76) on internal-external cross-validation and 0.82 (95% CI: 0.80 to 0.83) on external validation. Calibration was variable across practices, with some over-prediction in the validation population (calibration-in-the-large, -0.87; 95% CI: -0.96 to -0.78). Clinical utility on external validation was improved after recalibration. CONCLUSION: The eFalls prediction model shows good performance and could support proactive stratification for falls prevention services if appropriately embedded into primary care EHR systems.

Characterising trends in the initiation, timing, and completion of the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) process: Retrospective analysis of routine data from a large UK hospital trust.

AIM: To assess patient socio-demographic and disease characteristics associated with the initiation, timing, and completion of emergency care and treatment planning in a large UK-based hospital trust. METHODS: Secondary retrospective analysis of data across 33 months extracted from digitally stored Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) plans within the electronic health record system of an acute hospital trust in England, UK. RESULTS: Data analysed from ReSPECT plans (n = 23,729), indicate an increase in the proportion of admissions having a plan created from 4.2% in January 2019 to 6.9% in September 2021 (mean = 8.1%). Forms were completed a median of 41 days before death (a median of 58 days for patients with capacity, and 21 days for patients without capacity). Do not attempt resuscitation was more likely to be recorded for patients lacking capacity, with increasing age (notably for patients aged over 74 years), being male, having ethnicity recorded as 'Asian or Asian British' or 'Black or Black British', and the absence of multiple disease groups. Having a preferred place of death recorded as 'hospital' led to a five-fold increase in the likelihood of dying in hospital. CONCLUSION: Variation in the initiation, timing, and completion of ReSPECT plans was identified by applying an evaluation framework. Digital storage of ReSPECT plan data presents opportunities for assessing trends and completion of the ReSPECT planning process and benchmarking across sites. Further research is required to monitor and understand any inequity in the implementation of the ReSPECT process in routine care.

A multicentre observational study to investigate feasibility of a direct oral penicillin challenge in de-labelling 'low risk' patients with penicillin allergy by non-allergy healthcare professionals (SPACE study): Implications for healthcare systems.

OBJECTIVE: The huge burden of inaccurate penicillin allergy labels (PALs) is an important driver of antimicrobial resistance. This is magnified by insufficient allergy specialists and lack of 'point-of-care' tests. We investigated the feasibility of non-allergy healthcare professionals (HCPs) delivering direct oral penicillin challenges (DPCs) for penicillin allergy de-labelling. METHODS: This prospective observational study was conducted in three hospitals in England across three settings (acute medical, pre-surgical and haematology-oncology). Patients with a PAL were screened and stratified as low risk/high risk. Low risk patients (non-immune mediated symptoms, benign rash, tolerated amoxicillin since and family history) underwent a DPC. RESULTS: N = 2257 PALs were screened, 1054 were eligible; 643 were approached, 373 declined, 270 consented and 259 risk stratified (low risk = 155; high risk = 104). One hundred and twenty-six low risk patients underwent DPC, 122 (96.8%) were de-labelled with no serious allergic reactions. Conversion rate from screening-to-consent was 12% [3.3% and 17.9% in acute and elective settings respectively; odds ratios for consent were 3.42 (p < 0.001) and 5.53 (p < 0.001) in haematology-oncology and pre-surgical setting respectively. Common reasons for failure to progress in the study included difficulty in reaching patients, clinical instability/medical reasons, lacking capacity to consent and psychological factors. INTERPRETATION: DPCs can be delivered by non-allergy HCPs. A high proportion of patients with PALs did not progress in the study pathway. Strategies to deliver DPC at optimal points of the care pathway are needed to enhance uptake. Elective settings offer greater opportunities than acute settings for DPC. The safety and simplicity of DPCs lends itself to adoption by healthcare systems beyond the UK, including in resource-limited settings.

Causally estimating the effect of YouTube's recommender system using counterfactual bots.

In recent years, critics of online platforms have raised concerns about the ability of recommendation algorithms to amplify problematic content, with potentially radicalizing consequences. However, attempts to evaluate the effect of recommenders have suffered from a lack of appropriate counterfactuals-what a user would have viewed in the absence of algorithmic recommendations-and hence cannot disentangle the effects of the algorithm from a user's intentions. Here we propose a method that we call "counterfactual bots" to causally estimate the role of algorithmic recommendations on the consumption of highly partisan content on YouTube. By comparing bots that replicate real users' consumption patterns with "counterfactual" bots that follow rule-based trajectories, we show that, on average, relying exclusively on the YouTube recommender results in less partisan consumption, where the effect is most pronounced for heavy partisan consumers. Following a similar method, we also show that if partisan consumers switch to moderate content, YouTube's sidebar recommender "forgets" their partisan preference within roughly 30 videos regardless of their prior history, while homepage recommendations shift more gradually toward moderate content. Overall, our findings indicate that, at least since the algorithm changes that YouTube implemented in 2019, individual consumption patterns mostly reflect individual preferences, where algorithmic recommendations play, if anything, a moderating role.

PeRsOnaliSed care Planning for oldER people with frailty (PROSPER): protocol for a randomised controlled trial.

BACKGROUND: Frailty is common in older age and is characterised by loss of biological reserves across multiple organ systems. These changes associated with frailty mean older people can be vulnerable to sudden, dramatic changes in health because of relatively small problems. Older people with frailty are at increased risk of adverse outcomes including disability, hospitalisation, and care home admission, with associated reduction in quality of life and increased NHS and social care costs. Personalised Care Planning offers an anticipatory, preventative approach to supporting older adults to live independently for longer, but it has not been robustly evaluated in a population of older adults with frailty. METHODS: Following an initial feasibility study, this multi-centre, individually randomised controlled trial aims to establish whether personalised care planning for older people improves health-related quality of life. It will recruit 1337 participants from general practices across Yorkshire and Humber and Mid-Mersey in the North of England. Eligible patients will be aged 65 and over with an electronic frailty index score of 0.21 or above, living in their own homes, without severe cognitive impairment and not in receipt of end-of-life care. Following confirmation of eligibility, informed consent and baseline data collection, participants will be individually randomised to the PeRsOnaliSed care Planning for oldER people with frailty (PROSPER) intervention or usual care in a 2.6:1 allocation ratio. Participants will not be blinded to allocation, but data collection and analysis will be blinded. The intervention will be delivered over 12 weeks by a Personal Independence Co-ordinator worker based within a voluntary sector organisation, Age UK. The primary outcomes are health-related quality of life, measured using both the physical and mental components of the Short-Form 12 Item Health Questionnaire at 12 months after randomisation. Secondary outcomes comprise activities of daily living, self-management capabilities and loneliness, admission to care homes, hospitalisations, and health and social care resource use at 12 months post randomisation. Parallel cost-effectiveness and process evaluations will be conducted alongside the trial. DISCUSSION: The PROSPER study will evaluate the effectiveness and cost-effectiveness of a personalised care planning approach for older people with frailty and inform the process of its implementation. TRIAL REGISTRATION: ISRCTN16123291 .  Registered on  28 August 2020.

Correction to "Photothermal Microscopy and Spectroscopy with Nanomechanical Resonators".

[This corrects the article DOI: 10.1021/acs.jpcc.3c04361.].

Tailoring CONSORT-SPI to improve the reporting of smoking cessation intervention trials: An expert consensus study.

BACKGROUND AND AIMS: Inadequate reporting of smoking cessation intervention trials is common and leads to significant challenges for researchers. The aim of this study was to tailor CONSORT (Consolidated Standards of Reporting Trials)-SPI (Social and Psychological Interventions) guidelines to improve reporting of trials of behavioural interventions to promote smoking cessation. METHOD: Informed by missing data from the IC-SMOKE (Intervention and Comparison group support provided in SMOKing cEssation) systematic review project, this study used a multi-stage Delphi process to examine which items could be added or modified to improve the reporting of smoking cessation trials. The first stage involved an on-line survey of 17 international experts in smoking cessation and trial methodology voting on the importance of items for inclusion in the updated guidelines. This was followed by a face-to-face expert consensus meeting attended by 15 of these experts, where the final inclusion and exclusion of new items and modifications were agreed upon. A nine-point Likert scale was used to establish consensus, with suggested modifications requiring agreement of 75% or more. Disagreements in the first stage were presented again at the second stage for discussion and a second round of voting. Only items which reached the threshold for agreement were included. RESULTS: The experts agreed on the inclusion of 10 new items and the specification of 12 existing items. This included modifications that could apply to trials more widely (e.g. the rationale for the comparator), but also modifications that were very specific to smoking cessation trials (e.g. the reporting of smoking cessation outcomes). CONCLUSIONS: A Delphi study has developed a modified CONSORT-SPI guideline (CONSORT-SPI-SMOKE) to improve the reporting of trials of behavioural interventions to promote smoking cessation.

Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.

Factors associated with wearing a facemask in shops in England following removal of a legal requirement to do so during the COVID-19 pandemic.

OBJECTIVES: We aimed to identify psychological factors associated with the use of facemasks in shops in England following removal of legal requirements to do so, and to compare associations with and without legal restrictions. DESIGN: Repeated cross-sectional online surveys (n ≈ 2000 adults) between August 2020 and April 2022 (68,716 responses from 45,682 participants) using quota sampling. METHODS: The outcome measure was whether those who had visited a shop for essentials in the previous seven days reported always having worn a facemask versus sometimes or not at all. Psychological predictor variables included worry, perceived risk and severity of COVID-19 and the perceived effectiveness of facemasks. Socio-demographic variables and measures of clinical vulnerability were also measured. For the period following removal of legal restrictions, multivariable regression was used to assess associations between the primary outcome variable and predictors adjusting for socio-demographic and clinical vulnerability measures. The analysis was repeated including interactions between psychological predictors and presence versus absence of legal restrictions. RESULTS: Worry about COVID-19, beliefs about risks and severity of COVID-19 and effectiveness of facemasks were substantially and independently associated with the use of facemasks. Removal of legal obligations to wear facemasks was associated with a 25% decrease in wearing facemasks and stronger associations between psychological predictors and wearing facemasks. CONCLUSIONS: Legal obligations increase rates of wearing a facemask. Psychological factors associated with wearing a facemask could be targets for interventions aiming to alter rates of wearing a facemask. These interventions may be more effective when there are no legal obligations to wear a face covering in place.

Spatial Biology of Breast Cancer.

Spatial findings have shaped on our understanding of breast cancer. In this review, we discuss how spatial methods, including spatial transcriptomics and proteomics and the resultant understanding of spatial relationships, have contributed to concepts regarding cancer progression and treatment. In addition to discussing traditional approaches, we examine how emerging multiplex imaging technologies have contributed to the field and how they might influence future research.

Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer.

Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM)-a nanoporous layer of matrix that physically separates the primary tumour from the stroma. Single cells can invade through nanoporous three-dimensional matrices due to protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through the physiological BM, as they do during breast cancer progression, remains unclear. Here we developed a three-dimensional in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces-but not invadopodia-to breach the BM. Forces are generated from a combination of global cell volume expansion, which stretches the BM, and local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.

Photothermal Microscopy and Spectroscopy with Nanomechanical Resonators.

In nanomechanical photothermal absorption spectroscopy and microscopy, the measured substance becomes a part of the detection system itself, inducing a nanomechanical resonance frequency shift upon thermal relaxation. Suspended, nanometer-thin ceramic or 2D material resonators are innately highly sensitive thermal detectors of localized heat exchanges from substances on their surface or integrated into the resonator itself. Consequently, the combined nanoresonator-analyte system is a self-measuring spectrometer and microscope responding to a substance's transfer of heat over the entire spectrum for which it absorbs, according to the intensity it experiences. Limited by their own thermostatistical fluctuation phenomena, nanoresonators have demonstrated sufficient sensitivity for measuring trace analyte as well as single particles and molecules with incoherent light or focused and wide-field coherent light. They are versatile in their design, support various sampling methods-potentially including hydrated sample encapsulation-and hyphenation with other spectroscopic methods, and are capable in a wide range of applications including fingerprinting, separation science, and surface sciences.

Nanomechanical Photothermal Near Infrared Spectromicroscopy of Individual Nanorods.

Understanding light-matter interaction at the nanoscale requires probing the optical properties of matter at the individual nanoabsorber level. To this end, we developed a nanomechanical photothermal sensing platform that can be used as a full spectromicroscopy tool for single molecule and single particle analysis. As a demonstration, the absorption cross-section of individual gold nanorods is resolved from a spectroscopic and polarization standpoint. By exploiting the capabilities of nanomechanical photothermal spectromicroscopy, the longitudinal localized surface plasmon resonance in the NIR range is unraveled and quantitatively characterized. The polarization features of the transversal surface plasmon resonance in the VIS range are also analyzed. The measurements are compared with the finite element method, elucidating the role played by electron surface and bulk scattering in these plasmonic nanostructures, as well as the interaction between the nanoabsorber and the nanoresonator, ultimately resulting in absorption strength modulation. Finally, a comprehensive comparison is conducted, evaluating the signal-to-noise ratio of nanomechanical photothermal spectroscopy against other cutting-edge single molecule and particle spectroscopy techniques. This analysis highlights the remarkable potential of nanomechanical photothermal spectroscopy due to its exceptional sensitivity.

The effectiveness of anti-stigma interventions for reducing mental health stigma in young people: A systematic review and meta-analysis.

Experiencing mental health stigma during adolescence can exacerbate mental health conditions, reduce quality of life and inhibit young people's help-seeking for their mental health needs. For young people, education and contact have most often been viewed as suitable approaches for stigma reduction. However, evidence on the effectiveness of these anti-stigma interventions has not been consistent. This systematic review evaluated the effectiveness of interventions to reduce mental health stigma among youth aged 10-19 years. The review followed Cochrane and PRISMA guidelines. Eight databases were searched: PubMed, PsycINFO, MEDLINE, Web of Science, Scopus, EMBASE, British Education Index and CNKI. Hand searching from included studies was also conducted. Randomised controlled trials and experimental designs that included randomised allocation to interventions and control groups were included in the review. Narrative synthesis was employed to analyse the results. A meta-analysis was conducted to determine the effectiveness of included interventions. Twenty-two studies were included in the review. Eight studies reported positive effects, 11 studies found mixed effects and 3 studies reported no effect on indicators of mental health stigma among youth. Seven of the effective studies were education-based. Eleven studies were suitable for meta-analysis, and the multivariate meta-analytic model indicated a small, significant effect at post-intervention (d = .21, p < .001), but not at follow-up (d = .069, p = .347). Interventions to reduce stigma associated with mental health conditions showed small, short-term effects in young people. Education-based interventions showed relatively more significant effects than other types of interventions.

Supporting Pain Self-Management in Patients With Cancer: App Development Based on a Theoretical and Evidence-Driven Approach.

BACKGROUND: To inform the development of an intervention, it is essential to have a well-developed theoretical understanding of how an intervention causes change, as stated in the UK Medical Research Council guidelines for developing complex interventions. Theoretical foundations are often ignored in the development of mobile health apps intended to support pain self-management for patients with cancer. OBJECTIVE: This study aims to systematically set a theory- and evidence-driven design for a pain self-management app and specify the app's active features. METHODS: The Behavior Change Wheel (BCW) framework, a step-by-step theoretical approach to the development of interventions, was adopted to achieve the aim of this study. This started by understanding and identifying sources of behavior that could be targeted to support better pain management. Ultimately, the application of the BCW framework guided the identification of the active contents of the app, which were characterized using the Behavior Change Technique Taxonomy version 1. RESULTS: The theoretical analysis revealed that patients may have deficits in their capability, opportunity, and motivation that prevent them from performing pain self-management. The app needs to use education, persuasion, training, and enablement intervention functions because, based on the analysis, they were found the most likely to address the specified factors. Eighteen behavior change techniques were selected to describe precisely how the intervention functions can be presented to induce the desired change regarding the intervention context. In other words, they were selected to form the active contents of the app, potentially reducing barriers and serving to support patients in the self-management of pain while using the app. CONCLUSIONS: This study fully reports the design and development of a pain self-management app underpinned by theory and evidence and intended for patients with cancer. It provides a model example of the BCW framework application for health app development. The work presented in this study is the first systematic theory- and evidence-driven design for a pain app for patients with cancer. This systematic approach can support clarity in evaluating the intervention's underlying mechanisms and support future replication.

Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial.

INTRODUCTION: Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing. METHODS AND ANALYSIS: The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation. ETHICS AND DISSEMINATION: This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal. TRIAL REGISTRATION: ISRCTN20579216.

Cost-effective DNA methylation profiling by FML-seq.

Current methods for profiling DNA methylation require costly reagents, sequencing, and labor time. We introduce fragmentation at methylated loci and sequencing (FML-seq), a sequencing library protocol that greatly reduces all these costs. Relative to other techniques tested on the same human cell lines, FML-seq produces similar measurements of absolute and differential cytosine methylation at a fraction of the price. FML-seq enables inexpensive, high-throughput experimental designs for large-scale epigenetics research projects.