Parallel Evaluation Research Articles

The research on dance motion quality evaluation based on spatiotemporal convolutional neural networks

With the rapid development of artificial intelligence and computer vision technology, dance action recognition and quality assessment have become a challenging and important research field. Traditional dance movement recognition methods often rely on manual feature extraction and expert scoring, which have problems such as strong subjectivity, low efficiency, and difficulty in handling complex movements. To address these issues, this study proposes a dance action recognition and quality assessment method based on Spatio Temporal Convolutional Neural Network (ST-CNN). Specifically, it includes a feature extraction network based on 3D spatiotemporal description operators and a multi-scale aggregated long short memory network for extracting spatial features of single frame images and fusing video sequence features composed of all frames. This approach can effectively capture dynamic changes in dance movements by combining information from spatial and temporal dimensions, thereby achieving more accurate recognition and evaluation. In addition, to address the high storage and computational requirements of convolutional neural networks during training, we integrated dance video sequences into an IoT architecture to address parallel recognition and evaluation of multiple videos. Finally, we validated the proposed method on the public datasets NTU-RGB 60 and NTU-RGB 120, and the experimental results demonstrated the effectiveness of the method.

Improving screening, brief intervention and referral to treatment for unhealthy alcohol use in diverse, low-resourced primary care clinics

BackgroundImplementation of screening brief intervention and referral to treatment (SBIRT) and medication-assisted treatment for alcohol use disorder (MAUD) remains low in primary care. ANTECEDENT (Partnerships to Enhance Alcohol Screening, Treatment, and Intervention) was a practice-facilitator led implementation study to increase SBIRT and MAUD use in diverse primary care clinics.MethodsFrom November 2019 – April 2023, we conducted a convergent parallel mixed methods evaluation. Participants were small and medium-sized primary care clinics in the Northwestern U.S. Clinics received foundational support (i.e., baseline/exit assessment, access to SBIRT Oregon website) and the option for supplemental implementation support (e.g., practice facilitation, expert consultation) over the 15-month intervention to improve SBIRT and MAUD. Qualitative and quantitative data regarding clinic characteristics, implementation strategies, and SBIRT/MAUD outcomes were collected through practice facilitator interviews, periodic reflections and clinic contact logs, interviews, pre-post surveys, and electronic health record (EHR) queries. Quantitative analyses included descriptive statistics, logistic regression, and the Wilcoxon sign-ranked test. Qualitative analysis took an immersion crystallization approach. Data were reviewed in a matrix to evaluate intervention adoption, implementation, and effectiveness.ResultsWe recruited 75 unique clinics; 66 participated and 48 (73%) completed the study. Eight participating clinics chose to receive foundational support only (12%) while 58 chose to engage in supplemental support (88%) activities. Clinics that received supplemental support and completed the intervention (n = 42) engaged in practice facilitation (Mean: 293 min, range: 75–550 min); data review (38%), HIT support (31%), expert consultation (19%), and peer-to-peer learning (5%). Pre- and post-intervention assessments showed significant improvement in self-reported SBIRT process outcomes. Performance data improved among the subset of completing clinics able to produce data (n = 17). Clinics described positive experiences with ANTECEDENT support and highlighted remaining barriers to SBIRT and MAUD implementation.ConclusionsParticipating clinics engaged in a diverse range of supportive activities. A flexible approach using practice facilitation and implementation support could be helpful for low-resourced primary care clinics in improving SBIRT and MAUD for unhealthy alcohol use.

Impact of metabolism-related markers on outcomes in ovarian cancer patients: Findings of the MITO16A/MaNGO-OV2 trial.

In ovarian cancer, expression of metabolism-related markers has been investigated in several studies focusing on individual markers; however, a parallel quantitative evaluation of markers mapping to distinct metabolic processes and their prognostic value in large patient cohorts is still lacking. Here, by using immunohistochemistry followed by digital pathology, we investigated the expression of several markers related to glycolysis including monocarboxylate transporter 1 and 4 (MCT1, MCT4), glutamine metabolism (glutaminase, GLS) and hypoxia/acidosis (carbonic anhydrase 9, CA IX) in tissue microarrays of > 300 patients recruited in the MITO16A clinical trial, which involved treatment of ovarian cancer patients with carboplatin/taxol plus bevacizumab. Regarding the prognostic impact of these markers, results indicate that GLS expression correlated with progression-free survival, but this effect disappeared when data were corrected for multiple testing. All other markers showed no correlation with clinical outcome. These results indicate marked heterogeneity of expression of metabolism-associated markers in ovarian cancer; however, there was a lack of association with clinical benefit after chemotherapy/anti-vascular endothelial growth factor treatment. Notwithstanding the lack of prognostic value, knowledge of the pattern of expression of these biomarkers in tumors can be useful for patient stratification purposes when new drugs targeting these metabolic pathways will be tested.

Male fertility is preserved following ixekizumab treatment-a real life pilot study.

Preserving fertility is crucial when managing male patients with spondyloarthritis (SpA) and/or psoriasis (PsO), especially in young men. Chronic inflammation, hormonal dysregulation, and immunosuppressive therapies can negatively impact male fertility. Over the past decades, positive data have emerged regarding the reproductive safety of various therapies in men. Ixekizumab (IXE), a high-affinity monoclonal antibody targeting IL-17A, has shown a safe profile for male fertility in small studies. This pilot study assesses the impact of IXE treatment on sperm parameters in SpA and/or PsO patients in a real-world setting. Consecutive adult male SpA and/or PsO patients eligible for or undergoing IXE treatment were prospectively enrolled. Demographic data, disease characteristics, laboratory assessments, comorbidities, and previous treatments were recorded. Sperm analysis was conducted after a minimum of 6 months of IXE treatment, and also before treatment inititation in a subgroup of patients. Parallel sperm evaluations were performed in a control group of healthy donors. Ten patients were enrolled: 8 with SpA and 2 with PsO. After 6 months of IXE treatment, all patients had normal sperm parameters. One SpA and PsO patient with baseline oligozoospermia showed normal parameters at follow-up and achieved a successful pregnancy post-treatment. Compared with controls, IXE-treated patients had lower sperm concentrations but higher vitality. In our limited size pilot study on SpA and PsO patients, Ixekizumab exposure did not impair male fertility. Sperm parameters remained within normal ranges after a minimum of 6 months of treatment. Early Ixekizumab treatment may preserve or potentially reverse fertility impairment.

High dynamic range mapping for the evaluation of parallel transmit arrays.

Demonstration of a high dynamic-range and high SNR method for acquiring absolute maps from a combination of gradient echo and actual-flip-angle measurements that is especially useful during the construction of parallel-transmit arrays. Low flip angle gradient echo images, acquired when transmitting with each channel individually, are used to compute relative maps. Instead of computing these in a conventional manner, the equivalence of the problem to the ESPIRiT parallel image reconstruction method is used to compute maps with a higher SNR. Absolute maps are generated by calibration against a single actual flip-angle acquisition when transmitting on all channels simultaneously. Depending on the number of receiver channels and the location of the receive elements with respect to the subject being investigated, moderate to high gains in the SNR of the acquired maps can be achieved. The proposed method is especially suited for the acquisition of maps during the construction of transceiver arrays. Compared to the original method, maps with higher SNR can be computed without the need for additional measurements, and maps can also be generated using previously acquired data. Furthermore, easy adoption and fast estimation of receiver channels is possible because of existing highly optimized open-source implementations of ESPIRiT, such as in the BART toolbox.

Using Nobel Prize case-based learning in Medical Immunology to cultivate critical thinking dispositions for medical undergraduates

BackgroundCritical thinking has been regarded as an essential skill for college students, which is especially imperative for medical students to possess the ability to have in-depth insight into complex clinical situations. Medical Immunology is an overarching principle connecting multiple medical subjects, which emphasizes that immunity is both beneficial and harmful to the host, thus putting higher demands on students’ critical thinking. The utilization of Nobel Prize stories has been cited as a thematic framework for classroom teaching of other courses, showing numerous educational benefits. Therefore, this study rejuvenated a case-based teaching approach by creating and introducing a vibrant material library centered on numerous iconic Nobel Prize cases in Medical Immunology and evaluating its effects on the critical thinking of medical students.MethodsA total of 70 second-year medical undergraduates from the Beijing University of Chinese Medicine were divided into a control group and an experimental group of 35 cases each. Throughout the semester, the control received the traditional teaching method, and the experimental group adopted case-based teaching based on the Nobel prize-centered material library. The process of teaching design and practice was described using “Antitoxin and immunoserum therapy” as a classical example. A unified assessment of the critical thinking dispositions of participants was conducted at the beginning and end of the semester using the Critical Thinking Disposition Inventory-Chinese Version (CTDI-CV).ResultsIntra-group longitudinal comparisons and inter-group parallel evaluations indicated that, compared with the conventional teaching approach, Nobel Prize case-based learning induced a statistically significant increase in the overall score of the CTDI-CV, as well as the scores within the subdimensions of truth-seeking, analyticity, and maturity in judgment (p < 0.05). Pearson correlation analysis further indicated a positive correlation between the total score of the CTDI-CV and the final grade (p < 0.05), which emphasized the crucial role of critical thinking dispositions in academic achievement.ConclusionThe case-based classroom teaching centered on Nobel Prize cases for Medical Immunology can effectively improve the critical thinking dispositions of medical undergraduates, which contributes to cultivating high-level medical and healthcare talents with excellent comprehensive quality in the new era.

Remote monitoring of rheumatoid arthritis (REMORA): study protocol for a stepped wedge cluster randomized trial and process evaluation of an integrated symptom tracking intervention

BackgroundManagement of rheumatoid arthritis (RA) relies on symptoms reported by patients during infrequent outpatient clinic visits. These reports are often incomplete and inaccurate due to poor recall, leading to suboptimal treatment decisions and outcomes. Asking people to track symptoms in-between visits and integrating the data into clinical pathways may improve this. However, knowledge on how to implement this into practice and its impact on services and outcomes remains scarce in RA. Therefore, we evaluate the comparative effectiveness and cost-effectiveness of integrated symptom tracking in people with RA over and above usual care, while generating insights on factors for successful implementation.MethodsIn this superiority stepped wedge cluster-randomized controlled trial with continuous recruitment short exposure design, 16 rheumatology outpatient departments (clusters) recruit a total of 732 people with active RA. They initially offer clinic visits according to standard of care before switching in pairs to visits with integrated symptom tracking. Clusters switch in randomized order every 3 weeks. Integrated symptom tracking consists of (1) a mobile app for patients to track their symptoms daily and other RA aspects weekly/monthly, and (2) an interactive dashboard visualizing the app data, which healthcare professionals access from their electronic health record system. Clinic visits happen according to usual practice, with tracked symptom data only reviewed during visits. Our primary outcome is a difference in marginal mean disease activity score at 12 ± 3 months between standard of care and integrated symptom tracking, after accounting for baseline values, cluster, and other covariates. Secondary outcomes include patient-reported disease activity, quality of life and quality-adjusted life-years, medication/resource use, consultation and decision-making experience, self-management, and illness perception. We also conduct interviews and observations as part of a parallel process evaluation to gather information on implementation.DiscussionOur trial will generate high-quality evidence of comparative and cost-effectiveness of integrated symptom tracking compared to standard of care in people with RA, with our process evaluation delivering knowledge on successful implementation. This optimizes the chances of integrated symptom tracking being adopted more widely if we find it is (cost-) effective.Trial registrationRegistered 4-Jun-2024 on https://www.isrctn.com/, ISRCTN51539448.Trial open science framework repositoryhttps://osf.io/sj9ha/.

A Systematic Review of Dental Antibiotic Stewardship Interventions.

Antimicrobial resistance is a significant threat to global health. Antimicrobial stewardship is reducing inappropriate antimicrobial prescribing to counter it. Dentists prescribe ~10% of all antibiotics worldwide, yet up to 90% of antibiotic prescriptions by dentists are inappropriate. The aim of this systematic review was to update a 2017 review evaluating the effects of antibiotic stewardship interventions in dental settings, using the international consensus on core outcomes for dental antibiotic stewardship. Systematic database searches were undertaken in April 2023, of the: Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE via OVID, EMBASE via OVID, Dentistry and Oral Sciences Source, the US National Institutes of Health Trials Register, the World Health Organisation International Clinical Trials Registry Platform and the ISRCTN registry databases. Randomised controlled trials (or non-randomised studies with clearly reported mechanism of group formation and inclusion criteria) of interventions to optimise and/or reduce dental antibiotic prescribing were eligible for inclusion. Two authors independently screened for eligible studies. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, certainty of evidence assessed using GRADE. Meta-analysis was planned whether the results of studies reported similar outcomes, otherwise narrative synthesis was undertaken. Three eligible studies randomising 2148 participants were included. The interventions were combinations of education, audit and feedback and written behaviour change messages, guideline summary, practice visits and patient leaflets. None of the control groups received an intervention. All three included studies measured the quantity of antibiotics prescribed and two measured the appropriateness of prescribing. None measured patient-reported or adverse outcomes. Two included studies were assessed as 'high risk' and one with 'low risk' of bias. There was high-certainty evidence that audit and personalised feedback with individualised behaviour change messages can be effective. Evidence for in-person education was low-certainty. Guideline dissemination alone was ineffective at improving antibiotic prescribing. Due to different outcomes reported, meta-analysis was inappropriate. Although various dental antibiotic stewardship interventions have been reported in the literature, none provided high-certainty evidence of effectiveness and only three have been evaluated using a randomised design. To strengthen the body of evidence, well-powered, robust, randomised controlled trials are required, with adequate follow-up, reporting the internationally-agreed core outcomes and including a parallel process evaluation is recommended. PROSPERO (CRD42023411476).

B-036 Systematic Evaluation of Antibody-Antigen Interactions for Suitability in Immunoassays Using Parallel Microarray ELISA

Abstract Background A critical step in immunoassay development is the selection of the appropriate capture and detection antibodies. The use of suboptimal antibodies can drastically affect the quality of the final assay. Traditional selection methods involve a direct testing of potential antibodies in the final assay setting; a time-consuming and material-intensive exercise that is often too complex to test all possibilities. Alternatives, such as abstract K-on/K-off determinations via SPR or BLI can be costly and often show limited translatability to the ultimate assay format. Here, we describe a novel systematic approach to rapidly screen antibody-antigen interactions for key assay specifications and test for translatability of the findings. Methods Nanoliter volumes of potential capture antibodies were spotted onto the bottom of ELISA wells, generating a microarray of antibodies in each well (&amp;gt;11,000 spots per plate). For the analysis of capture antibody-antigen interactions, a titration series of biotinylated analyte in negative sample matrix was applied. Binding was visualized using strep-polyHRP, precipitating TMB and high resolution scanning of each ELISA well. Antibody pair performance was investigated using unlabeled analyte and biotinylated detection antibody options. Sensitivity, specificity, dynamic range, binding speed, binding strength and matrix compatibility were investigated using time courses, concentration ranges, dilutions, interferent spikes and pH/salt/detergent challenges. Signals were quantified to calculate and statistically compare each possible interaction. Results Antibody-antigen interactions were investigated via parallel microarray ELISA for two example immunoassays: the HBsAg and cTnI test. For both analytes, a panel of antibodies was screened revealing antibodies with diverse characteristics. Striking differences were observed depending on the sample matrix composition. Without optimization, antibodies could be identified showing dynamic assay ranges of 3-4 log orders. Time course experiments revealed high-affinity antibodies suitable for rapid diagnostic tests. For HBsAg, levels down to 0.01 IU/mL (∼40 pg/mL) could be reproducibly detected, which is well below the minimal requirement of 0.13 IU/mL. Reactivity against multiple virus serotypes could be confirmed. Interestingly, for the cTnI test, a strong synergistic effect was observed when specific monoclonal antibodies were combined in the capture mix, resulting in a 6-fold sensitivity enhancement compared to their separate performances. Finally, we show that the results obtained with the parallel microarray ELISA approach are highly translatable to the final assay format, ranging from bead-based dry-chemistry assays to chemiluminescent immunoassays. Conclusions The parallel microarray ELISA evaluation presents a robust and reliable method for identifying the best antibodies for an immunoassay. It allows for a systematic and quantitative screen of numerous antibody options within 1-2 weeks under real immunoassay conditions with minimal antibody amounts. This method has shown to be highly translatable and is customizable to accommodate required assay specifications.

Preventing recurrence of endometriosis-related pain by means of long-acting progestogen therapy: the PRE-EMPT RCT.

Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women's lived experience of endometriosis and a pretrial economic model. Thirty-four United Kingdom hospitals. Women of reproductive age undergoing conservative surgery for endometriosis. Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: -0.8, 95% confidence interval -5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval -0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word 'woman' is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

Effective parallel evaluation of molecular design, expression and bioactivity of novel recombinant butyrylcholinesterase medical countermeasures

Current medical countermeasures (MCMs) for nerve agent poisoning have limited efficacy, and can cause serious adverse effects, prompting the requirement for new broad-spectrum therapeutics. Human plasma-derived butyrylcholinseterase (huBChE) is a promising novel bioscavenger MCM which has shown potential in animal studies, however, is economically prohibitive to manufacture at scale. This study addresses current challenges for the economical production of a bioactive and long-acting recombinant huBChE (rBChE) in mammalian cells by being the first to directly compare novel rBChE design strategies. These include co-expression of a proline rich attachment domain (PRAD) and fusion of BChE with a protein partner. Additionally, a pre-purification screening method developed in this study enables parallel comparison of the expression efficiency, activity and broad-spectrum binding to nerve agents for ten novel rBChE molecular designs. All designed rBChE demonstrated functionality to act as broad-spectrum MCMs to G, V and A series nerve agents. Expression using the ExpiCHO™ Max protocol provided greatest expression levels and activity for all constructs, with most rBChE expressing poorly in Expi293™. Fc- or hSA-fused rBChE significantly outperformed constructs designed to mimic huBChE, including PRAD-BChE, and proved an effective strategy to significantly improve enzyme activity and expression. Choice of protein partner, directionality and the addition of a linker also impacted fusion rBChE activity and expression. Overall, hSA fused rBChE provided greatest expression yield and activity, with BChE-hSA the best performing construct. The purified and characterised BChE-hSA demonstrated similar functionality to huBChE to be inhibited by GD, VX and A-234, supporting the findings of the pre-screening study and validating its capacity to assess and streamline the selection process for rBChE constructs in a cost-effective manner. Collectively, these outcomes contribute to risk mitigation in early-stage development, providing a systematic method to compare rBChE designs and a focus for future development.

Diagnostic Performance of Serum Leucine-Rich Alpha-2-Glycoprotein 1 in Pediatric Acute Appendicitis: A Prospective Validation Study.

Introduction: Leucine-rich alpha-2-glycoprotein 1(LRG-1) is a human protein that has shown potential usefulness as a biomarker for diagnosing pediatric acute appendicitis (PAA). This study aims to validate the diagnostic performance of serum LRG-1 in PAA. Material and Methods: This work is a subgroup analysis from BIDIAP (BIomarkers for DIagnosing Appendicitis in Pediatrics), a prospective single-center observational cohort, to validate serum LRG-1 as a diagnostic tool in PAA. This analysis included 200 patients, divided into three groups: (1) healthy patients undergoing major outpatient surgery (n = 56), (2) patients with non-surgical abdominal pain (n = 52), and (3) patients with a confirmed diagnosis of PAA (n = 92). Patients in group 3 were divided into complicated and uncomplicated PAA. In all patients, a serum sample was obtained during recruitment, and LRG-1 concentration was determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). Comparative statistical analyses were performed using the Mann-Whitney U, Kruskal-Wallis, and Fisher's exact tests. The area under the receiver operating characteristic curves (AUC) was calculated for all pertinent analyses. Results: Serum LRG-1 values, expressed as median (interquartile range) were 23,145 (18,246-27,453) ng/mL in group 1, 27,655 (21,151-38,795) ng/mL in group 2 and 40,409 (32,631-53,655) ng/mL in group 3 (p < 0.0001). Concerning the type of appendicitis, the serum LRG-1 values obtained were 38,686 (31,804-48,816) ng/mL in the uncomplicated PAA group and 51,857 (34,013-64,202) ng/mL in the complicated PAA group (p = 0.02). The area under the curve (AUC) obtained (group 2 vs. 3) was 0.75 (95% CI 0.67-0.84). For the discrimination between complicated and uncomplicated PAA, the AUC obtained was 0.66 (95% CI 0.52-0.79). Conclusions: This work establishes normative health ranges for serum LRG-1 values in the pediatric population and shows that serum LRG-1 could be a potentially helpful tool for diagnosing PAA in the future. Future prospective multicenter studies, with the parallel evaluation of urinary and salivary LRG-1, are necessary to assess the implementability of this molecule in actual clinical practice.

PAIN RELIEF AFTER INSTRUMENTED SPINAL SURGERY

BackgroundOver 55,000 spinal operations are performed annually in the NHS. Effective postoperative analgesia facilitates early mobilisation and assists rehabilitation and hospital discharge, but is difficult to achieve with conventional, opioid-based, oral analgesia. The clinical and cost-effectiveness of two alternative techniques, namely intrathecal opioid and the more novel erector-spinae plane blockade, is unknown. The Pain Relief After Instrumented Spinal Surgery (PRAISE) trial aims to evaluate these techniques.MethodsPRAISE is a multicentre, prospective, parallel group, patient-blinded, randomised trial, seeking to recruit 456 adult participants undergoing elective, posterior lumbar-instrumented spinal surgery from up to 25 NHS hospitals. Participants will be randomised 1:1:1 to receive (1) Usual Care with local wound infiltration, (2) Intrathecal Opioid plus Usual Care with local wound infiltration or (3) Erector Spinae Plane blockade plus Usual Care with no local wound infiltration. The primary outcome is pain on movement on a 100mm visual analogue scale at 24 hours post-surgery. Secondary outcomes include pain at rest, leg pain, quality of recovery (QoR-15), postoperative opioid consumption, time to mobilisation, length of hospital stay, health utility (EQ-5D-5L), adverse events and resource use. Parallel economic evaluation will estimate incremental cost-effectiveness ratios.ResultsDifferences in the primary outcome at 24 hours will be estimated by mixed-effects linear regression modelling, with fixed effects for randomisation factors and other important prognostic variables, and random effects for centre, using the as-randomised population. Treatment effects with 95% confidence intervals will be presented.ConclusionThe study is due to open in May 2024 and complete in 2026.Conflicts of InterestNo conflicts of interest declaredSources of FundingNIHR Health Technology Award – grant number NIHR153170Trial presentations so farAPOMP 2023 and 2024; RCOA conference, York, November 2023; Faculty of Pain Management training day, London, February 2024.

A parallel variable-fidelity algorithm for efficient constrained multi-objective aerodynamic design optimization

Modern aerodynamic design optimization aims to discover optimal configurations using computational fluid dynamics under complex flow conditions, which is a typical expensive multi-objective optimization problem. The multi-objective evolutionary algorithm based on decomposition (MOEA/D) combined with efficient global optimization is a promising method but requires enhanced efficiency and faces limitations in its application to multi-objective aerodynamic design optimization (MOADO). To address the issues, an efficient parallel MOEA/D assisted with variable-fidelity optimization (VFO) is proposed for solving MOADO, called the MOEA/D-VFO algorithm. Variable-fidelity surrogates are built for objectives and constraints, achieving higher accuracy using fewer high-fidelity samples and a great number of low-fidelity samples. By retaining more good candidates, the sub-optimization problems defined by decomposing original objectives are capable of discovering more favorable samples using MOEA/D, which prompts optimization convergence. A constraint-handling strategy is developed by incorporating the probability of feasibility functions in the sub-optimizations. The selection of new samples for parallel evaluation is improved by filtering out poor candidates and selecting effective promising samples, which improves the feasibility and diversity of solved Pareto solutions. A Pareto front (PF) can be efficiently found in a single optimization run. The proposed approach is demonstrated by four analytical test functions and verified by two aerodynamic design optimizations of airfoils with and without constraints, respectively. The results indicate that the MOEA/D-VFO approach can greatly improve optimization efficiency and obtain the PF satisfying constraints within an affordable computational budget.

Uncertain Quality-Diversity: Evaluation Methodology and New Methods for Quality-Diversity in Uncertain Domains

Quality-Diversity optimisation (QD) has proven to yield promising results across a broad set of applications. However, QD approaches struggle in the presence of uncertainty in the environment, as it impacts their ability to quantify the true performance and novelty of solutions. This problem has been highlighted multiple times independently in previous literature. In this work, we propose to uniformise the view on this problem through four main contributions. First, we formalise a common framework for uncertain domains: the Uncertain QD setting, a special case of QD in which fitness and descriptors for each solution are no longer fixed values but distribution over possible values. Second, we propose a new methodology to evaluate Uncertain QD approaches, relying on a new per-generation sampling budget and a set of existing and new metrics specifically designed for Uncertain QD. Third, we propose three new Uncertain QD algorithms: Archive-sampling, Parallel-Adaptivesampling and Deep-Grid-sampling. We propose these approaches taking into account recent advances in the QD community toward the use of hardware acceleration that enable large numbers of parallel evaluations and make sampling an affordable approach to uncertainty. Our final and fourth contribution is to use this new framework and the associated comparison methods to benchmark existing and novel approaches. We demonstrate once again the limitation of MAP-Elites in uncertain domains and highlight the performance of the existing Deep-Grid approach, and of our new algorithms. The goal of this framework and methods is to become an instrumental benchmark for future works considering Uncertain QD.

Improve Parallel Resistance of Hashcash Tree

Denial of Service (DoS) attacks remain a persistent threat to online systems, necessitating continual innovation in defense mechanisms. In this work, we present an improved algorithm for mitigating DoS attacks through the augmentation of client puzzle protocols. Building upon the foundation of hashcash trees, a recently proposed data structure combining hashcash and Merkle trees, we introduce a new version of the data structure that enhances resistance against parallel computation (a common tactic employed by attackers). By incorporating the labels of children and the next node in a breadth-first traversal into the hash function, we establish a sequential processing order that inhibits parallel node evaluation. The added dependency on the next node significantly elevates the complexity of constructing hashcash trees, introducing a linear number of synchronization points and fortifying resilience against potential attacks. Empirical evaluation demonstrates the efficacy of our approach, showcasing its ability to accurately control puzzle difficulty while bolstering system security against DoS threats.

Experiences with implementing advance care planning (ACP-GP) in Belgian general practice in the context of a cluster RCT: a process evaluation using the RE-AIM framework

BackgroundGeneral practice is often recommended as an ideal setting to initiate advance care planning (ACP), but uptake of ACP in this setting is low. ACP-GP is a complex intervention to facilitate ACP for patients with chronic, life-limiting illness in Belgian general practice. It aims to increase patient ACP engagement and general practitioner (GP) ACP self-efficacy. In a cluster-randomized controlled trial, the intervention was not superior to control in increasing these outcomes. A parallel process evaluation aimed to enhance understanding of how the intervention was implemented, and which factors might have influenced trial results.MethodsWe conducted a mixed-methods process evaluation following the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework. Data sources include recruitment and implementation monitoring, questionnaires for patients and GPs, and semi-structured (focus group) interviews with patients and GPs. Questionnaire data were analyzed descriptively. Qualitative data were first analyzed inductively; themes were then assigned deductively to RE-AIM dimensions.ResultsThirty-five GPs and 95 patients were recruited to the trial; GP reach was low. Sixteen GPs and 46 patients provided questionnaire data at 3 months post-baseline; qualitative data were transcribed for 14 GPs and 11 patients. Adoption of intervention components was moderate to good, with the exception of the documentation template for GPs. Interviews revealed varying patient attitudes towards ACP, but patients nonetheless emphasized that conversations made them feel reassured. GPs especially valued a positive framing of ACP. When adopted, the intervention was well-implemented and participant satisfaction was high. However, intention for maintenance was moderate, with GPs raising questions of how to sustainably implement ACP conversations in the future.ConclusionsImplementing the complex ACP-GP intervention in general practice is feasible, and can be successful. However, the implementation process is challenging and the sustainability is suboptimal. Our findings will guide future research and recommendations for facilitating and implementing ACP in general practice.Trial registrationISRCTN12995230; prospectively registered on 19/06/2020.

Quantitative cellular pathology of the amygdala in temporal lobe epilepsy and correlation with magnetic resonance imaging volumetry, tissue microstructure, and sudden unexpected death in epilepsy risk factors.

Amygdala enlargement can occur in temporal lobe epilepsy, and increased amygdala volume is also reported in sudden unexpected death in epilepsy (SUDEP). Apnea can be induced by amygdala stimulation, and postconvulsive central apnea (PCCA) and generalized seizures are both known SUDEP risk factors. Neurite orientation dispersion and density imaging (NODDI) has recently provided additional information on altered amygdala microstructure in SUDEP. In a series of 24 surgical temporal lobe epilepsy cases, our aim was to quantify amygdala cellular pathology parameters that could predict enlargement, NODDI changes, and ictal respiratory dysfunction. Using whole slide scanning automated quantitative image analysis methods, parallel evaluation of myelin, axons, dendrites, oligodendroglia, microglia, astroglia, neurons, serotonergic networks, mTOR-pathway activation (pS6) and phosphorylated tau (pTau; AT8, AT100, PHF) in amygdala, periamygdala cortex, and white matter regions of interest were compared with preoperative magnetic resonance imaging data on amygdala size, and in 13 cases with NODDI and evidence of ictal-associated apnea. We observed significantly higher glial labeling (Iba1, glial fibrillary acidic protein, Olig2) in amygdala regions compared to cortex and a strong positive correlation between Olig2 and Iba1 in the amygdala. Larger amygdala volumes correlated with lower microtubule-associated protein (MAP2), whereas higher NODDI orientation dispersion index correlated with lower Olig2 cell densities. In the three cases with recorded PCCA, higher MAP2 and pS6-235 expression was noted than in those without. pTau did not correlate with SUDEP risk factors, including seizure frequency. Histological quantitation of amygdala microstructure can shed light on enlargement and diffusion imaging alterations in epilepsy to explore possible mechanisms of amygdala dysfunction, including mTOR pathway activation, that in turn may increase the risk for SUDEP.

Development and validation of an ELISA to measure regenerating island-derived protein 3E in canine blood.

Regenerating island-derived proteins (REG) are upregulated in people with sepsis, pancreatitis, and gastrointestinal diseases. One member of the REG family, namely REG3E, was recently identified in pancreatic tissue and plasma of dogs, with high expression in pancreatitis and sepsis. We aimed to develop and validate an ELISA to measure REG3E concentrations in canine blood. An indirect sandwich ELISA was developed using recombinant canine REG3E protein and polyclonal anti-canine REG3E antibodies raised in guinea pigs and rabbits. Antibody specificity was assessed using western blot and mass spectrometric analysis of protein purified from canine plasma. Assay validation included evaluation of dilutional linearity, parallelism, spiking recovery, repeatability and reproducibility, stability, interferences, and comparison of serum and heparinized plasma. Antibodies bound specifically to REG3E with no evidence of cross-reactivity with other proteins. The limit of detection of the ELISA was 15 ng/mL, and the lower limit of quantification was 30 ng/mL. The assay demonstrated good to excellent linearity, dilutional and mixing parallelism, and recovery, with mean observed-to-expected ratios of 104%, 107%, 102%, and 92%, respectively, and no evidence of a hook effect. Coefficients of variation were ≤8.5% for repeatability and ≤14.3% for reproducibility at three different levels. Measurements of REG3E in plasma were not significantly influenced by different storage conditions, freeze-thawing cycles, hemolysis, lipemia, or icterus. There was no significant difference between REG3E concentrations in heparinized plasma and serum samples. The canine REG3E ELISA has acceptable precision, accuracy, linearity, and reproducibility for the measurement of REG3E in canine plasma and serum.

Clinical effectiveness and cost-effectiveness of Structured Psychological Support for people with probable personality disorder in mental health services in England: study protocol for a randomised controlled trial

IntroductionEvidence-based psychological treatments for people with personality disorder usually involve attending group-based sessions over many months. Low-intensity psychological interventions of less than 6 months duration have been developed, but their...