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Implementation framework for AI deployment at scale in healthcare systems

Artificial intelligence (AI) and digital health technologies are increasingly used in the medical field. Despite promises of leading the future of personalized medicine and better clinical outcomes, implementation of AI faces barriers for deployment at scale. We introduce a novel implementation framework that can facilitate digital health designers, developers, patient groups, policymakers, and other stakeholders, to co-create and solve issues throughout the life cycle of designing, developing, deploying, monitoring, and maintaining algorithmic models. This framework targets health systems that integrate multiple machine learning (ML) models with various modalities. This design thinking approach promotes clinical utility beyond model prediction, combining privacy preservation with clinical parameters to establish a reward function for reinforcement learning, ranking competing models. This allows leveraging explainable AI (xAI) methods for clinical interpretability. Governance mechanisms and orchestration platforms can be integrated to monitor and manage models. The proposed framework guides users toward human-centered AI design and developing AI-enhanced health system solutions.

The burden of hand trauma surgery on primary care in the United Kingdom: a nation-wide analysis of antibiotic and opioid prescriptions.

Although surgical site infection (SSI) risk after hand trauma surgery is around 5%, the severity of these infections is not known. The risk of superficial SSI in a cohort study was evaluated using NHS UK-wide primary care records (n = 641,223), using the Clinical Practice Research Datalink GOLD database. Within this cohort, a subcohort of those who had undergone a hand surgery operation for trauma were identified (n = 3,088). Antibiotic and analgesic prescriptions were analysed at 30 and 90 days postoperatively. By 30 days, 6.2% had been prescribed antibiotics appropriate for SSI, rising to 14.4% (CI [13.2 to 15.8]) by 90 days. By 30 days, 10% had been prescribed opioid analgaesia and by 90 days this had increased to 13.8%. Antibiotics prescriptions for SSI in primary care are substantially higher than the NICE estimate for SSI overall and the expected risk in hand trauma. The implications of this study are that many patients are receiving treatment for SSI in primary care and may be in more pain, for longer, than we expect. Further exploration of this is warranted and future research in hand trauma surgery should capture adverse events occurring outside of the hospital environment.Level of evidence: II.

Conservative Management of paediatric atypical necrotising cervical lymphadenitis: A Case Report

Surgical Site Infection After Hand Trauma Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

Management of metacarpal shaft fractures.

AIMS: The aims of this study were to describe the epidemiology of metacarpal shaft fractures (MSFs), assess variation in treatment and complications following standard care, document hospital resource use, and explore factors associated with treatment modality. METHODS: A multicentre, cross-sectional retrospective study of MSFs at six centres in the UK. We collected and analyzed healthcare records, operative notes, and radiographs of adults presenting within ten days of a MSF affecting the second to fifth metacarpal between 1 August 2016 and 31 July 2017. Total emergency department (ED) attendances were used to estimate prevalence. RESULTS: A total of 793 patients (75% male, 25% female) with 897 MSFs were included, comprising 0.1% of 837,212 ED attendances. The annual incidence of MSF was 40 per 100,000. The median age was 27 years (IQR 21 to 41); the highest incidence was in men aged 16 to 24 years. Transverse fractures were the most common. Over 80% of all fractures were treated non-surgically, with variation across centres. Overall, 12 types of non-surgical and six types of surgical treatment were used. Fracture pattern, complexity, displacement, and age determined choice of treatment. Patients who were treated surgically required more radiographs and longer radiological and outpatient follow-up, and were more likely to be referred for therapy. Complications occurred in 5% of patients (39/793). Most patients attended planned follow-up, with 20% (160/783) failing to attend at least one or more clinic appointments. CONCLUSION: MSFs are common hand injuries among young, working (economically active) men, but there is considerable heterogeneity in treatment, rehabilitation, and resource use. They are a burden on healthcare resources and society, thus further research is needed to optimize treatment.

Optimising the manufacture of perfluorocarbon nanodroplets through varying sonication parameters.

Perfluorocarbon nanodroplets (PFC-NDs) are promising ultrasound-responsive theranostic agents with applications in both diagnostic imaging and drug delivery. The acoustic vaporisation threshold, extravasation potential, and stability of PFC-NDs are all affected by their size. However, methods to ensure reproducible size and concentration during production by sonication are lacking. To address this need, we examined the effect of temperature, sonication time, sonication intensity, PFC concentration and sonicator tip height on ND characteristics. PFC-NDs with a perfluoro-n-pentane (PFP) core and a phospholipid shell were manufactured by probe-sonication. Pulsed sonication was used to maintain the sample temperature below the boiling point of PFP. Median particle diameter was measured using nanoparticle tracking analysis. PFC-ND diameter increased with increasing PFP concentration, with a stronger relationship as sonicator tip height increased. Above 5% v/v PFP, there was a qualitative increase in the number of particles visible by light microscopy. Increasing the sonication duration did not yield a significant change in ND size. A minimum amplitude of 60% was required for mixing to occur, with amplitudes of 80% and 100% resulting in foam production. Sonicator power output was linear with respect to time but differed depending on sample volume, composition, and vessel geometry. This study indicates that controlling the processing parameters can facilitate reproducible manufacturing of PFC-NDs.

T cell memory response to MPXV infection exhibits greater effector function and migratory potential compared to MVA-BN vaccination.

In 2022, a global mpox outbreak occurred, and remains a concern today. The T cell memory response to MPXV (monkeypox virus) infection has not been fully investigated. In this study, we evaluate this response in convalescent and MVA-BN (Modified Vaccinia Ankara - Bavarian Nordic) vaccinated individuals using VACV-infected cells. Strong CD8+ and CD4+ T cell responses are observed, and T cell responses are biased towards viral early expressed proteins. We identify seven immunodominant HLA-A*02:01 restricted MPXV-specific epitopes and focus our detailed phenotypic and scRNAseq analysis on the immunodominant HLA-A*02:01-G5R18-26-specific CD8+ T cell response. While tetramer+CD8+ T cells share similar differentiation and activation phenotypes, T cells from convalescent individuals show greater cytotoxicity, migratory potential to site of infection and TCR clonal expansion. Our data suggest that effective functional profiles of MPXV-specific memory T cells induced by Mpox infection may have an implication on the long-term protective responses to future infection.

SPIRIT 2025 Statement: Updated Guideline for Protocols of Randomized Trials.

IMPORTANCE: The protocol of a randomized trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Herein, we systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomized trial. OBSERVATIONS: We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (harms, outcomes, nonpharmacological treatment) and other reporting guidelines (Template for Intervention Description and Replication [TIDieR]). The potential modifications were rated in a 3-round Delphi survey followed by a consensus meeting. Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of 2 new protocol items, revision to 5 items, deletion/merger of 5 items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open-science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrollment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. CONCLUSIONS AND RELEVANCE: Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policy makers, regulators, and other reviewers.

Complications of Thyroid RFA

Radiofrequency ablation (RFA) has been performed internationally for over 10 years and has proven to be efficacious in the treatment of thyroid nodules. As the utilization of RFA for symptomatic nodules has increased, so has recognition of the procedural complications. The overall complication rate of patients who undergo thyroid RFA is low, reportedly up to 3.3%, with major complications occurring even more rarely. Fortunately, most complications are self-limited and resolve over time. However, a review of these complications is important for early recognition, optimal patient management, and to direct technical improvements, all of which will be discussed here.

MIKROBE: a feasibility study for a randomised controlled trial of one-stage or two-stage surgery for prosthetic knee infection.

BACKGROUND: Total knee replacement surgery is common, with over 107,000 operations performed in the UK in 2019. After surgery, about 1% of patients develop a deep infection, known as a prosthetic joint infection. Two types of operations, one- or two-stage revision surgery, are routinely performed to treat the infection. Re-infection rates are similar, but there is uncertainty regarding longer-term outcomes for patients. The aim of this study was to establish the feasibility of conducting a future randomised controlled trial that will compare clinical and cost-effectiveness of one-stage versus two-stage revision knee surgery for prosthetic joint infection. METHODS: Following eligibility screening, consenting patients took part in an audio-recorded consultation with their surgeon and were then randomised on a 1:1 allocation to one-stage or two-stage revision surgery. Patient-reported outcome measures were administered at baseline and 3 and 6 months postoperatively. Embedded qualitative work with patient participants and nonparticipants and with surgeons to understand the acceptability of trial processes and involvement was undertaken. Patient and public involvement and engagement activities were conducted throughout the study. RESULTS: Of 136 patients screened, only 3 were randomised and had surgery as part of the study. Qualitative data were collected from the three participants, as well as from two eligible patients who declined participation and two who withdrew from participation after the initial patient-surgeon consultation. Five surgeons took part in qualitative interviews prior to study end. CONCLUSION: This study indicated that a larger randomised controlled trial evaluating one-stage versus two-stage revision knee surgery for prosthetic joint infection is not feasible with the current straightforward randomised controlled trial design. Future research needs to consider the most appropriate study design and methodology to address this important research question. TRIAL REGISTRATION: No.: NCT04458961.

Dysregulated immune proteins in plasma in the UK Biobank predict Multiple Myeloma 12 years before clinical diagnosis

KLF5 Is a Key Regulator of IMiD-Induced Neutropenia

Although immunomodulatory drugs (IMiDs, lenalidomide [LEN] & pomalidomide [POM]) have had a huge impact on the therapeutic landscape in multiple myeloma (MM), IMiD-induced neutropenia remains a clinical challenge. Understanding the molecular basis of IMiD-associated myelosuppression could improve the rational design of novel agents which mitigate this important side effect whilst retaining therapeutic efficacy against MM cells. We have previously established an experimental system to carry out single cell multiomic analyses of neutrophil differentiation ex vivo, allowing us to study the impact of exposure to IMiDs, which caused a maturation impairment and decrease in the abundance of differentiating granulocytes1. These findings aligned with previous clinical observations of a myeloid maturation arrest which is associated with IMiD-induced neutropenia in MM patients, with Cereblon (CRBN)-driven IKZF1 degradation previously implicated as the underlying cause. However, restoration of IKZF1 expression only partially rescues the IMiD-associated neutrophil maturation arrest, suggesting that other mechanisms might also contribute. The purpose of the current study was to interrogate our single cell multiomic dataset to characterise the impact of IMiDs on the dynamic genome regulatory landscape during neutrophil development and thereby identify putative novel neo-substrates that might contribute to myelosuppression. Analysis of single cell RNA seq (n=3 donors and 111,109 cells) and multiome datasets (n=3 donors and 47,452 cells) of ex vivo neutrophil differentiation and its perturbation by IMiDs, allowed us to construct a gene regulatory map to identify putative driver genes implicated in the pathobiology of IMiD-mediated neutrophil maturation arrest. Combined gene expression and chromatin accessibility analysis based on the detection of 330,334 peak-to-gene links correlated chromatin architecture to neutrophil terminal differentiation potential. Myeloid progenitors contained relaxed chromatin, whilst IMiD-associated abnormal myeloid precursors states were characterized by premature chromatin compaction (as reflected by a 30% decline in filtered peaks) and priming towards a pro-apoptotic state, despite bearing gene expression profiles largely reminiscent of intact neutrophils and precursors. This finding was corroborated by the reduction of accessible enhancer loci (4.5-14.8%), suggesting a repression of transcriptional activity in the treated populations. To enrich for candidate transcription factors, we selected motifs that were not altered in expression at the transcript level in the granulocyte-monocyte progenitor and metamyelocyte clusters but showed marked IMiD-induced changes in their associated regulons at the transcript level. Furthermore, ATAC-seq footprinting allowed us to infer altered transcription factor binding dynamics in the same cells. As expected, IKZF1 met these criteria alongside SPI1,CEBPA, ZBTB7A, ZBTB7B, KLF5, PPARA, PPARG additional candidate genes. To further prioritise candidate neo-substrates, we intersected our data with an extensive proteomic screening to enrich for CRBN-interacting small molecules. Amongst the genes overlapping in both our multiomic analysis and proteomic screen was KLF5, a known transcription factor involved in the regulation of neutrophil differentiation in mice. Moreover, we also identified downregulation of KLF5 binding partners C/EBPβ and C/EBPδ and the downstream target PPARG alongside a gradual switch from the overarching (during normal granulopoiesis) glycolytic metabolic machinery towards increased fatty acid oxidation. This surrogate pathway has been previously associated with skewed neutrophil effector functions and described in genome-wide association studies (GWAS) focusing on abnormal neutrophil counts. Intracellular FACS analysis confirmed rapid KLF5 degradation upon exposure to IMiDs, confirming that this is a likely IMiD-associated CRBN neo-substrate. Proximity assays, rescue studies and conformation capture assays to dissect the relevant key regulatory elements are underway. Our study has identified KLF5 as a putative novel regulator of IMiD-induced neutropenia which might inform the rational design of new therapeutic agents to mitigate this problematic side effect of widely used drugs in MM. 1.https://doi.org/10.1182/blood-2023-182041

Constructing a Computational Workflow for the Identification of Novel Cellular and Molecular Drivers of Human Granulopoiesis

Neutrophils are crucial immune cells with complex and heterogeneous transcriptional programs. To understand the dynamic changes governing human granulopoiesis, we previously developed an ex vivo myeloid cell differentiation assay using human mobilised peripheral blood CD34+ cells from healthy donors and conducted single cell multiomic analysis. We constructed a multimodal atlas of human granulopoiesis that captured the full spectrum of human myeloid cells spanning from early myeloid progenitors through to neutrophil populations, thus enabling the study the genome regulatory events underlying neutrophil maturation with unprecedented resolution1. Our aim was to design a computational analytical workflow enabling the exploration of the cellular and molecular drivers of normal human granulopoiesis alongside the precise characterisation of the dynamic changes in the genome regulatory landscape dictating myeloid cell commitment and terminal neutrophil differentiation. Our dataset included transcriptomic (scRNA; n=3 donors and 29,300 cells) and simultaneous profiled gene expression and chromatin accessibility (scGEX & scATAC; n=3 donors and 17,219 cells) analyses from mature neutrophils and myeloid precursors. We successfully co-embedded our data with a published reference dataset encompassing neutrophils and myeloid progenitors from heathy donors, confirming the overlap of the transcriptomic signatures. The transition from transcriptome-based to epigenome-based cluster labels improved annotation resolution, enabling precise identification of previously unexplored subtypes within neutrophil and precursor populations. Further investigation of both modalities revealed distinct chromatin conformations, but almost identical transcriptomic signatures, for clusters of band and mature neutrophils approaching the end of their lifespan. The exhausted pro-apoptotic neutrophils displayed dynamically increased chromatin compaction as evidenced by a 42.1% decline in accessible peaks detected, indicating an earlier stage towards programmed cell death commitment compared to robust neutrophils. Next, we used our resource atlas to interrogate the underlying genome regulatory networks and characterise cell-type-specific cis regulatory elements (CREs) involved in human granulopoiesis. We coupled transcription factor (TF) and target gene identification using Scanpy with SCENIC analysis, enabling a comparative study focusing on open chromatin regions. We then linked the pre-identified cell-type-specific activities for 178 differentially present TFs to chromatin accessibility changes using ArchR and performed motif enrichment and peak-to-gene linkage identification using the integrated scGEX dataset. As a result, we were able to underpin the connection between neutrophil terminal differentiation potential and the dynamic changes in chromatin architecture. We analysed the role of our candidate TFs by imputing regulatory single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) focusing on neutrophil biology and absolute counts. This showed an increased transcriptional activity for our candidate TFs, with an overall enrichment frequency of detected regulatory SNPs, within the metamyelocyte compartment, thus further highlighting the role of this differentiation stage as a regulatory switch towards terminal neutrophil maturation. We used reference chromatin immunoprecipitation sequencing (ChIP-seq) data from mature neutrophils and progenitors focusing on histone modification marks and CTCF sites to further annotate de novo genome-wide cell-type-specific CREs using REgulamentary2. These findings were visualised using Multi-Dimensional Viewer, a comprehensive analytical interpretation tool, generating a publicly available resource atlas benefiting from the seamless interaction with this multiomic dataset. We present a computational analytical workflow that enables large-scale multiomic data mining to study the molecular underpinnings of normal neutrophil development, by precisely characterising the dynamical changes of the regulatory landscape during human granulopoiesis and generating testable hypothesis through regulatory SNPs assessment. 1. https://doi.org/10.1182/blood-2023-182041 2. https://doi.org/10.1101/2024.05.24.595662

Benchmarking transformer-based models for medical record deidentification: A single centre, multi-specialty evaluation

IRAK3 is upregulated in rheumatoid arthritis synovium and delays the onset of experimental arthritis

<jats:p>Tumour necrosis factor (TNF) is a potent inducer of endotoxin tolerance-associated molecules, such as interleukin-1 receptor-associated kinase 3 (IRAK3), and also a therapeutic target in inflammatory autoimmune diseases, as it upregulates the production of inflammatory mediators. The role of IRAK3 was assessed in rheumatoid arthritis (RA), a disease which is amenable to TNF blockade. As a variant of IRAK3 lacks the death domain required for its canonical role, isoform expression was determined in different inflammatory milieu by immunoblotting. RA synovial explant expression of IRAK3 was measured by qPCR. The expression of the larger, “classical” IRAK3 isoform predominated in macrophages treated with various stimuli. The expression of IRAK3 was higher in RA synovium compared to osteoarthritis synovium. Using collagen-induced arthritis, a murine model of RA, the immunomodulatory role of IRAK3 was investigated with wild-type (WT) and IRAK3-deficient mice expressing the MHC-II A<jats:sup>q</jats:sup> allele. Disease progression was significantly accelerated in IRAK3<jats:sup>−/−</jats:sup> mice. In addition, the circulating levels of IL-1β were greater, and there were fewer Tregs both before and after the onset of disease. Inflammatory gene expression was higher in the arthritic paws of IRAK3<jats:sup>−/−</jats:sup> mice. This study demonstrates that IRAK3 deficiency accelerates the progression of arthritis and increases molecular markers of disease severity.”</jats:p>

Primary Care Resource Utilisation and Costs of Fragility Fractures in Postmenopausal Women in the UK Using CPRD Data Mapped to OMOP Common Data Model

Large Scale Propensity Score Matching With Time-Stratification in Older Women With or Without Fractures in the UK

INCIDENCE OF IMMINENT SUBSEQUENT FRACTURE IN POSTMENOPAUSAL WOMEN AS CAPTURED IN PRIMARY CARE COMPARED TO HOSPITAL RECORDS IN UK AND SPAIN

HOSPITAL RESOURCE UTILIZATION AND COSTS OF IMMINENT SUBSEQUENT FRACTURES IN POSTMENOPAUSAL WOMEN: A DISTRIBUTED NETWORK ANALYSIS USING DATA FROM THE UK AND SPAIN MAPPED TO OMOP COMMON DATA MODEL

Feasibility of a Federated Network Analysis Using Real-World Data Mapped to OMOP Common Data Model to Estimate Healthcare Resource Utilisation and Costs of Imminent Subsequent Fracture