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The antidiabetic drug metformin acts on the bone microenvironment to promote myeloma cell adhesion to preosteoblasts and increase myeloma tumour burden in vivo.
Multiple myeloma is a haematological malignancy that is dependent upon interactions within the bone microenvironment to drive tumour growth and osteolytic bone disease. Metformin is an anti-diabetic drug that has attracted attention due to its direct antitumor effects, including anti-myeloma properties. However, the impact of the bone microenvironment on the response to metformin in myeloma is unknown. We have employed in vitro and in vivo models to dissect out the direct effects of metformin in bone and the subsequent indirect myeloma response. We demonstrate how metformin treatment of preosteoblasts increases myeloma cell attachment. Metformin-treated preosteoblasts increased osteopontin (OPN) expression that upon silencing, reduced subsequent myeloma cell adherence. Proliferation markers were reduced in myeloma cells cocultured with metformin-treated preosteoblasts. In vivo, mice were treated with metformin for 4 weeks prior to inoculation of 5TGM1 myeloma cells. Metformin-pretreated mice had an increase in tumour burden, associated with an increase in osteolytic bone lesions and elevated OPN expression in the bone marrow. Collectively, we show that metformin increases OPN expression in preosteoblasts, increasing myeloma cell adherence. In vivo, this translates to an unexpected indirect pro-tumourigenic effect of metformin, highlighting the importance of the interdependence between myeloma cells and cells of the bone microenvironment.
A scoping review to map public-facing websites for non-traumatic wrist disorders with quality evaluation.
INTRODUCTION: Public-facing resources for non-traumatic wrist disorders (NTWD) exist, but care recipients and healthcare professionals alike are uncertain where to access the most useful resources and have raised concerns over the quality of information provided. Previous studies involving stakeholders highlight a need for quality evaluation of these resources. The aim of this study was to identify website resources accessible to UK-based online health seekers and explore their content through quality assessment. METHODS: A scoping review of public-facing websites was conducted in accordance with Joanna Briggs Institute guidelines and PRISMA-ScR checklist. An a-priori search strategy was performed of publicly accessible websites using lay terms were entered into a simple Google search. The DISCERN tool was used to appraise the quality of health information with additional data charted to pre-determined criteria. RESULTS: The 82 websites meeting inclusion criteria scored an average of 2/5 DISCERN. Nine funding categories existed with private service websites were the most common. 18 different diagnoses were found with twenty different management interventions were recommended. CONCLUSION: Considerable variation was found in the quality of websites providing information which people with NTWD are likely to access. Quality and trustworthiness of website information on NTWD are not the preserve of any sector or organisation and we identified potential for improvements across the board.
Development and evaluation of a new semi-quantitative and morphometric scoring system for magnetic resonance imaging in adolescents with Osgood Schlatter Disease (The OSIS Score).
BACKGROUND: Osgood Schlatter Disease (OSD) is a common injury in adolescents. A recent systematic review identified multiple tissue characteristics evaluated in imaging studies, but the studies used different imaging modalities, used varying MRI protocols and were of poor study quality, which led to conflicting findings and hamper the clinical utility of MRI scans. This study aimed to develop and evaluate the reliability of a semi-quantitative MRI scoring system for use in adolescents with OSD. MATERIALS AND METHODS: Based on a systematic review, we used an expert-led process to develop a scoring list to describe soft tissues, cartilage, bone, and morphometric characteristics in adolescents with OSD. 1.5 T MRI was performed on the most symptomatic knee in adolescents with OSD. A trained radiologist and a research trainee each assessed 10 cases twice to assess the intra- and inter-rater reliability of the scoring list. RESULTS: The final 18 item scoring list included an assessment of the patellar tendon, infrapatellar bursa, cartilage, and the tibial epiphysis, metaphysis, and tibial tuberosity, which were scored by signal intensity, degree, and signal homogeneity. Patellar height, patella morphology, patellar tendon attachment, and tendon thickness and width were quantified. Ten adolescents with OSD (13.2 ± 1.1, 30 % female) were included for reliability. Most features showed good to very good (κ and ICC > 0.6) reliability. The exceptions were intra-rater reliability for superficial bursa homogeneity (κ = 0.51) and inter-rater reliability for signal degree in the patellar tendon (κ = 0.55), tibial epiphysis (κ = 0.53) and tibial tuberosity (κ = 0.52) and patella morphology ratio (ICC: -0.16, p = 0.67. Reliability for patella height and patellar tendon width had the highest reliability (intra-rater ICC (0.75-0.98); inter-rater ICC (0.48-0.93)). CONCLUSION: This semi-quantitative scoring system for MRI allows the comprehensive and reliable assessment of features relevant for evaluating affected tissues in adolescent patients with OSD.
A prognostic model for use before elective surgery to estimate the risk of postoperative pulmonary complications (GSU-Pulmonary Score): a development and validation study in three international cohorts.
BACKGROUND: Pulmonary complications are the most common cause of death after surgery. This study aimed to derive and externally validate a novel prognostic model that can be used before elective surgery to estimate the risk of postoperative pulmonary complications and to support resource allocation and prioritisation during pandemic recovery. METHODS: Data from an international, prospective cohort study were used to develop a novel prognostic risk model for pulmonary complications after elective surgery in adult patients (aged ≥18 years) across all operation and disease types. The primary outcome measure was postoperative pulmonary complications at 30 days after surgery, which was a composite of pneumonia, acute respiratory distress syndrome, and unexpected mechanical ventilation. Model development with candidate predictor variables was done in the GlobalSurg-CovidSurg Week dataset (global; October, 2020). Two structured machine learning techniques were explored (XGBoost and the least absolute shrinkage and selection operator [LASSO]), and the model with the best performance (GSU-Pulmonary Score) underwent internal validation using bootstrap resampling. The discrimination and calibration of the score were externally validated in two further prospective cohorts: CovidSurg-Cancer (worldwide; February to August, 2020, during the COVID-19 pandemic) and RECON (UK and Australasia; January to October, 2019, before the COVID-19 pandemic). The model was deployed as an online web application. The GlobalSurg-CovidSurg Week and CovidSurg-Cancer studies were registered with ClinicalTrials.gov, NCT04509986 and NCT04384926. FINDINGS: Prognostic models were developed from 13 candidate predictor variables in data from 86 231 patients (1158 hospitals in 114 countries). External validation included 30 492 patients from CovidSurg-Cancer (726 hospitals in 75 countries) and 6789 from RECON (150 hospitals in three countries). The overall rates of pulmonary complications were 2·0% in derivation data, and 3·9% (CovidSurg-Cancer) and 4·7% (RECON) in the validation datasets. Penalised regression using LASSO had similar discrimination to XGBoost (area under the receiver operating curve [AUROC] 0·786, 95% CI 0·774-0·798 vs 0·785, 0·772-0·797), was more explainable, and required fewer covariables. The final GSU-Pulmonary Score included ten predictor variables and showed good discrimination and calibration upon internal validation (AUROC 0·773, 95% CI 0·751-0·795; Brier score 0·020, calibration in the large [CITL] 0·034, slope 0·954). The model performance was acceptable on external validation in CovidSurg-Cancer (AUROC 0·746, 95% CI 0·733-0·760; Brier score 0·036, CITL 0·109, slope 1·056), but with some miscalibration in RECON data (AUROC 0·716, 95% CI 0·689-0·744; Brier score 0·045, CITL 1·040, slope 1·009). INTERPRETATION: This novel prognostic risk score uses simple predictor variables available at the time of a decision for elective surgery that can accurately stratify patients' risk of postoperative pulmonary complications, including during SARS-CoV-2 outbreaks. It could inform surgical consent, resource allocation, and hospital-level prioritisation as elective surgery is upscaled to address global backlogs. FUNDING: National Institute for Health Research.
A scoping review to map evidence regarding key domains and questions in the management of non-traumatic wrist disorders.
INTRODUCTION: Non-traumatic wrist disorders (NTWD) are commonly encountered yet sparse resources exist to aid management. This study aimed to produce a literature map regarding diagnosis, management, pathways of care and outcome measures for NTWDs in the United Kingdom. METHODS: An interdisciplinary team of clinicians and academic researchers used Joanna Briggs Institute guidelines and the PRISMA ScR checklist in this scoping review. A mixed stakeholder group of patients and healthcare professionals identified 16 questions of importance to which the literature was mapped. An a-priori search strategy of both published and non-published material from five electronic databases and grey literature resources identified records. Two reviewers independently screened records for inclusion using explicit eligibility criteria with oversight from a third. Data extraction through narrative synthesis, charting and summary was performed independently by two reviewers. RESULTS: Of 185 studies meeting eligibility criteria, diagnoses of wrist pain, De Quervain's syndrome and ulna-sided pain were encountered most frequently, with uncontrolled non-randomised trial or cohort study being the most frequently used methodology. Diagnostic methods used included subjective questioning, self-reported pain, palpation and special tests. Best practice guidelines were found from three sources for two NTWD conditions. Seventeen types of conservative management, and 20 different patient-reported outcome measures were suggested for NTWD. CONCLUSION: Substantial gaps in evidence exist in all parts of the patient journey for NTWD when mapped against an analytic framework (AF). Opportunities exist for future rigorous primary studies to address these gaps and the preliminary concerns about the quality of the literature regarding NTWD.
Impact of COVID-19 on vascular patients worldwide: analysis of the COVIDSurg data.
BACKGROUND: The COVIDSurg collaborative was an international multicenter prospective analysis of perioperative data from 235 hospitals in 24 countries. It found that perioperative COVID-19 infection was associated with a mortality rate of 24%. At the same time, the COVER study demonstrated similarly high perioperative mortality rates in vascular surgical patients undergoing vascular interventions even without COVID-19, likely associated with the high burden of comorbidity associated with vascular patients. This is a vascular subgroup analysis of the COVIDSurg cohort. METHODS: All patients with a suspected or confirmed diagnosis of COVID-19 in the 7 days prior to, or in the 30 days following a vascular procedure were included. The primary outcome was 30-day mortality. Secondary outcomes were pulmonary complications (adult respiratory distress syndrome, pulmonary embolism, pneumonia and respiratory failure). Logistic regression was undertaken for dichotomous outcomes. RESULTS: Overall, 602 patients were included in this subgroup analysis, of which 88.4% were emergencies. The most common operations performed were for vascular-related dialysis access procedures (20.1%, N.=121). The combined 30-day mortality rate was 27.2%. Composite secondary pulmonary outcomes occurred in half of the vascular patients (N.=275, 45.7%). CONCLUSIONS: Mortality following vascular surgery in COVID positive patients was significantly higher than levels reported pre-pandemic, and similar to that seen in other specialties in the COVIDSurg cohort. Initiatives and surgical pathways that ensure vascular patients are protected from exposure to COVID-19 in the peri-operative period are vital to protect against excess mortality.
The impact of inter-infection time on antimicrobial resistance profiles in women with multiple urinary tract infections over time
Background: Urinary tract infection (UTI) treatment in primary care is increasingly complicated by antimicrobial resistance (AMR), and antimicrobial susceptibility profiles are rarely available to prescribers at the point of prescription. Susceptibility profiles from previous urine culture results could inform prescribing, but little is known about associations between previous and current susceptibilities and the impact of time between infections (inter-infection time) on these associations. Methods: We analyzed routinely collected healthcare records of women ≥16 years in Oxfordshire, UK, who had ≥2 culture-positive urine specimens consistent with a UTI between 2013-2019. We used generalized additive logistic models to estimate associations between resistance to each of eight commonly prescribed antibiotics at first UTI and at second UTI and their interaction with inter-infection time, adjusted for age and calendar year. Results: In 10,216 women, significant associations were observed between AMR at first and second UTIs. For all antibiotics, these were largest for short inter-infection times. Pivmecillinam resistance at first UTI (OR:41.70, 95% CI:27.70-62.80), followed by fosfomycin (OR:19.90, CI:13.66-28.92), and ciprofloxacin resistance (OR:19.65, 95% CI: 16.30-23.75), were strongly associated with resistance to the same antibiotic at the second UTI for inter-infection times ≤3 months. Lower magnitude associations were observed for other antibiotics. For UTIs caused by E. coli only, these associations were generally larger. Conclusions: In a cohort of women experiencing UTIs, AMR at the first UTI and inter-infection time were key determinants of AMR in the second UTI. This information could inform empiric antimicrobial treatment to limit treatment failure in women with recurrent UTI.
Reducing routine group and save testing in emergency laparoscopic appendicectomy surgery: a quality improvement project assessing the triple bottom line.
INTRODUCTION: There is compelling evidence supporting the omission of routine group and save (G&S) testing pre-operatively in emergency laparoscopy where appendicitis is suspected. Most studies are retrospective; however, one study prospectively demonstrated safe application in laparoscopic cholecystectomies only. We sought to assess safety, cost, and environmental and social savings-the triple bottom line-of omitting routine G&S testing in laparoscopic appendicectomies, by undertaking a quality improvement project at a busy district general hospital. METHODS: All patients who underwent an emergency laparoscopy +/- appendicectomy, between 1 November 2020 and 31 October 2021, were retrospectively reviewed, and cross-referenced to haematological testing and blood product dispensation data. A cost of £15 was applied to processed G&S samples and £1.89 to rejected samples. A carbon cost of 1,066 g CO2 emissions (CO2 e) was applied to all samples. We then prospectively undertook a 6-month pilot intervention to omit routine G&S testing in these cases. Patients from either cohort who required blood transfusions underwent a deep dive to identify risk factors. RESULTS: Pre-intervention, 281/392 (71.7%) of patients had valid G&S samples prior to their procedure and no patient required blood products during their episode. Post-intervention, 56/189 (29.1%) patients had valid G&S samples. One patient with chronic anaemia required a preoperative blood transfusion. Pre-intervention, G&S testing cost £22.24 and 1.7 kg CO2 e per laparoscopy. Post-intervention, the cost reduced to £9.78 and 0.7 kg CO2 e per laparoscopy. The intervention saved £5,021 and 353 kg CO2 e, and our institution has adopted a selective approach, based on clinical risk, for these cases indefinitely. CONCLUSION: Routine G&S testing in emergency laparoscopy +/- appendicectomy is unnecessary, costing money and time and producing carbon emissions. With effective communication of risk-mitigating factors, practice can shift from high to low rates of preoperative testing. There are further savings accessible by applying this method to other surgical procedures using a risk-based approach.
Overseas general practitioners (GPs) and opioid prescriptions in England.
The substantial recent rise in opioid prescription rates, along with increasing evidence of misuse and associated morbidity and mortality, raises serious concerns about the appropri- ateness of these drugs for pain management. This study investigates prescription behaviour differences across opioid drug categories between UK-trained and overseas-trained GPs. Us- ing panel data covering all English practices from 2018 to 2021, we find a strong association between practices with more overseas GPs and opioid prescription patterns. Regional dif- ferences emerge, with GPs from North America prescribing more opioids and those from Africa and Asia prescribing less, relative to the UK-trained counterparts. Heterogeneous cultural norms, different training environments, and varying epidemiological patterns might explain these different prescribing behaviours. Comprehensive cross-country assessments of GP competencies could identify areas for targeted training, helping to align the practices of foreign-trained GPs with UK standards while supporting the attraction of global talent.
Use of Machine Learning to Compare Disease Risk Scores and Propensity Scores Across Complex Confounding Scenarios: A Simulation Study.
PURPOSE: The surge of treatments for COVID-19 in the second quarter of 2020 had a low prevalence of treatment and high outcome risk. Motivated by that, we conducted a simulation study comparing disease risk scores (DRS) and propensity scores (PS) using a range of scenarios with different treatment prevalences and outcome risks. METHOD: Four methods were used to estimate PS and DRS: logistic regression (reference method), least absolute shrinkage and selection operator (LASSO), multilayer perceptron (MLP), and XgBoost. Monte Carlo simulations generated data across 25 scenarios varying in treatment prevalence, outcome risk, data complexity, and sample size. Average treatment effects were calculated after matching. Relative bias and average absolute standardized mean difference (ASMD) were reported. RESULT: Estimation bias increased as treatment prevalence decreased. DRS showed lower bias than PS when treatment prevalence was below 0.1, especially in nonlinear data. However, DRS did not outperform PS in linear or small sample data. PS had comparable or lower bias than DRS when treatment prevalence was 0.1-0.5. Three machine learning (ML) methods performed similarly, with LASSO and XgBoost outperforming the reference method in some nonlinear scenarios. ASMD results indicated that DRS was less impacted by decreasing treatment prevalence compared to PS. CONCLUSION: Under nonlinear data, DRS reduced bias compared to PS in scenarios with low treatment prevalence, while PS was preferable for data with treatment prevalence greater than 0.1, regardless of the outcome risk. ML methods can outperform the logistic regression method for PS and DRS estimation. Both decreasing sample size and adding nonlinearity and nonadditivity in data increased bias for all methods tested.
Investigating the lymphatic system in intestinal inflammation
We set out to understand the colonic lymphatic vasculature in the context of outflow from the colon, with the ambition of using this knowledge to develop methods to promote exit of inflammatory cells from the tissue as an alternative way to treat patients with inflammatory bowel disease. Our studies converged on the identification of tissue folds as central anatomical units that orchestrate interstitial fluid outflow from the colon. We observed that the luminal surface of the mammalian colon is characterised by undulations of the mucosa and submucosa forming tissue folds. In humans these included haustral folds and intrahaustral folds of lesser prominence between muscular bands of taenia coli. Mice lacked taenia coli and haustra but nonetheless possessed folds, especially in the proximal colon. The functional significance of these colonic tissue undulations, beyond increasing surface area for absorption, had not previously been determined. Here, through murine in vivo and 3D imaging studies, we show that tissue folds orchestrated the collection and outflow of interstitial fluid from the colon. We demonstrate that lymphatics line the base of colonic crypts and specifically branched toward the epithelium within folds. Colonic folds functioned as reservoirs feeding lymphatic and venous outflow, and phagocytic scavenging by fold-associated mononuclear phagocytes augmented this reservoir property. Colonic lymphoid follicles were enriched within these tissue folds, surrounded by lymphatics and postcapillary venules. Human colonic lymphoid follicles were likewise positioned within the elevation of tissue folds. Our findings suggest that colonic folds are distinct anatomical units conserved across species that organise uptake, immunosurveillance, and outflow of interstitial cargo, while restraining the spread of inflammation. Indeed, the loss of tissue folds during ulcerative colitis may facilitate distal-to-proximal spread of pathology.
A new model measuring bacterial phagocytosis and phagolysosomal oxidation in humans using the intradermal injection of methylene blue-labeled Escherichia coli.
Phagocytosis is an important leukocyte function; however, using existing models it cannot be measured in human tissues in vivo. To address this, we characterized a new phagocytosis model using intradermal methylene blue-labeled Escherichia coli injection (MBEC). Methylene blue (MB) is a licensed human medicine and bacterial stain potentially useful for labeling E. coli that is safe for human injection. Ex vivo coculture of leukocytes with MBEC caused MB to transfer into neutrophils and macrophages by phagocytosis. During this, a "red shift" in MB fluorescence was shown to be caused by phagolysosomal oxidation. Hence, MBEC coculture could be used to measure phagocytosis and phagolysosomal oxidation in humans, ex vivo. In healthy volunteers, inflammatory exudate sampling using suction blisters 2 to 24 h after intradermal MBEC injection showed that tissue-acquired neutrophils and monocytes contained more MB than their circulating counterparts, whereas blood and inflamed tissue T, B, and natural killer cells were MBlo. This was validated with spectral flow cytometry by visualizing the MB emission spectrum in tissue-acquired neutrophils. Neutrophil MB emission spectra demonstrated more red shift at 24 h compared with earlier time points, in keeping with progressive phagolysosomal MB oxidation in neutrophils over time in vivo. This new MBEC model can therefore measure bacterial phagocytosis and phagolysosomal oxidation in human skin, in vivo. This has a number of important research applications, e.g. in studying human phagocyte biology, testing novel antimicrobials, and understanding why certain groups such as males, the elderly or those with diabetes, recent surgery, or malnutrition are at increased risk of bacterial infection.