Treat-to-target urate-lowering therapy and hospitalizations for gout: results from a nationwide cohort study in England.

OBJECTIVE: To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout. METHODS: Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalizations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalizations for gout. RESULTS: Of 292 270 people with incident gout, 7719 (2.64%) had one or more hospitalizations for gout, with an incidence rate of 4.64 hospitalizations per 1000 person-years (95% CI 4.54, 4.73). There was an associated increased risk of hospitalizations within the first 6 months after ULT initiation, when compared with people who did not initiate ULT [adjusted Hazard Ratio (aHR) 4.54; 95% CI 3.70, 5.58; P < 0.001]. Hospitalizations did not differ significantly between people prescribed vs not prescribed colchicine prophylaxis in fully adjusted models. From 12 months after initiation, ULT associated with a reduced risk of hospitalizations (aHR 0.77; 95% CI 0.71, 0.83; P < 0.001). In ULT initiators, attainment of a serum urate <360 micromol/l within 12 months of initiation associated with a reduced risk of hospitalizations (aHR 0.57; 95% CI 0.49, 0.67; P < 0.001) when compared with people initiating ULT but not attaining this target. CONCLUSION: ULT associates with an increased risk of hospitalizations within the first 6 months of initiation but reduces hospitalizations in the long term, particularly when serum urate targets are achieved.

The epidemiology of psoriatic arthritis in the UK: a health intelligence analysis of UK Primary Care Electronic Health Records 1991-2020.

OBJECTIVES: Epidemiological estimates of psoriatic arthritis (PsA) underpin the provision of healthcare, research, and the work of government, charities and patient organizations. Methodological problems impacting prior estimates include small sample sizes, incomplete case ascertainment, and representativeness. We developed a statistical modelling strategy to provide contemporary prevalence and incidence estimates of PsA from 1991 to 2020 in the UK. METHODS: Data from Clinical Practice Research Datalink (CPRD) were used to identify cases of PsA between 1st January 1991 and 31st December 2020. To optimize ascertainment, we identified cases of Definite PsA (≥1 Read code for PsA) and Probable PsA (satisfied a bespoke algorithm). Standardized annual rates were calculated using Bayesian multilevel regression with post-stratification to account for systematic differences between CPRD data and the UK population, based on age, sex, socioeconomic status and region of residence. RESULTS: A total of 26293 recorded PsA cases (all definitions) were identified within the study window (77.9% Definite PsA). Between 1991 and 2020 the standardized prevalence of PsA increased twelve-fold from 0.03 to 0.37. The standardized incidence of PsA per 100,000 person years increased from 8.97 in 1991 to 15.08 in 2020, an almost 2-fold increase. Over time, rates were similar between the sexes, and across socioeconomic status. Rates were strongly associated with age, and consistently highest in Northern Ireland. CONCLUSION: The prevalence and incidence of PsA recorded in primary care has increased over the last three decades. The modelling strategy presented can be used to provide contemporary prevalence estimates for musculoskeletal disease using routinely collected primary care data.

Implementing treat-to-target urate-lowering therapy during hospitalisations for gout flares.

OBJECTIVES: To evaluate a strategy designed to optimise care and increase uptake of urate-lowering therapy (ULT) during hospitalisations for gout flares. METHODS: We conducted a prospective cohort study to evaluate a strategy that combined optimal in-hospital gout management with a nurse-led, follow-up appointment, followed by handover to primary care. Outcomes, including ULT initiation, urate target attainment, and re-hospitalisation rates, were compared between patients hospitalised for flares in the 12 months post-implementation and a retrospective cohort of hospitalised patients from 12 months pre-implementation. RESULTS: 119 and 108 patients, respectively, were hospitalised for gout flares in the 12 months pre- and post-implementation. For patients with 6-month follow-up data available (n = 94 and n = 97, respectively), the proportion newly initiated on ULT increased from 49.2% pre-implementation to 92.3% post-implementation (age/sex-adjusted odds ratio (aOR) 11.5; 95% confidence interval (CI) 4.36-30.5; p < 0.001). After implementation, more patients achieved a serum urate ≤360 micromol/L within 6 months of discharge (10.6% pre-implementation vs. 26.8% post-implementation; aOR 3.04; 95% CI 1.36-6.78; p = 0.007). The proportion of patients re-hospitalised for flares was 14.9% pre-implementation vs. 9.3% post-implementation (aOR 0.53, 95% CI 0.22 to 1.32; p = 0.18). CONCLUSION: Over 90% of patients were initiated on ULT after implementing a strategy to optimise hospital gout care. Despite increased initiation of ULT during flares, recurrent hospitalisations were not more frequent following implementation. Significant relative improvements in urate target attainment were observed post-implementation; however, for the majority of hospitalised gout patients to achieve urate targets, closer primary-secondary care integration is still needed.

Natural mineral fibers: conducting inhalation toxicology studies-part B: development of a nose-only exposure system for repeat-exposure in vivo study of Libby amphibole aerosol.

BACKGROUND: Exposure to asbestos is associated with malignant and nonmalignant respiratory disease. To strengthen the scientific basis for risk assessment on fibers, the National Institute of Environmental Health Sciences (NIEHS) has initiated a series of studies to address fundamental questions on the toxicology of naturally occurring asbestos and related mineral fibers after inhalation exposure. A prototype nose-only exposure system was previously developed and validated. The prototype system was expanded to a large-scale exposure system in this study for conducting subsequent in vivo rodent inhalation studies of Libby amphibole (LA) 2007, selected as a model fiber. RESULTS: The exposure system consisting of six exposure carousels was able to independently deliver stable LA 2007 aerosol to individual carousels at target concentrations of 0 (control group), 0.1, 0.3, 1, 3, or 10 mg/m3. A single aerosol generator was used to provide aerosol to all carousels to ensure that exposure atmospheres were chemically and physically similar, with aerosol concentration as the only major variable among the carousels. Transmission electron microscopy (TEM) coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis of aerosol samples collected at the exposure ports indicated the fiber dimensions, chemical composition, and mineralogy were equivalent across exposure carousels and were comparable to the bulk LA 2007 material. CONCLUSION: The exposure system developed is ready for use in conducting nose-only inhalation toxicity studies of LA 2007 in rats. The exposure system is anticipated to have applicability for the inhalation toxicity evaluation of other natural mineral fibers of concern.

Natural mineral fibers: conducting inhalation toxicology studies - part A: Libby Amphibole aerosol generation and characterization method development.

BACKGROUND: Asbestos has been classified as a human carcinogen, and exposure may increase the risk of diseases associated with impaired respiratory function. As the range of health effects and airborne concentrations that result in health effects across asbestos-related natural mineral fiber types are not fully understood, the National Institute of Environmental Health Sciences has established a series of research studies to characterize hazards of natural mineral fibers after inhalation exposure. This paper presents the method development work of this research project. RESULTS: A prototype nose-only exposure system was fabricated to explore the feasibility of generating natural mineral fiber aerosol for in vivo inhalation toxicity studies. The prototype system consisted of a slide bar aerosol generator, a distribution/delivery system and an exposure carousel. Characterization tests conducted using Libby Amphibole 2007 (LA 2007) demonstrated the prototype system delivered stable and controllable aerosol concentration to the exposure carousel. Transmission electron microscopy (TEM) analysis of aerosol samples collected at the exposure port showed the average fiber length and width were comparable to the bulk LA 2007. TEM coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis further confirmed fibers from the aerosol samples were consistent with the bulk LA 2007 chemically and physically. CONCLUSIONS: Characterization of the prototype system demonstrated feasibility of generating LA 2007 fiber aerosols appropriate for in vivo inhalation toxicity studies. The methods developed in this study are suitable to apply to a multiple-carousel exposure system for a rat inhalation toxicity testing using LA 2007.

Validation of the Musculoskeletal Health Questionnaire in inflammatory arthritis: a psychometric evaluation.

Objectives: The Musculoskeletal Health Questionnaire (MSK-HQ) is a recently developed Patient Reported Outcome Measure for use across patients with musculoskeletal conditions. This study provides a validation of the MSK-HQ examining construct validity and reliability in inflammatory arthritis. Methods: 287 adults with inflammatory arthritis completed the MSK-HQ and other Patient Reported Outcome Measures at baseline and after 3 months. Construct validity was assessed using item response theory methods. Concurrent validity was considered in relation to the HAQ and EuroQol-5D in all patients, as well as the RA Impact of Disease (RAID), PsA Impact of Disease scales, and AS Quality of Life Questionnaire (ASQoL) in disease subtypes. Results: The MSK-HQ was approximately normally distributed with no evidence of floor or ceiling effects. A unidimensional structure was confirmed. Two items were less weakly related to the latent musculoskeletal health variable, providing some evidence of multidimensionality. Reliability was high (α = 0.93). The total score correlated highly with the HAQ (r = -0.81) and EuroQol-5D index (r = 0.80) in all patients, RAID in RA patients (r = -0.88), PsA Impact of Disease in PsA patients (r = -0.88), and ASQoL in AS patients (r = -0.86). Test-retest reliability was high (rICC = 0.73). Conclusion: This study provides evidence for the validity and reliability of the MSK-HQ in people with inflammatory arthritis. The major advantage of the MSK-HQ is that it is not disease specific and has high content validity in rheumatological conditions. The MSK-HQ score will be of value in clinical rheumatology practice, providing a measure that can be used across disease areas.

Prevalence of unmet needs for spasticity management in care home residents in the East Midlands, United Kingdom: a cross-sectional observational study.

OBJECTIVE: To establish the prevalence of unmet need for spasticity management in care home residents in two counties of the United Kingdom. DESIGN: Cross-sectional observational study with a six-month follow-up arm for participants with identified unmet needs. SETTING: 22 care homes in Derbyshire and Nottinghamshire. SUBJECTS: 60 care home residents with upper motor neuron syndrome-related spasticity. INTERVENTIONS: No intervention. When unmet needs around spasticity management were identified, the participant's general practitioner was advised of these in writing. MAIN MEASURES: Resistance to Passive Movement Scale to assess spasticity; recording of (a) the presence of factors which may aggravate spasticity, (b) potential complications of spasticity, (c) spasticity-related needs and (d) current interventions to manage spasticity. Two assessors judged the presence or absence of needs for spasticity management and whether these needs were met by current care. RESULTS: Out of 60 participants, 14 had no spasticity-related needs; 46 had spasticity-related needs; 11 had needs which were being met by current care and 35 participants had spasticity-related needs at baseline which were not being met by their current care. These were most frequently related to the risk of contracture development or problems with skin hygiene or integrity in the upper limb. In total, 6 participants had one or more pressure sores and 35 participants had one or more established joint contractures. A total of 31 participants were available for follow-up. Informing general practitioners of unmet needs resulted in no change to spasticity management in 23/31 cases. CONCLUSION: Care home residents in this study had high levels of unmet need for spasticity management.

Evaluation of a low-cost staining method for improved visualization of sweet potato whitefly (Bemisia tabaci) eggs on multiple crop plant species.

BACKGROUND: The sweet potato whitefly (Bemisia tabaci) is a globally important insect pest that damages crops through direct feeding and by transmitting viruses. Current B. tabaci management revolves around the use of insecticides, which are economically and environmentally costly. Host plant resistance is a sustainable option to reduce the impact of whiteflies, but progress in deploying resistance in crops has been slow. A major obstacle is the high cost and low throughput of screening plants for B. tabaci resistance. Oviposition rate is a popular metric for host plant resistance to B. tabaci because it does not require tracking insect development through the entire life cycle, but accurate quantification is still limited by difficulties in observing B. tabaci eggs, which are microscopic and translucent. The goal of our study was to improve quantification of B. tabaci eggs on several important crop species: cassava, cowpea, melon, sweet potato and tomato. RESULTS: We tested a selective staining process originally developed for leafhopper eggs: submerging the leaves in McBryde's stain (acetic acid, ethanol, 0.2% aqueous acid Fuchsin, water; 20:19:2:1) for three days, followed by clearing under heat and pressure for 15 min in clearing solution (LGW; lactic acid, glycerol, water; 17:20:23). With a less experienced individual counting the eggs, B. tabaci egg counts increased after staining across all five crops. With a more experienced counter, egg counts increased after staining on melons, tomatoes, and cowpeas. For all five crops, there was significantly greater agreement on egg counts across the two counting individuals after the staining process. The staining method worked particularly well on melon, where egg counts universally increased after staining for both counting individuals. CONCLUSIONS: Selective staining aids visualization of B. tabaci eggs across multiple crop plants, particularly species where leaf morphological features obscure eggs, such as melons and tomatoes. This method is broadly applicable to research questions requiring accurate quantification of B. tabaci eggs, including phenotyping for B. tabaci resistance.

Cosimulation of the index finger extensor apparatus with finite element and musculoskeletal models.

Musculoskeletal modeling has been effective for simulating dexterity and exploring the consequences of disability. While previous approaches have examined motor function using multibody dynamics, existing musculoskeletal models of the hand and fingers have difficulty simulating soft tissue such as the extensor mechanism of the fingers, which remains underexplored. To investigate the extensor mechanism and its impact on finger motor function, we developed a finite element model of the index finger extensor mechanism and a cosimulation method that combines the finite element model with a multibody dynamic model. The finite element model and cosimulation were validated through comparison with experimentally derived tissue strains and fingertip endpoint forces respectively. Tissue strains predicted by the finite element model were consistent with the experimentally observed strains of the 9 postures tested in cadaver specimens. Fingertip endpoint forces predicted using the cosimulation were well aligned in both force (difference within 0.60 N) and direction (difference within 30°with experimental results. Sensitivity of the extensor mechanism to changes in modulus and adhesion configuration were evaluated for ± 50% of experimental moduli, presence of the radial and ulnar adhesions, and joint capsule. Simulated strains and endpoint forces were found to be minimally sensitive to alterations in moduli and adhesions. These results are promising and demonstrate the ability of the cosimulation to predict global behavior of the extensor mechanism, while enabling measurement of stresses and strains within the structure itself. This model could be used in the future to predict the outcomes for different surgical repairs of the extensor mechanism.

Giant cell arteritis presenting with unilateral sixth nerve palsy.

Giant cell arteritis (GCA) usually presents with headache, scalp tenderness and raised inflammatory markers. GCA presenting with a clinically evident cranial nerve palsy is rare and may result in a delayed or missed diagnosis if not suspected. We present the rare case of a woman in her 70s with histologically confirmed GCA presenting with a unilateral sixth nerve palsy, which responded to treatment with high-dose oral prednisolone.

Piloting a new model of personalised care for people with fibromyalgia in primary care with secondary care multidisciplinary support.

OBJECTIVE: An estimated 5.5 million people in England have high-impact chronic pain, which is severe pain associated with significant disability. Current models of healthcare often fail to address their broad range of symptoms and address their complex non-medical needs. METHODS: A pilot project was designed with the aim of improving the quality of care and addressing unmet needs of patients high-impact musculoskeletal (MSK) pain through providing a personalised approach to their pain and wider psychosocial needs. The model comprised a longer initial appointment with a general practitioner, a later follow-appointment, and support of the multidisciplinary team (MDT) (informally and through a formal MDT meeting) with both primary care clinicians and specialists based in secondary care. RESULTS: Forty six patients were seen using this model, with prominent themes of consultations including self-management, social needs, mental health and understanding their diagnosis. Evaluation of the pilot demonstrated improvements in MSK and non-MSK symptoms, together with improved patient confidence in self-management and knowledge and understanding of their condition. Multidisciplinary working proved to be invaluable in addressing patients' wider needs but also upskilling and supporting primary care clinicians. Primary care staff also found it to be a satisfying way to care for patients, and developed increasing skills and confidence in supporting patients with chronic pain. CONCLUSION: This model of care appears to be an effective way to help primary care teams to provide more holistic personalised care to a group of patients who are highly complex and so often forgotten.

Ensuring fair, safe, and interpretable artificial intelligence-based prediction tools in a real-world oncological setting.

BACKGROUND: Cancer patients often experience treatment-related symptoms which, if uncontrolled, may require emergency department admission. We developed models identifying breast or genitourinary cancer patients at the risk of attending emergency department (ED) within 30-days and demonstrated the development, validation, and proactive approach to in-production monitoring of an artificial intelligence-based predictive model during a 3-month simulated deployment at a cancer hospital in the United States. METHODS: We used routinely-collected electronic health record data to develop our predictive models. We evaluated models including a variational autoencoder k-nearest neighbors algorithm (VAE-kNN) and model behaviors with a sample containing 84,138 observations from 28,369 patients. We assessed the model during a 77-day production period exposure to live data using a proactively monitoring process with predefined metrics. RESULTS: Performance of the VAE-kNN algorithm is exceptional (Area under the receiver-operating characteristics, AUC = 0.80) and remains stable across demographic and disease groups over the production period (AUC 0.74-0.82). We can detect issues in data feeds using our monitoring process to create immediate insights into future model performance. CONCLUSIONS: Our algorithm demonstrates exceptional performance at predicting risk of 30-day ED visits. We confirm that model outputs are equitable and stable over time using a proactive monitoring approach.

Patients with cancer often need to visit the hospital emergency department (ED), for example due to treatment side effects. Predicting these visits might help us to better manage the treatment of patients who are at risk. Here, we develop a computer-based tool to identify patients with cancer who are at risk of an unplanned ED visit within 30 days. We use health record data from over 28,000 patients who had visited a single cancer hospital in the US to create and test the model. The model performed well and was consistent across different demographic and disease groups. We monitor model behavior over time and show that it is stable. The approach we take to monitoring model performance may be a particularly useful contribution toward implementing similar predictive models in the clinic and checking that they are performing as intended.

FEBio: finite elements for biomechanics.

In the field of computational biomechanics, investigators have primarily used commercial software that is neither geared toward biological applications nor sufficiently flexible to follow the latest developments in the field. This lack of a tailored software environment has hampered research progress, as well as dissemination of models and results. To address these issues, we developed the FEBio software suite (http://mrl.sci.utah.edu/software/febio), a nonlinear implicit finite element (FE) framework, designed specifically for analysis in computational solid biomechanics. This paper provides an overview of the theoretical basis of FEBio and its main features. FEBio offers modeling scenarios, constitutive models, and boundary conditions, which are relevant to numerous applications in biomechanics. The open-source FEBio software is written in C++, with particular attention to scalar and parallel performance on modern computer architectures. Software verification is a large part of the development and maintenance of FEBio, and to demonstrate the general approach, the description and results of several problems from the FEBio Verification Suite are presented and compared to analytical solutions or results from other established and verified FE codes. An additional simulation is described that illustrates the application of FEBio to a research problem in biomechanics. Together with the pre- and postprocessing software PREVIEW and POSTVIEW, FEBio provides a tailored solution for research and development in computational biomechanics.

Quantifying the population burden of musculoskeletal disorders, including impact on sickness absence: analysis of national Scottish data.

Objectives: Musculoskeletal disorders (MSDs) account for the greatest burden of years lived with disability globally. To prevent disability, good-quality services need to be commissioned, appropriate for local need. We analysed data collected systematically from a new musculoskeletal service serving 70% of the population of Scotland to evaluate: age- and sex-specific occurrence; anatomical distribution; and impact and effect on work ability. Methods: A new centralized telephone-based triage for people with musculoskeletal disorders was set up in Scotland in 2015. Available to most of the population aged >16 years (>3 million people), data were collected systematically into a database detailing: anatomical site, nature of onset, duration, impact/risk (modified STarT score), deprivation level and, for those in employment, sickness absence. Results: Data were available from 219 314 new callers, 2015-18. Calls were more frequently from women (60%), increased with age until the eighth decade, and 66% reported symptoms that had been present for >6 weeks. Callers were more likely to be living in more deprived areas in each age band between 20 and 64 years and tended to have higher-impact symptoms. The majority (53%) of callers were in employment, and 19% of these were off sick because of their symptoms. Sickness absence was more common among those with highest impact/risk scores from deprived areas with more acute symptoms. Discussion: Large-scale systematic data collection for MSDs emphasizes the size and impact of the burden among adults aged >16 years. A socio-economic gradient is evident in terms of prevalence and impact of MSDs, particularly for sickness absence.

Management of gout following 2016/2017 European (EULAR) and British (BSR) guidelines: An interrupted time-series analysis in the United Kingdom.

Background: Following studies reporting sub-optimal gout management, European (EULAR) and British (BSR) guidelines were updated to encourage the prescription of urate-lowering therapy (ULT) with a treat-to-target approach. We investigated whether ULT initiation and urate target attainment has improved following publication of these guidelines, and assessed predictors of these outcomes. Methods: We used the Clinical Practice Research Datalink to assess attainment of the following outcomes in people (n = 129,972) with index gout diagnoses in the UK from 2004-2020: i) initiation of ULT; ii) serum urate ≤360 µmol/L and ≤300 µmol/L; iii) treat-to-target urate monitoring. Interrupted time-series analyses were used to compare trends in outcomes before and after updated EULAR and BSR management guidelines, published in 2016 and 2017, respectively. Predictors of ULT initiation and urate target attainment were modelled using logistic regression and Cox proportional hazards. Findings: 37,529 (28.9%) of 129,972 people with newly-diagnosed gout had ULT initiated within 12 months. ULT initiation improved modestly over the study period, from 26.8% for those diagnosed in 2004 to 36.6% in 2019 and 34.7% in 2020. Of people diagnosed in 2020 with a serum urate performed within 12 months, 17.1% attained a urate ≤300 µmol/L, while 36.0% attained a urate ≤360 µmol/L. 18.9% received treat-to-target urate monitoring. No significant improvements in ULT initiation or urate target attainment were observed after updated BSR or EULAR management guidance, relative to before. Comorbidities, including chronic kidney disease (CKD), heart failure and obesity, and diuretic use associated with increased odds of ULT initiation but decreased odds of attaining urate targets within 12 months: CKD (adjusted OR 1.61 for ULT initiation, 95% CI 1.55 to 1.67; adjusted OR 0.51 for urate ≤300 µmol/L, 95% CI 0.48 to 0.55; both p < 0.001); heart failure (adjusted OR 1.56 for ULT initiation, 95% CI 1.48 to 1.64; adjusted OR 0.85 for urate ≤300 µmol/L, 95% CI 0.76 to 0.95; both p < 0.001); obesity (adjusted OR 1.32 for ULT initiation, 95% CI 1.29 to 1.36; adjusted OR 0.61 for urate ≤300 µmol/L, 95% CI 0.58 to 0.65; both p < 0.001); and diuretic use (adjusted OR 1.49 for ULT initiation, 95% CI 1.44 to 1.55; adjusted OR 0.61 for urate ≤300 µmol/L, 95% CI 0.57 to 0.66; both p < 0.001). Interpretation: Initiation of ULT and attainment of urate targets remain poor for people diagnosed with gout in the UK, despite updated management guidelines. If the evidence-practice gap in gout management is to be bridged, strategies to implement best practice care are needed. Funding: National Institute for Health Research.

Glis1 and oxaloacetate in nucleus pulposus stromal cell somatic reprogramming and survival.

Regenerative medicine aims to repair degenerate tissue through cell refurbishment with minimally invasive procedures. Adipose tissue (FAT)-derived stem or stromal cells are a convenient autologous choice for many regenerative cell therapy approaches. The intervertebral disc (IVD) is a suitable target. Comprised of an inner nucleus pulposus (NP) and an outer annulus fibrosus (AF), the degeneration of the IVD through trauma or aging presents a substantial socio-economic burden worldwide. The avascular nature of the mature NP forces cells to reside in a unique environment with increased lactate levels, conditions that pose a challenge to cell-based therapies. We assessed adipose and IVD tissue-derived stromal cells through in vitro transcriptome analysis in 2D and 3D culture and suggested that the transcription factor Glis1 and metabolite oxaloacetic acid (OAA) could provide NP cells with survival tools for the harsh niche conditions in the IVD.