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.

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.

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.

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.

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.

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.

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.

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.

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.

FEBio finite element model of a pediatric cervical spine.

OBJECTIVE: The underlying biomechanical differences between the pediatric and adult cervical spine are incompletely understood. Computational spine modeling can address that knowledge gap. Using a computational method known as finite element modeling, the authors describe the creation and evaluation of a complete pediatric cervical spine model. METHODS: Using a thin-slice CT scan of the cervical spine from a 5-year-old boy, a 3D model was created for finite element analysis. The material properties and boundary and loading conditions were created and model analysis performed using open-source software. Because the precise material properties of the pediatric cervical spine are not known, a published parametric approach of scaling adult properties by 50%, 25%, and 10% was used. Each scaled finite element model (FEM) underwent two types of simulations for pediatric cadaver testing (axial tension and cardinal ranges of motion [ROMs]) to assess axial stiffness, ROM, and facet joint force (FJF). The authors evaluated the axial stiffness and flexion-extension ROM predicted by the model using previously published experimental measurements obtained from pediatric cadaveric tissues. RESULTS: In the axial tension simulation, the model with 50% adult ligamentous and annulus material properties predicted an axial stiffness of 49 N/mm, which corresponded with previously published data from similarly aged cadavers (46.1 ± 9.6 N/mm). In the flexion-extension simulation, the same 50% model predicted an ROM that was within the range of the similarly aged cohort of cadavers. The subaxial FJFs predicted by the model in extension, lateral bending, and axial rotation were in the range of 1-4 N and, as expected, tended to increase as the ligament and disc material properties decreased. CONCLUSIONS: A pediatric cervical spine FEM was created that accurately predicts axial tension and flexion-extension ROM when ligamentous and annulus material properties are reduced to 50% of published adult properties. This model shows promise for use in surgical simulation procedures and as a normal comparison for disease-specific FEMs.

Biomechanical effects of laminectomies in the human lumbar spine: a finite element study.

BACKGROUND CONTEXT: Previous studies have analyzed the effect of laminectomy on intervertebral disc (IVD), facet-joint-forces (FJF), and range of motion (ROM), while only two have specifically reported stresses at the pars interarticularis (PI) with posterior element resection. These studies have been performed utilizing a single subject, questioning their applications to a broader population. PURPOSE: We investigate the effect of graded PI resection in a three-dimensional manner on PI stress to provide surgical guidelines for avoidance of iatrogenic instability following lumbar laminectomy. Additionally, quantified FJF and IVD stresses can provide further insight into the development of adjacent segment disease. STUDY DESIGN: Biomechanical finite element (FE) method investigation of the lumbar spine. METHODS: FE models of the lumbar spine of three subjects were created using the open-source finite element software, FEBio. Single-level laminectomy, two-level laminectomy, and ventral-to-dorsal PI resection simulations were performed with varying degrees of PI resection from 0% to 75% of the native PI. These models were taken through cardinal ROM under standard loading conditions and PI stresses, FJF, IVD stresses, and ROM were analyzed. RESULTS: The three types of laminectomy simulated in this study showed a nonlinear increase in PI stress with increased bone resection. Axial rotation generated the most stress at the PI followed by flexion, extension and lateral bending. At 75% bone resection all three types of laminectomy produced PI stresses that were near the ultimate strength of human cortical bone during axial rotation. FJF decreased with increased bone resection for the three laminectomies simulated. This was most notable in axial rotation followed by extension and lateral bending. IVD stresses varied greatly between the nonsurgical models and likewise the effect of laminectomy on IVD stresses varied between subjects. ROM was mostly unaffected by the laminectomies performed in this study. CONCLUSIONS: Regarding the risk of iatrogenic spondylolisthesis, the combined results are sufficient evidence to suggest surgeons should be particularly cautious when PI resection exceeds 50% bone resection for all laminectomies included in this study. Lastly, the effects seen in FJF and IVD stresses indicate the degree to which the remainder of the spine must experience compensatory biomechanical changes as a result of the surgical intervention.

Febio finite element models of the human cervical spine.

Finite element (FE) analysis has proven to be useful when studying the biomechanics of the cervical spine. Although many FE studies of the cervical spine have been published, they typically develop their models using commercial software, making the sharing of models between researchers difficult. They also often model only one part of the cervical spine. The goal of this study was to develop and evaluate three FE models of the adult cervical spine using open-source software and to freely provide these models to the scientific community. The models were created from computed tomography scans of 26-, 59-, and 64-year old female subjects. These models were evaluated against previously published experimental and FE data. Despite the fact that all three models were assigned identical material properties and boundary conditions, there was notable variation in their biomechanical behavior. It was therefore apparent that these differences were the result of morphological differences between the models.

Finite element modeling to compare craniocervical motion in two age-matched pediatric patients without or with Down syndrome: implications for the role of bony geometry in craniocervical junction instability.

OBJECTIVE: Instability of the craniocervical junction (CCJ) is a well-known finding in patients with Down syndrome (DS); however, the relative contributions of bony morphology versus ligamentous laxity responsible for abnormal CCJ motion are unknown. Using finite element modeling, the authors of this study attempted to quantify those relative differences. METHODS: Two CCJ finite element models were created for age-matched pediatric patients, a patient with DS and a control without DS. Soft tissues and ligamentous structures were added based on bony landmarks from the CT scans. Ligament stiffness values were assigned using published adult ligament stiffness properties. Range of motion (ROM) testing determined that model behavior most closely matched pediatric cadaveric data when ligament stiffness values were scaled down to 25% of those found in adults. These values, along with those assigned to the other soft-tissue materials, were identical for each model to ensure that the only variable between the two was the bone morphology. The finite element models were then subjected to three types of simulations to assess ROM, anterior-posterior (AP) translation displacement, and axial tension. RESULTS: The DS model exhibited more laxity than the normal model at all levels for all of the cardinal ROMs and AP translation. For the CCJ, the flexion-extension, lateral bending, axial rotation, and AP translation values predicted by the DS model were 40.7%, 52.1%, 26.1%, and 39.8% higher, respectively, than those for the normal model. When simulating axial tension, the soft-tissue structural stiffness values predicted by the DS and normal models were nearly identical. CONCLUSIONS: The increased laxity exhibited by the DS model in the cardinal ROMs and AP translation, along with the nearly identical soft-tissue structural stiffness values exhibited in axial tension, calls into question the previously held notion that ligamentous laxity is the sole explanation for craniocervical instability in DS.