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WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Pain): methods to assess pain behaviour in rodent models of endometriosis
Pain is a debilitating symptom of endometriosis, and its mechanisms are often explored using rodent models. However, a lack of harmonization amongst models and behavioural measures, in addition to inconsistent reporting, might limit the overall clinical relevance and hinder translation of findings. An additional challenge is accurately linking rodent behaviour to human experiences of endometriosis. This study aimed to: (i) review current measures of pain-associated behaviours used in endometriosis studies; (ii) recommend best practices for each method and their suitability to study endometriosis-associated pain; and (iii) develop internationally agreed-upon standard operating procedures ('EPHect-EM-Pain SOPs'). The World Endometriosis Research Foundation (WERF) assembled an international working group, from which a 'pain behaviour working group' consisting of experts in the field was established. The group used additional consultation from experimental pain model scientists in the broader field. Stimulus-evoked (reflexive) and stimulus-independent (spontaneous) measures are currently used to assess pain-associated behaviours in rodents with experimental endometriosis. All existing methods offer advantages and limitations regarding ethological relevance, output quality, and equipment/training requisites. Internationally standardized pain SOPs as well as summary documentation outlining the minimum and standard requirements for several behavioural measures were developed, as well as consensus recommendations on experimental designs and documentation. To more closely reflect the lived experiences of those with endometriosis, the consortium recommends that, following validation, multiple types of pain-related and/or parallel rodent behaviours (e.g. anxiety) should be quantified as surrogate outcome measures for endometriosis-associated pain. These harmonized methods and documentation for endometriosis research will facilitate essential comparisons among studies, improve translational applicability, and provide a superior holistic view of animal (and thus human) wellbeing.
WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Heterologous): heterologous rodent models
Endometriosis, defined as the growth of endometrial-like tissues outside the uterus, is a common disease among women. Numerous in vivo rodent models of endometriosis have been developed to explore multiple aspects of this poorly understood disease. Heterologous models utilize human endometrial tissues engrafted into immunocompromized mice, while homologous models engraft rodent endometrium into immunocompetent mice or rats. Heterologous models of endometriosis more closely replicate the human disease; however, the murine humoral immune response must be suppressed to prevent rejection of the xenograft tissue. Although the innate immune system remains intact, suppression of the humoral response leads to a markedly different local and systemic immune environments compared to humans. Despite this limitation, experiments using heterologous models have contributed significantly to our understanding of endometriosis establishment and progression, the pre-clinical effectiveness of various therapeutic strategies, and genetically modifiable host factors that contribute to disease. Unfortunately, a lack of harmonization of the models used by different laboratories has impeded the reproducibility and comparability of results between groups. Therefore, the World Endometriosis Research Foundation (WERF) formed an international working group of experts in heterologous models of endometriosis to develop guidelines and protocols that could contribute to unifying experimental approaches across laboratories. Nine critical variables were identified: (i) mouse strain; (ii) human tissue type; (iii) hormonal status of the human tissue donor; (iv) human tissue preparation; (v) method and location of tissue placement; (vi) hormonal status of the recipient animal; (vii) whether or not mice were engrafted with human immune cells; (viii) endpoint assessments; and (ix) number and type of replicates. Herein, we outline important considerations for each major variable and make recommendations for unification of approaches. Widespread adoption of harmonized protocols and implementation of standardized documentation and reporting should further improve the reproducibility and translation of experimental findings both within and between laboratories.
WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Homologous): homologous rodent models
In vivo models of endometriosis enable the discovery and preclinical testing of new therapies. Several rodent models of endometriosis exist, but a lack of harmonization impedes reproducibility and comparability of results among investigators. Homologous models are advantageous as they allow the contribution of the immune system/inflammation to be studied. We reviewed published homologous rodent models of endometriosis to develop standard operating procedures ('EPHect-EM-Homologous-SOPs') to guide and facilitate the choice and implementation of these models and harmonize documentation to enhance interpretation and comparability of results. The World Endometriosis Research Foundation (WERF) established an international working group of experts in models of endometriosis and formed a working sub-group to discuss homologous rodent models of endometriosis. A systematic literature review and detailed analysis of protocols was performed. The identified models have advantages and limitations regarding physiological relevance and utility. To harmonize key variables for endometriosis rodent models, the working group focused on species and animal strains, placement of ectopic tissue, uterine tissue volume, method of induction, hormonal status, and uterine tissue 'type'. A decision tree and recommendations on model use were developed for mice and rats to serve as guides for the use of harmonized EPHect-EM-Homologous-SOPs, experimental design, reporting standards, and research of question-dependent key variables. No 'ideal' homologous model of endometriosis was identified. The choice of model for specific research should be guided according to a best-fit strategy. Harmonization of SOPs, documentation, and reporting standards will improve replicability and translational applicability of studies and better highlight where de novo model creation is needed.
A framework for the development and implementation of open trauma guidelines: A Delphi consensus validation.
INTRODUCTION: Lower limb open fractures are severe injuries that can lead to long-term sequelae. Clinical guidelines for managing these patients are associated with expedited treatment and better outcomes. However, few countries have implemented guidelines for open lower limb fractures. The aim of this study was to develop and validate a framework for the introduction of clinical guidelines in settings that do not have one at present. METHODS: Using the qualitative analysis for the Limitations to the Implementation of Open Trauma Guidelines (LINEAGE) study, a framework proposal was designed. This included 4 clusters of inter-related concepts, including clinician, team, health and cultural factors. To validate this framework a modified Delphi study was devised. The elements of the framework were translated into 12 statements that were compiled in a Delphi questionnaire. A panel of orthopaedic and plastic surgeons was assembled to obtain structured feedback and assess the degree of consensus regarding the framework proposal. RESULTS: Using purposive sampling, 43 clinicians enrolled in an international expert panel, including 20 orthopaedic and 23 plastic surgeons based in countries with no guidelines at present. Following three Delphi rounds, 11 out of the 12 assessed statements achieved the threshold for validation. The single statement that did not reach consensus status was then removed from the framework. DISCUSSION: Frameworks are a well-described aid in implementation science, being able to describe complexity and propose strategies for improvement. We present the first validated framework for the development and implementation of open fracture guidelines.
Applying population mechanistic modelling to find determinants of chimeric antigen receptor T-cells dynamics in month-one lymphoma patients
Background: Chimeric antigen receptor (CAR) T-cells have been utilized for the treatment of several malignancies, including Non-Hodgkin lymphomas. A myriad of product- and patient-specific factors determines the extent of patient response, and determining which are most impactful requires analysis of clinical data. Methods: We used population-level ordinary differential equation models to fit clinical flow cytometry and tumour biopsy data from the TRANSCEND-NHL-001 (NCT02631044) study [1]. We analyzed the impact of lymphodepletion, CAR T-cell phenotypes, and other factors on CAR T-cell dynamics for 30 days after infusion. Results: We quantified the relative contribution of antigen-dependent and independent sources of proliferation on CAR T-cell dynamics, finding that both make a large contribution and that antigen-independent proliferation was highly correlated with patient IL-15 and IL-7 blood concentrations. The proportion of CAR T-cells in naïve, memory, or effector cells was found to have a limited impact on CAR T-cell dynamics, compared with lymphodepletion and tumour burden. Conclusions: This study shows how models can be used to link endogenous T-cells, CAR T-cells, and their phenotypes, and may be useful for determining whether a given patient may be responding poorly to treatment, by observing the dynamics of their endogenous T-cells. The framework we developed can be utilized for other CAR T constructs and indications, to test product alterations or biological hypotheses at the population level.
Fully automated measurement of paediatric cerebral palsy pelvic radiographs with BoneFinder : external validation using a national surveillance database.
AIMS: BoneFinder is a machine-learning tool that can automatically calculate Reimers migration percentage (RMP) and head-shaft angle (HSA) from paediatric cerebral palsy (CP) pelvic radiographs. This study's primary aim was to compare BoneFinder's fully automated measurements to manual measurements made by clinicians and HipScreen-assisted measurements made by clinicians. METHODS: Using the radiological database within Cerebral Palsy Integrated Care Pathway Scotland (CPIPS), BoneFinder's automatic RMP and HSA measurements were compared across the same set of radiographs to: routine manual measurements performed by clinical experts from the CPIPS database; additional manual measurements performed by two clinicians; and measurements performed by the same two clinicians using the smartphone application HipScreen. RESULTS: A total of 509 anteroposterior pelvic radiographs (1,018 hips; mean age 7.4 years (1 to 17)) were selected at random from the CPIPS database. Gross Motor Function Classification System levels were I (n = 69), II (n = 37), III (n = 97), IV (n = 120), and V (n = 186). The mean absolute difference (MAD) in RMP between BoneFinder and CPIPS measurements, manual measurements, and HipScreen was 7.6% (SD 10.0%), 5.5% (SD 9.1%), and 5.8% (SD 9.2%), respectively. Interobserver reliability of RMP measurement across all methods was excellent (intraclass correlation coefficient (ICC) 0.89 (95% CI 0.87 to 0.91); p < 0.001). Good ICC was found between BoneFinder and CPIPS measurements (ICC 0.80 (95% CI 0.65 to 0.87); p < 0.001). The area under the receiver operating characteristic curve for BoneFinder's ability to detect a hip with a RMP ≥ 30%/40%/50% was 0.95/0.97/0.98, respectively. ICC of HSA measurement across all raters was moderate (ICC 0.72 (95% CI 0.67 to 0.76); p < 0.001). Image artefact was present in 138 of 1,018 hips (14%). In these images, MAD increased and ICC decreased for both RMP and HSA measurement between BoneFinder and CPIPS, indicating a decline in agreement. CONCLUSION: Fully automated RMP and HSA measurements using BoneFinder were highly reliable with clinically acceptable measurement error. Further refinement of BoneFinder is required for analysis of radiographs with artefact.
Hip surveillance in children with cerebral palsy in the UK : history, challenges, and future directions.
Cerebral palsy (CP) is associated with musculoskeletal complications in children, notably hip migration, which can progress to hip dislocation and joint degeneration. Without regular radiological monitoring, early-stage hip migration can be missed, potentially leading to complex, high-risk operations later in life. Hip surveillance programmes, such as the Swedish Uppföljningsprogram för Cerebral Pares (CPUP) and UK-based Cerebral Palsy Integrated Pathway (CPIP) and CPIP Scotland (CPIPS), aim to identify and address hip pathology proactively through serial radiological and clinical assessments. This helps to standardize care, reduce the incidence of hip dislocation, and prevent the need for salvage procedures. In turn, this preserves hip function, reduces pain, and improves quality of life. These programmes are surveillance rather than screening, as they do not dictate treatment or alter the course of the disease, but have been shown to reduce the burden of hip pathology in population studies. Despite the proven benefits of hip surveillance, widespread adoption has been slow due to the challenges of funding, coordinating radiological assessments, ensuring timely radiological interpretation, and limited clinician resources. Challenges also persist in determining the optimal interventions for hip migration and in engaging patients, families, and clinicians in these processes. Recent advances in technology, including machine learning tools and smartphone applications, show promise in improving the efficiency and accuracy of hip surveillance. Additionally, prospective clinical research aims to improve our understanding of the optimal treatment strategies for hip migration. Overall, hip surveillance continues to evolve, with potential for ongoing improvements in care and long-term outcomes for children with CP.
Navigating the barriers and facilitators to implementation of AI in healthcare : a scoping review.
AIMS: There is increasing emphasis on applying AI techniques to enhance healthcare delivery and decision-making. However, despite much interest and early promise, a major challenge is translation into clinical practice. To address the challenges of AI deployment, optimize implementation, and establish strategies for effective utilization of AI technology in healthcare, we aimed to answer the question: what are the key determinants influencing effective deployment of AI technology in healthcare? METHODS: We followed PRISMA-ScR and the Joanna Briggs Institute Methodology guidelines for scoping reviews; the research protocol was published prospectively on Open Science Framework. We searched PubMed, Cochrane, Ovid MEDLINE, Scopus, and IEEE Xplore for papers published in English from 2000, including systematic/scoping reviews and meta-analyses with full text available. RESULTS: The initial search was limited to AI medical imaging technology. It identified 1,511 papers, of which 523 met the eligibility criteria based on title and abstract screening. A total of 488 papers were excluded due to context or irrelevant content, leaving 35 papers for full-text review. No systematic/scoping reviews specifically addressing the deployment of AI medical imaging solutions were identified, prompting the inclusion criteria to be broadened to encompass any study designs related to all relevant technology. Overall, 15 papers were included in the final scoping review. CONCLUSION: The successful deployment of AI in healthcare is challenging, due to barriers which can be ethical, technological, regulatory, financial, or patient- and workforce-related. Facilitators to drive successful implementation include planning, organizational culture, patient involvement, stakeholder engagement, education, and leadership. Leveraging these essential barriers and facilitators provides a foundation for developing implementation strategies that streamline the deployment of AI technology in healthcare.
Social contact and the perceived impact of social distancing on health outcomes during the COVID-19 pandemic among community dwelling older adults taking part in the OPAL cohort study.
BACKGROUND: During the COVID-19 pandemic, social distancing and reduced social contact may have affected older adults' health. OBJECTIVES: To evaluate the perceived impact of social distancing on older adults' health and explore the association between social contact and health outcomes. DESIGN: Cross-sectional and longitudinal analyses of the OPAL cohort study. SUBJECTS: Community dwelling older adults. METHODS: We sent questionnaires to participants of an existing cohort study (n = 4328). Questions included the amount and type of social contact, and how often they went outside. Participants rated the impact of social distancing on their health. Sociodemographic factors and quality of life were available from previous questionnaires. We examined quality of life prior to and during the pandemic and explored the cross-sectional relationship between social contact and health using logistic regression. RESULTS: There were 3856/4328 (89%) questionnaires returned. EQ-5D scores changed little compared to pre-pandemic scores but 25% of participants reported their overall health had worsened. The telephone was the most used method of contact (78%). Video calls were used least with 35% of participants not using them or having no access to them. 13% of respondents never went outside. Lower levels of contact were associated with increased risk of reporting worse health (Odds ratio (OR) 1.04 (95% CI 1.01-1.08)). Those experiencing financial strain and who spent less time outside experienced the largest increase in risk of reporting perceived worsened overall health. Those reporting a strain to get by financially were 4 times more likely to report worsened health than those who described themselves as quite comfortably off (OR 4.00 (95% CI 1.86-8.16)). Participants who reported never going outside were twice as likely to report worsened health compared to those who went outside daily (OR 2.00 (95% CI 1.57-2.54)). CONCLUSIONS: Less contact with other people was associated with perceived worsening in overall health. Although many older people reported using online technology, such as video calls, a substantial proportion were not using them. Older people facing financial strain were more likely to report worsened health, highlighting the impact of social inequalities during the pandemic. Going outside less was also associated with perceived worsened health.
Five-year outcomes for patients with a displaced fracture of the distal tibia
Aims To report the outcomes of patients with a fracture of the distal tibia who were treated with intramedullary nail versus locking plate in the five years after participating in the Fixation of Distal Tibia fracture (FixDT) trial. Methods The FixDT trial reported the results for 321 patients randomized to nail or locking plate fixation in the first 12 months after their injury. In this follow-up study, we report the results of 170 of the original participants who agreed to be followed up until five years. Participants reported their Disability Rating Index (DRI) and health-related quality of life (EuroQol five-dimension three-level questionnaire) annually by self-reported questionnaire. Further surgical interventions related to the fracture were also recorded. Results There was no evidence of a difference in patient-reported disability, health-related quality of life, or the need for further surgery between participants treated with either type of fixation at five years. Considering the combined results for all participants, there was no significant change in DRI scores after the first 12 months of follow-up (difference between 12 and 24 months, 3.3 (95% confidence interval -1.8 to 8.5); p = 0.203), with patients reporting around 20% disability at five years. Conclusion This study shows that the moderate levels of disability and reduced quality of life reported by participants 12 months after a fracture of the distal tibia persist in the medium term, with little evidence of improvement after the first year.
Risk of death by suicide following self-harm presentations to healthcare: development and validation of a multivariable clinical prediction rule (OxSATS).
BACKGROUND: Assessment of suicide risk in individuals who have self-harmed is common in emergency departments, but is often based on tools developed for other purposes. OBJECTIVE: We developed and validated a predictive model for suicide following self-harm. METHODS: We used data from Swedish population-based registers. A cohort of 53 172 individuals aged 10+ years, with healthcare episodes of self-harm, was split into development (37 523 individuals, of whom 391 died from suicide within 12 months) and validation (15 649 individuals, 178 suicides within 12 months) samples. We fitted a multivariable accelerated failure time model for the association between risk factors and time to suicide. The final model contains 11 factors: age, sex, and variables related to substance misuse, mental health and treatment, and history of self-harm. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines were followed for the design and reporting of this work. FINDINGS: An 11-item risk model to predict suicide was developed using sociodemographic and clinical risk factors, and showed good discrimination (c-index 0.77, 95% CI 0.75 to 0.78) and calibration in external validation. For risk of suicide within 12 months, using a 1% cut-off, sensitivity was 82% (75% to 87%) and specificity was 54% (53% to 55%). A web-based risk calculator is available (Oxford Suicide Assessment Tool for Self-harm or OxSATS). CONCLUSIONS: OxSATS accurately predicts 12-month risk of suicide. Further validations and linkage to effective interventions are required to examine clinical utility. CLINICAL IMPLICATIONS: Using a clinical prediction score may assist clinical decision-making and resource allocation.
Getting Recovery Right After Neck Dissection (GRRAND-F): Mixed-methods feasibility study to design a pragmatic randomised controlled trial.
OBJECTIVE: To determine the feasibility of a randomised controlled trial to estimate the effectiveness and cost-effectiveness of a rehabilitation intervention following neck dissection (ND) after head and neck cancer (HNC). DESIGN: Two-arm, open, pragmatic, parallel, multicentre, randomised controlled feasibility trial. SETTING: Two UK NHS hospitals. PARTICIPANTS: People who had HNC in whom a ND was part of their care. We excluded those with a life expectancy of six months or less, pre-existing, long-term neurological disease affecting the shoulder and cognitive impairment. INTERVENTION: Usual care (standard care supplemented with a booklet on postoperative self-management) was received by all participants. The GRRAND intervention programme consisted of usual care plus up to six individual physiotherapy sessions including neck and shoulder range of motion and progressive resistance exercises, advice and education. Between sessions, participants were advised to complete a home exercise programme. RANDOMISATION: 1:1 randomisation. Allocation was based on minimisation, stratified by hospital site and spinal accessory nerve sacrifice. It was not possible to mask treatment received. MAIN OUTCOME MEASURES: Primary: Participant recruitment, retention and fidelity to the study protocol and interventions from study participants and staff at six months post-randomisation (and 12 months for those reaching that time-point). Secondary: clinical measures of pain, function, physical performance, health-related quality of life, health utilisation and adverse events. RESULTS: 36 participants were recruited and enrolled. The study achieved five of its six feasibility targets. These included consent - 70% of eligible participants were consented; intervention fidelity - 78% participants discharged completed the intervention sessions; contamination - none - no participants in the control arm received the GRRAND-F intervention and retention - 8% of participants were lost to follow-up. The only feasibility target that was not achieved was the recruitment target where only 36 of the planned 60 participants were recruited over 18 months. This was principally due to the COVID-19 pandemic which caused all research activity to be paused or reduced, with a subsequent reduction in. CONCLUSIONS: Based on the findings a full-trial can now be designed to better understand whether this proposed intervention is effective. CLINICAL TRIAL REGISTRATION: https://www.isrctn.com/ISRCTN1197999, identifier ISRCTN11979997.