Recent Submissions

  • Improving the delivery of acute NIV at Kings Mill Hospital: A closed loop quality improvement project.

    Slaich, Bhavandeep; Garrett, Frederick
    Background: The British Thoracic Society (BTS) Acute Non-Invasive Ventilation (NIV) standards state all patients who require acute NIV should be initiated on NIV within two hours of hospital admission. The delivery of acute NIV is a time critical intervention as prompt application of acute NIV substantially reduces mortality for patients with acute hypercapnic respiratory failure. Objective: This audit aimed to assess the number of patients for whom there is a delay in the initiation of acute NIV. We also assessed the outcome of admission for patients started on acute NIV. Methods: Data was collected on patients admitted to Kings Mill Hospital for acute NIV between 1/2/2019 and 31/3/2019. Awareness and knowledge of acute NIV was highlighted as an area for improvement. E-learning packages on 'Acute NIV' were designed and sent to medical-staff. The audit was repeated for patients admitted for acute NIV between 1/2/2020 and 31/3/2020 and analysed using chi-square tests. Results: 25 patients were included in the initial audit and 30 patients in the re-audit. Prior to intervention 31% of patients had a delay in the initiation of acute NIV, which increased to 77% post-intervention (p < 0.0001). Prior to intervention there was a mortality rate of 17% and a mortality rate of 13% post-intervention (p > 0.05). Conclusion: Further work is required to ensure the sustained delivery of acute NIV to BTS standards, however variable achievements in the targets does not seem to have a significant adverse effect on patient outcomes.
  • Reduction of needlestick injuries among nurses and healthcare assistants through an intervention: national hospital sri lanka (NHSL)

    Dilshara Prathapasinghe, Imesh (BMJ Leader, 2019-11)
    Introduction Cutaneous injuries, resulting from needle sticks, injection devices and sharps are a major issue for all health care workers and cause a considerable threat of spreading blood-related infections like HIV. Aim To reduce NSI among nurses (NO) and health care assistants (HCA) in the NHSL, by assessing the current gaps in the Knowledge, attitude and practice and designing intervention to mitigate the harm and reduce the injuries. Method An Interventional study was conducted in three components, pre-interventional, interventional and post interventional. Random sampling technique was applied to select the appropriate number of nurses and health care assistants. Pre-interventional component: To identify the gaps in the present managerial practices on NSI, a pre-tested structured questionnaire on knowledge, attitude and practices was administered. Interventional component: Two separate in-service programmes were conducted for both categories. WHO recommended injection safety tool kit was also introduced. Post-interventional component: Outcome of the interventions were assessed by measuring the pre- and post-test knowledge, attitude, and practice of the same participants. The same tool was administered. Results Both Groups (NO and HCA) showed a highly significance different after interventions, on Reporting system for NSI: p value (0.05, 0.001). Awareness on Post Exposure prophylaxis (0.003, 0.049). Non–significance difference among nursing officers on Knowledge attitude and practice. All the p values observed 0.05 < and z evident with negative findings. Only Knowledge component among the HCA indicates a significant difference. Conclusion and recommendation It was recommended to conduct more awareness programs and training modules on post exposure management of NSI because it has shown positive Results in both categories. WHO injection safety tool kit has also shown positive Results.
  • Antibiotic prophylaxis in breast surgery: a meta-analysis to identify the optimal strategy to reduce infection rates in breast surgery.

    Akbari, Amir R
    Intro: Breast surgeries are an increasingly frequent operation, with an exponential rise in breast cancer diagnoses, and women opting for cosmetic surgeries. SSIs are the most common post-operative complication with many negative consequences including sepsis and even death. These are treated with prophylactic antibiotics prior to surgery. Breast surgery is currently defined as 'clean', although literature indicates that the infection rate is higher than should be expected for this classification. The aim of this meta-analysis is to evaluate whether pre-operative antibiotics reduce SSI frequency and which class of antibiotics achieve the best reduction. Methods: A literature search through online libraries was used to find clinical trials investigating pre-breast-surgery antibiotics and SSI frequency. These were grouped all together and separately by class of antibiotics. Additionally studies investigating breast cancer surgeries and non-cancer surgeries were grouped separately. A forest-plot was created for each group to calculate an estimated effect, these were then compared against each other. Results: Use of antibiotics resulted in a reduction in SSI frequency by 3.55% overall, and reduced frequency in all types of surgeries performed. Cephalosporins reduced SSI frequency by 2.23%, Beta-lactamase inhibitors 4.17% and macrolides achieved the greatest effect with a 14.58% reduction. Conclusion: This meta-analysis proves that antibiotics reduce SSI frequency in breast surgery and supports the notion to remove the 'clean' classification. This definition may result in failure to provide prophylaxis, resulting in patients suffering from preventable SSIs and their negative consequences. Macrolides were the most effective followed by beta-lactamase inhibitors and cephalosporins, this may be implemented in structuring new guidelines favouring use of macrolides before conducting breast surgery.
  • Invasive coronary physiology assessment - safety of pressure wire study as a diagnostic tool at a district general hospital

    Dardas, Sotirios; Jesudason, Daniel (Heart, 2022-06)
    Introduction Pressure wire study (PWS) is a well-established tool for the assessment of the haemodynamic significance of intermediate coronary artery stenoses (40–90%). This, according to the 2018 ESC myocardial revascularization guidelines, has Class IA indication when evidence of ischaemia is not present. It can be used to calculate the fractional flow reserve (FFR), instantaneous wave-free ratio (iFR) or resting full cycle ratio (RFR) to guide revascularization decisions, with similar diagnostic accuracy between the tests. Despite the above, the utilization of PWS varies across the U.K., as reflected in the recent BCIS annual data. One possible explanation might be the fact that there are still numerous centres in the U.K, where diagnostic only coronary angiography lists take place, precluding the use of PWS at the same sitting. In our study, we aimed to review the safety of PWS as an invasive diagnostic tool and determine whether it could be incorporated in diagnostic only lists for the assessment of coronary stenoses.
  • 80 The cost of smoking in pregnancy - A retrospective study. Source

    Hills, A; Allison, C (European Journal of Obstetrics & Gynecology & Reproductive Biology, 2022-03)
    Introduction and study aims: The UK Department of Health aims to reduce smoking at time of delivery (SATOD) to below 6% by 2022. Sherwood Forest Hospital NHS Foundation Trust (SFHFT) had a SATOD of 16.5% in 2019-2020. The aim was to demonstrate how smoking continues to affect patients, to motivate and engage staff in smoking cessation strategies. Methods: Retrospective study of 25 non-smokers’ and 25 smokers’ who had delivered at SFHFT in the first quarter of 2020, comparing antenatal contacts and pregnancy-related complications. Inclusion criteria were maternal age (18 - 40 years) and BMI (18 - 25). Data was collected from Orion (electronic maternity pathway). The two groups were then compared using the Mann-Whitney U test. Results: The smoking group were 9 times less likely to attend appointments and had an average of 5.28 growth scans (compared to non-smokers 0.96 scans). They were 3 times more likely to have an antenatal complication - small for gestation age (SGA) [RR 9], fetal growth restriction (FGR) [RR 10], low Papp-A, antepartum haemorrhage, preterm birth, oligohydramnios and reduced fetal movements. Smokers were more likely to be induced for SGA/FGR (RR 5.5), have a baby below the 10th centile (RR3) and develop intrapartum complications (RR 1.45). Smokers were 3.6 times less likely to breast feed. All findings were clinically significant (p≤0.05). The cost of continued smoking in pregnancy for SFHFT is £1,731,560 per year. Conclusion: Despite increased surveillance in SATOD pregnancies, the short and long term consequences for these women and their babies are significant. It has previously been demonstrated that babies born with low birth weights are at increased risk of adult diseases, hence the true financial burden is therefore far greater and the continued need to decrease SATOD is clear.
  • What version of Hell's Kitchen?.

    Fleming, Robert J (Anaesthesia, 2022-07)
  • eQTL set-based association analysis identifies novel susceptibility loci for Barrett's esophagus and esophageal adenocarcinoma

    Jankowski, Janusz
    Background: Over 20 susceptibility single-nucleotide polymorphisms (SNPs) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTLs), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: While the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641 and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set based genetic association approach as an alternative method for TWAS analysis.
  • War Psychiatry: Identifying and Managing the Neuropsychiatric Consequences of Armed Conflicts.

    Akbari, Amir R
    War refugees and veterans have been known to frequently develop neuropsychiatric conditions including depression, post-traumatic stress disorder (PTSD), and anxiety disorders that tend to leave a long-lasting scar and impact their emotional response system. The shear stress, trauma, and mental breakdown from overnight displacement, family separation, and killing of friends and families cannot be described enough. Victims often require years of mental health support as they struggle with sleep difficulties, recurring memories, anxiety, grief, and anger. Everyone develops their coping mechanism which can involve dependence and long-term addiction to alcohol, drugs, violence, or gambling. The high prevalence of mental health disorders during and after the war indicates an undeniable necessity for screening those in need of treatment. For medical health professionals, it is crucial to identify such vulnerable groups who are prone to developing neuropsychiatric morbidities and associated risk factors. It is pivotal to develop and deploy effective and affordable multi-sectoral collaborative care models and therapy, which primarily depends upon family and primary care physicians in the conflict zones. Herein, we provide a brief overview regarding the identification and management of vulnerable populations, alongside discussing the challenges and possible solutions to the same.
  • Validation of methods for converting the original Disease Activity Score (DAS) to the DAS28

    Walsh, David A (Rheumatology Internatiaonal, 2018-12)
    The Disease Activity Score (DAS) is integral in tailoring the clinical management of rheumatoid arthritis (RA) patients and is an important measure in clinical research. Different versions have been developed over the years to improve reliability and ease of use. Combining the original DAS and the newer DAS28 data in both contemporary and historical studies is important for both primary and secondary data analyses. As such, a methodologically robust means of converting the old DAS to the new DAS28 measure would be invaluable. Using data from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28 data were used to develop new regression imputation formulas using the total DAS score (univariate), and using the separate components of the DAS score (multivariate). DAS were transformed to DAS28 using an existing formula quoted in the literature, and the newly developed formulas. Bland and Altman plots were used to compare the transformed DAS with the recorded DAS28 to ascertain levels of agreement. The current transformation formula tended to overestimate the true DAS28 score, particularly at the higher end of the scale. A formula which uses all separate components of the DAS was found to estimate the scores with a higher level of precision. A new formula is proposed that can be used by other early RA cohorts to convert the original DAS to DAS28.
  • Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts

    Walsh, David A (BMJ Open, 2019-05)
    Objectives: To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early rheumatoid arthritis (RA) inception cohorts with a focus on methotrexate (MTX) exposure. Design: Multicentre prospective early RA inception cohort studies; the early RA study (ERAS) and the early RA network (ERAN). Setting: Secondary care, ERAS nine centres, ERAN 23 centres in England, Wales and Ireland. Participants: Patients with new diagnosis of RA, n=2701. Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3-6 months, at 12 months and annually thereafter. Primary and secondary outcome measures: Primary outcome was the association of MTX exposure on RA-ILD diagnosis. Secondary outcomes were the association of demographic, comorbid and RA-specific factors on RA-ILD diagnosis and the association of MTX exposure on time to RA-ILD diagnosis. Results: Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of RA-ILD cases only developing after any conventional synthetic disease-modifying antirheumatic drug treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (OR 0.85, 95% CI 0.49 to 1.49, p=0.578) and a non-significant trend for delayed ILD diagnosis (OR 0.54, 95% CI 0.28 to 1.06, p=0.072). In an extended analysis including RA-ILD cases present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (OR 0.48, 95% CI 0.3 to 0.79, p=0.004) and longer time to ILD diagnosis (OR 0.41, 95% CI 0.23 to 0.75, p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first outpatient visit. Conclusions: MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence suggested that MTX may delay the onset of ILD.
  • Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population

    Walsh, David A (Osteoarthritis and Cartilage, 2019-03)
    Objective: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. Methods: 147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. Results: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0-10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. Conclusions: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal.
  • Peripheral brain-derived neurotrophic factor contributes to chronic osteoarthritis joint pain

    Walsh, David A (Pain, 2020-01)
    Brain-derived neurotrophic factor (BDNF) and the high-affinity receptor tropomyosin receptor kinase B (TrkB) have important roles in neuronal survival and in spinal sensitization mechanisms associated with chronic pain. Recent clinical evidence also supports a peripheral role of BDNF in osteoarthritis (OA), with synovial expression of TrkB associated with higher OA pain. The aim of this study was to use clinical samples and animal models to explore the potential contribution of knee joint BDNF/TrkB signalling to chronic OA pain. Brain-derived neurotrophic factor and TrkB mRNA and protein were present in knee synovia from OA patients (16 women, 14 men, median age 67 years [interquartile range: 61-73]). There was a significant positive correlation between mRNA expression of NTRK2 (TrkB) and the proinflammatory chemokine fractalkine in the OA synovia. Using the surgical medial meniscal transection (MNX) model and the chemical monosodium iodoacetate (MIA) model of OA pain in male rats, the effects of peripheral BDNF injection, vs sequestering endogenous BDNF with TrkB-Fc chimera, on established pain behaviour were determined. Intra-articular injection of BDNF augmented established OA pain behaviour in MIA rats, but had no effect in controls. Intra-articular injection of the TrkB-Fc chimera acutely reversed pain behaviour to a similar extent in both models of OA pain (weight-bearing asymmetry MIA: -11 ± 4%, MNX: -12 ± 4%), compared to vehicle treatment. Our data suggesting a contribution of peripheral knee joint BDNF/TrkB signalling in the maintenance of chronic OA joint pain support further investigation of the therapeutic potential of this target.
  • Remission vs low disease activity: function, quality of life and structural outcomes in the Early Rheumatoid Arthritis Study and Network

    Walsh, David A (Reumatology, 2020-06)
    Objectives: To examine associations between function, quality of life and structural outcomes in patients achieving remission vs low disease activity in early RA. Methods: Demographic, clinical and radiographic variables were collected at baseline and then annually from the Early Rheumatoid Arthritis Study (ERAS) and Early Rheumatoid Arthritis Network (ERAN) inception cohorts in routine care from 1986 to 2012. Disease activity was categorized: mean DAS28 score between years 1 and 5: remission [mean remission DAS (mRDAS) <2.6] or low [mean low DAS (mLDAS) 2.6-3.2]; sustained low/remission DAS28 (sLDAS/sRDAS) at years 1 and 2; and sustained Boolean remission (sBR) at years 1 and 2. Changes in HAQ and Short Form 36 Health Survey Questionnaire [SF-36; physical (PCS) and mental (MCS) component score]) and total Sharp van der Heijde (SvdH) scores for each disease activity category were modelled using multi-level models. Covariates included year of onset, age, gender and DMARD use at first visit. Results: Of 2701 patients, 562 (21%) were categorized mRDAS, 330 (12%) mLDAS, 279 (10%) sRDAS, 203 (7.5%) sLDAS and 93 (3%) sBR. Patients categorized as mRDAS had increasingly divergent improved HAQ, SF-36 PCS, MCS and total SvdH scores compared with mLDAS (P-values 0.001 to <0.0001, all time points). Patients categorized as sRDAS had better HAQ, SF-36 PCS and MCS scores (P-values 0.05 to <0.0001, all time points) and SvdH scores (P = 0.05, years 3-5) over sLDAS. sBR was associated with better HAQ, and SF-36 PCS and MCS scores over sLDAS (P-values 0.002 to <0.0001, all time points). Conclusion: These findings from routine care support ACR/EULAR guidelines that remission is a preferable goal over low disease activity in early RA.
  • Predictors of response to topical non-steroidal anti-inflammatory drugs in osteoarthritis: an individual patient data meta-analysis of randomised controlled trials

    Walsh, David A (Rheumatology, 2020-09)
    Objectives: To identify predictors of the specific (difference between treatment and placebo) and overall (change from baseline in treatment arm) treatment effects of topical NSAIDs in OA. Methods: Randomized controlled trials (RCTs) of topical NSAIDs in OA were identified through systematic literature searching and inquiry to pharmaceutical companies. The raw, de-identified data were analysed in one-stage individual patient data meta-analysis (IPD-MA). Negative values for treatment effects (0-100 scale) indicate pain reduction. Results: Of 63 eligible RCTs, 15 provided IPD (n = 1951 on topical NSAID), including 11 placebo-controlled RCTs (n = 1587 on topical NSAIDs, 1553 on placebo). Seven potential predictors of response were examined. Topical NSAIDs were superior to placebo [-6 (95% CI -9, -4)], with a small, but statistically significant greater effect in women than men [difference -4 (95% CI -8, -1)]. The overall treatment effect was 4-fold larger than the specific effect [-25 (95% CI -31, -19)] and increased with greater baseline pain severity (P < 0.001). No differences in efficacy were observed for age, BMI, features of inflammation, duration of complaints or radiographic OA severity. Conclusion: Topical NSAIDs are effective for OA pain relief. Greater overall pain relief in individuals with more baseline pain might be due to contextual and non-specific effects, including regression to the mean. Additional factors that have been linked either mechanistically or through empirical evidence to outcomes should be selected for inclusion across future RCTs in order to facilitate the identification of response predictors through IPD-MA.
  • Secular changes in the progression of clinical markers and patient reported outcomes in early rheumatoid arthritis

    Walsh, David A (Rheumatology, 2020-09)
    Objectives To examine secular trends in the progression of clinical and patient-reported outcomes in early RA. Methods A total of 2701 patients recruited to the Early Rheumatoid Arthritis Study or Early Rheumatoid Arthritis Network with year of diagnosis from 1986 to 2011. The 5-year progression rates for patients diagnosed at different points in time were modelled using mixed-effects regression; 1990, 2002 and 2010, were compared. Clinical markers of disease included the 28-joint count DAS and the ESR. Patient-reported markers included the HAQ, visual analogue scale of pain and global health, and the Short-Form 36. Results Statistically significant improvements in both 28-joint count DAS and ESR were seen over the 5 years in patients diagnosed with RA compared with those diagnosed earlier. By 5 years, 59% of patients with diagnosis in 2010 were estimated to reach low disease activity compared with 48% with diagnosis in 2002 and 32% with diagnosis in 1990. Whilst HAQ demonstrated statistically significant improvements, these improvements were small, with similar proportions of patients achieving HAQ scores of ≤1.0 by 5 years with a diagnosis in 1990 compared with 2010. Levels of the visual analogue scale and the Mental Component Scores of the Short-Form 36 indicated similar, statistically non-significant levels over the 5 years, irrespective of year diagnosed. Conclusion This study demonstrates improvements in inflammatory markers over time in early RA, in line with improved treatment strategies. These have not translated into similar improvements in patient-reported outcomes relating to either physical or mental health.
  • Brain perfusion patterns are altered in chronic knee pain: A spatial covariance analysis of arterial spin labelling MRI

    Walsh, David A (Pain, 202-06)
    Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity, for example, in postoperative pain after knee replacement. Other factors such as low mood, anxiety, and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain and 29 pain-free participants, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal component analysis of CBF identified 5 components that significantly discriminated chronic pain participants from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default mode, thalamus, and sensory regions. One component correlated positively with the pain sensitization score (r = 0.43, P = 0.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitization.
  • Patient Preferences for Osteoarthritis Pain and Chronic Low Back Pain Treatments in the United States: A Discrete-Choice Experiment

    Walsh, David A (Osteoarthritis and Cartilage, 2020-09)
    Objective: To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)-inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Methods: We used a discrete-choice experiment (DCE) to elicit preferences for attributes of OA and CLBP pharmaceutical treatments, and a best-worst scaling (BWS) exercise to further characterize the relative importance of treatment-related side-effect risks. The survey was completed online by 602 US residents with self-reported chronic, moderate-to-severe OA pain and/or CLBP who had tried, had contraindications for, or were unwilling to take currently available pharmaceutical therapies. In the DCE, respondents repeatedly chose between two hypothetical treatments defined by six attributes (symptom control; treatment-related risks of (1) severe joint problems, (2) heart attack, and (3) physical dependence; mode/frequency of administration; and cost). In the BWS exercise, respondents evaluated ten side-effect risks. Random-parameters logit models were estimated; conditional relative attribute importance, maximum acceptable risks, and willingness to pay were calculated. Results: The most important DCE attributes were improving symptom control (scaled conditional relative importance, 10.00) and reducing risk of physical dependence (6.99). The three most important BWS attributes were, in rank order, risks of stroke, physical dependence, and heart attack. Respondents were willing to accept a > 4% treatment-related risk of severe joint problems for even modest symptom improvement. Conclusion: A pharmaceutical treatment with a risk of severe joint problems was viewed as an acceptable alternative to other treatments with comparable efficacy but risks associated with NSAIDs or opioids.
  • Refining surgical models of osteoarthritis in mice and rats alters pain phenotype but not joint pathology

    Walsh, David A (PLoS One, 2020-09)
    TL]) or modified (MMTL left intact, transection of the coronary ligaments) DMM surgery, or sham surgery. Adult male Sprague Dawley rats (n = 76, weight 175-199g) underwent either modified meniscal transection (MMNX) surgery (transection of the medial meniscus whilst the medial collateral ligament is left intact) or sham surgery. Pain behaviours (weight bearing asymmetry [in mice and rats] and paw withdrawal thresholds [in rats]) were measured pre-surgery and weekly up to 16 weeks post-surgery. Post-mortem knee joints were scored for cartilage damage, synovitis, and osteophyte size. There was a significant increase in weight bearing asymmetry from 13 weeks following traditional, but not modified, DMM surgery when compared to sham operated mice. Both traditional and modified DMM surgery led to similar joint pathology. There was significant pain behaviour from 6 weeks following MMNX model compared to sham operated control rats. Synovitis was significant 4 weeks after MMNX surgery, whereas significant chondropathy was first evident 8 weeks post-surgery, compared to sham controls. Pain behaviour is not always present despite significant changes in medial tibial plateau cartilage damage and synovitis, reflecting the heterogeneity seen in human OA. The development of a slowly progressing surgical model of OA pain in the rat suggests that synovitis precedes pain behaviour and that chondropathy is evident later, providing the foundations for future mechanistic studies into the disease.
  • Association of subchondral bone marrow lesion localisation with weight bearing pain in people with knee osteoarthritis: data from the Osteoarthritis Initiative

    Walsh, David A (Arthritis Research & Therapy, 2021-01)
    Background Subchondral bone marrow lesions (BMLs) detected on MRI in knee osteoarthritis (OA) are associated with knee pain. The prevalence and progression of subchondral BMLs are increased by mechanical knee load. However, associations of subchondral BML location with weight-bearing knee pain are currently unknown. In this study, we aim to demonstrate associations of subchondral BML location and size with weight-bearing knee pain in knee OA. Methods We analyzed 1412 and 582 varus knees from cross-sectional and longitudinal Osteoarthritis Initiative datasets, respectively. BML scores were semi-quantitatively analyzed with the MRI Osteoarthritis Knee Score for 4 subchondral regions (median and lateral femorotibial, medial and lateral patellofemoral) and subspinous region. Weight-bearing and non-weight-bearing pain scores were derived from WOMAC pain items. Correlation and negative binomial regression models were used for analysis of associations between the BML scores and pain at baseline and changes in the BML scores and changes in pain after 24-month follow-up. Results Greater BML scores at medial femorotibial and lateral patellofemoral compartments were associated with greater weight-bearing pain scores, and statistical significance was retained after adjusting for BML scores at the other 4 joint compartments and other OA features, as well as for non-weight-bearing pain, age, sex, and body mass index (BMI) (medial femorotibial; B = 0.08, p = 0.02. patellofemoral; B = 0.13, p = 0.01). Subanalysis revealed that greater medial femorotibial BML scores were associated with greater pain on walking and standing (B = 0.11, p = 0.01, and B = 0.10, p = 0.04, respectively). Lateral patellofemoral BML scores were associated with pain on climbing, respectively (B = 0.14, p = 0.02). Increases or decreases over 24 months in BML score in the medial femorotibial compartment were significantly associated with increases or decreases in weight-bearing pain severity after adjusting for non-weight-bearing pain, age, sex, baseline weight-bearing pain, BMI, and BML at the other 4 joint compartments (B = 0.10, p = 0.01). Conclusions Subchondral BML size at the medial femorotibial joint compartment was specifically associated with the severity and the change in weight-bearing pain, independent of non-weight-bearing pain, in knee OA. Specific associations of weight-bearing pain with subchondral BMLs in weight-bearing compartments of the knee indicate that BMLs in subchondral bone contribute to biomechanically induced OA pain.

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