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Long-Term Safety of Risankizumab in Patients with Psoriatic Disease: A Comprehensive Analysis from Clinical Trials.
INTRODUCTION: Risankizumab has demonstrated a favourable safety profile in patients with psoriatic disease (moderate-to-severe psoriasis [PsO] and psoriatic arthritis [PsA]). We evaluated the long-term safety of risankizumab in psoriatic disease. METHODS: Long-term safety was evaluated by analysing data from 20 (phase 1-4) clinical trials for plaque PsO and four (phase 2-3) trials for PsA. Treatment-emergent adverse events (TEAEs) and AEs in areas of special interest were reported among patients receiving ≥ 1 dose of risankizumab. Exposure-adjusted event rates were presented as events (E) per 100 patient-years (PY). RESULTS: The long-term safety data analyses included 3658 patients with PsO (13,329.3 PY) and 1542 patients with PsA (3803.0 PY). The median (range) treatment duration for patients with PsO and PsA was 4.1 (0.2-8.8) years and 2.8 (0.2-4.0) years, respectively. In the PsO population, rates of TEAEs, serious AEs and AEs leading to discontinuation were 145.5 E/100 PY, 7.4 E/100 PY and 1.9 E/100 PY, respectively; in the PsA population, these rates were 142.6 E/100 PY, 8.6 E/100 PY, and 1.8 E/100 PY, respectively. The rates of serious infections (excluding COVID-19-related infections) in the PsO and PsA populations were 1.2 and 1.4 E/100 PY, respectively. The rates of opportunistic infections (excluding tuberculosis and herpes zoster) were low (
Exploring cellular changes in ruptured human quadriceps tendons at single-cell resolution.
Tendon ruptures in humans have often been studied during the chronic phase of injury, particularly in the context of rotator cuff disease. However, the early response to acute tendon ruptures remains less investigated. Quadriceps tendons, which require prompt surgical treatment, offer a model to investigate this early response. Therefore, this study aimed to explore the early cellular changes in ruptured compared to healthy human quadriceps tendons. Quadriceps tendon samples were collected from patients undergoing fracture repair (healthy) or tendon repair surgery (collected 7-8 days post-injury). Nuclei were isolated for single-nucleus RNA sequencing, and comprehensive transcriptomic analysis was conducted. The transcriptomes of 12,808 nuclei (7268 from healthy and 5540 from ruptured quadriceps tendons) were profiled, revealing 12 major cell types and several cell subtypes and states. Rupture samples showed increased expression of genes related to extracellular matrix organisation and cell cycle signalling, and a decrease in expression of genes in lipid metabolism pathways. These changes were predominantly driven by gene expression changes in the fibroblast, vascular endothelial cell (VEC), mural cell, and macrophage populations: fibroblasts shift to an activated phenotype upon rupture and there is an increase in the proportion of capillary and dividing VECs. A diverse immune environment was observed, with a shift from homeostatic to activated macrophages following rupture. Cell-cell interactions increased in number and diversity in rupture, and primarily involved fibroblast and VEC populations. Collectively, this transcriptomic analysis suggests that fibroblasts and endothelial cells are key orchestrators of the early injury response within ruptured quadriceps tendon. KEY POINTS: Tendon ruptures in humans have regularly been studied during the chronic phase of injury, but less is known about the early injury response after acute tendon ruptures. This study explored the early cellular changes in ruptured compared to healthy human quadriceps tendons at single-cell resolution. Fibroblasts and endothelial cells seem to be the key orchestrators of the early injury response within ruptured quadriceps tendon. Therefore, these cell types are obvious targets for interventions to enhance tendon healing. Overall, this study highlights that the development of more effective therapeutic options for tendon injury requires better understanding of the cellular, extracellular, and mechanical landscape of tendon tissue.
Practical guidance on the prevention and management of infection in multiple myeloma patients: A case-based approach.
The risk of infection in multiple myeloma patients is significant, due to immune dysfunction secondary to myeloma, immunosenescence and age-related comorbidities, given the elderly myeloma patient demographic. Newer treatments, despite providing unprecedented improvements in disease-control, have further elevated infection risk. This risk is so substantial that we are approaching a period where a subset of older myeloma patients may be more likely to die secondary to infectious complications imposed by redirected T-cell therapy rather than from myeloma. As a result, it is essential to provide myeloma patients with the appropriate prophylaxis and monitoring against infection. In this review, we discuss disease-related, patient-related and treatment-related reasons for the increased infection risk in myeloma patients, and how to both prevent and manage this risk through creating a dynamic, infection prevention plan that is personalised to the individual patient.
Medial unicompartmental knee arthroplasty in the ACL-deficient knee.
Symptomatic osteoarthritis (OA) of the knee develops often in association with anterior cruciate ligament (ACL) deficiency. Two distinct pathologies should be recognised while considering treatment options in patients with end-stage medial compartment OA and ACL deficiency. Patients with primary ACL deficiency (usually traumatic ACL rupture) can develop secondary OA (typically presenting with symptoms of instability and pain) and these patients are typically young and active. Patients with primary end stage medial compartment OA can develop secondary ACL deficiency (usually degenerate ACL rupture) and these patients tend to be older. Treatment options in either of these patient groups include arthroscopic debridement, reconstruction of the ACL, high tibial osteotomy (HTO) with or without ACL reconstruction, unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). General opinion is that a functionally intact ACL is a fundamental prerequisite to perform a UKA. This is because previous reports showed higher failure rates when ACL was deficient, probably secondary to wear and tibial loosening. Nevertheless in some cases of ACL deficiency with end-stage medial compartment OA, UKA has been performed in isolation and recent papers confirm good short- to mid-term outcome without increased risk of implant failure. Shorter hospital stay, fewer blood transfusions, faster recovery and significantly lower risk of developing major complications like death, myocardial infarction, stroke, deep vein thrombosis (as compared to TKA) make the UKA an attractive option, especially in the older patients. On the other hand, younger patients with higher functional demands are likely to benefit from a simultaneous or staged ACL reconstruction in addition to UKA to regain knee stability. These procedures tend to be technically demanding. The main aim of this review was to provide a synopsis of the existing literature and outline an evidence-based treatment algorithm.
Radiological outcomes following surgical fixation with wires versus moulded cast for patients with a dorsally displaced fracture of the distal radius: a radiographic analysis from the DRAFFT2 trial.
AIMS: The primary aim of this study was to report the radiological outcomes of patients with a dorsally displaced distal radius fracture who were randomized to a moulded cast or surgical fixation with wires following manipulation and closed reduction of their fracture. The secondary aim was to correlate radiological outcomes with patient-reported outcome measures (PROMs) in the year following injury. METHODS: Participants were recruited as part of DRAFFT2, a UK multicentre clinical trial. Participants were aged 16 years or over with a dorsally displaced distal radius fracture, and were eligible for the trial if they needed a manipulation of their fracture, as recommended by their treating surgeon. Participants were randomly allocated on a 1:1 ratio to moulded cast or Kirschner wires after manipulation of the fracture in the operating theatre. Standard posteroanterior and lateral radiographs were performed in the radiology department of participating centres at the time of the patient's initial assessment in the emergency department and six weeks postoperatively. Intraoperative fluoroscopic images taken at the time of fracture reduction were also assessed. RESULTS: Patients treated with surgical fixation with wires had less dorsal angulation of the radius versus those treated in a moulded cast at six weeks after manipulation of the fracture; the mean difference of -4.13° was statistically significant (95% confidence interval 5.82 to -2.45). There was no evidence of a difference in radial shortening. However, there was no correlation between these radiological measurements and PROMs at any timepoint in the 12 months post-injury. CONCLUSION: For patients with a dorsally displaced distal radius fracture treated with a closed manipulation, surgical fixation with wires leads to less dorsal angulation on radiographs at six weeks compared with patients treated in a moulded plaster cast alone. However, the difference in dorsal angulation was small and did not correlate with patient-reported pain and function.
A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
Differential item functioning between English, German, and Spanish PROMIS® physical function ceiling items.
PURPOSE: We investigated the validity of the German and Spanish translations of 35 new high functioning items added to the Patient Reported Outcomes Measurement Information System (PROMIS®) Physical Function item bank 2.0. We assessed differential item functioning (DIF) between three general population samples from Argentina, Germany, and the United States. METHODS: PROMIS Physical Function data was collected in online panels from 3601 individuals (mean age, 41.6 years old; range, 18-88 years; 53.7% female). Of these, 1001 participants completed the Spanish version, 1000 completed the German version, and 1600 completed the English version. DIF was assessed by a multiverse analysis that systematically varied analytic choices across the entire range of plausible options within the logistic ordinal regression framework. RESULTS: Translated items generally met the assumptions of unidimensionality, monotonicity, and local independence. The 272 different analyses suggest consistent DIF between languages in four items. Test characteristic curves suggested that the magnitude and impact of DIF on the test scores were negligible for all items at the test level. After correcting for potential DIF, we observed greater scoring for physical functioning in Argentina compared to the US, Cohen's d = 0.25, [0.17, 0.33], and Argentina compared to Germany, Cohen's d = 0.23, [0.15, 0.32]. CONCLUSIONS: Our findings support the universal applicability of PROMIS Physical Function items across general populations in Argentina, Germany, and the U.S. The sensitivity analyses indicate that the identification of DIF items was robust for different data analytic decisions. Multiverse analysis is a promising approach to address lack of clear cutoffs in DIF identification.
Recovery of Comfort and Capability After Upper Extremity Fracture Is Predominantly Associated With Mindset: A Longitudinal Cohort From the United Kingdom.
OBJECTIVES: To determine the relative influence of mindset and fracture severity on 9-month recovery trajectories of pain and capability after upper extremity fractures. DESIGN: Secondary use of longitudinal data. SETTING: Single Level-1 trauma center in Oxford, United Kingdom. PATIENT SELECTION: English-speaking adults with isolated proximal humerus, elbow, or distal radius fracture managed operatively or nonoperatively were included, and those with multiple fractures or cognitive deficit were excluded. OUTCOME MEASURES AND COMPARISONS: Incapability (Quick-DASH) and pain intensity (11-point rating scale) were measured at baseline, 2-4 weeks, and 6-9 months after injury. Cluster analysis was used to identify statistical groupings of mindset (PROMIS Depression and Anxiety, Pain Catastrophizing Scale, and Tampa Scale for Kinesiophobia) and fracture severity (low/moderate/high based on OTA/AO classification). The recovery trajectories of incapability and pain intensity for each mindset grouping were assessed, accounting for various fracture-related aspects. RESULTS: Among 703 included patients (age 59 ± 21 years, 66% women, 16% high-energy injury), 4 statistical groupings with escalating levels of distress and unhelpful thoughts were identified (fracture severity was omitted considering it had no differentiating effect). Groups with less healthy mindset had a worse baseline incapability (group 2: β = 4.1, 3: β = 7.5, and 4: β = 17) and pain intensity (group 3: β = 0.70 and 4: β = 1.4) (P < 0.01). Higher fracture severity (β = 4.5), high-energy injury (β = 4.0), and nerve palsy (β = 8.1) were associated with worse baseline incapability (P < 0.01), and high-energy injury (β = 0.62) and nerve palsy (β = 0.76) with worse baseline pain intensity (P < 0.01). Groups 3 and 4 had a prolonged rate of recovery of incapability (β = 1.3, β = 7.0) and pain intensity (β = 0.19, β = 1.1) (P < 0.02). CONCLUSIONS: Patients with higher levels of unhelpful thinking and feelings of distress regarding symptoms experienced worse recovery of pain and incapability, with a higher effect size than fracture location, fracture severity, high-energy injury, and nerve palsy. These findings underline the importance of anticipating and addressing mental health concerns during recovery from injury. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Artificial neural networks outperform linear regression in estimating 9-month patient-reported outcomes after upper extremity fractures with increasing number of variables.
OBJECTIVE: To compare performance between linear regression (LR) and artificial neural network (ANN) models in estimating 9-month patient-reported outcomes (PROs) after upper extremity fractures using various subsets of early mental, social, and physical health variables. METHODS: We studied 734 patients with isolated shoulder, elbow, or wrist fracture who completed demographics, mental and social health measures, and PROs at baseline, 2-4 weeks, and 6-9 months postinjury. PROs included 3 measures of capability (QuickDASH, PROMIS-UE-PF, PROMIS-PI) and one of pain intensity. We developed ANN and LR models with various selections of variables (20, 23, 29, 34, and 54) to estimate 9-month PROs using a training subset (70%) and internally validated them using another subset (15%). We assessed the accuracy of the estimated value being within one MCID of the actual 9-month PRO value in a test subset (15%). RESULTS: ANNs outperformed LR in estimating 9-month outcomes in all models except the 20-variable model for capability measures and 20-variable and 23-variable models for pain intensity. The accuracy of ANN versus LR in the primary model (29-variable) was 83% versus 73% (Quick-DASH), 68% versus 65% (PROMIS-UE-PF), 66% versus 62% (PROMIS-PI), and 78% versus 65% (pain intensity). Mental and social health factors contributed most to the estimations. CONCLUSION: ANNs outperform LR in estimating 9-month PROs, particularly with a larger number of variables. Given the otherwise relatively comparable performance, aspects such as practicality of collecting greater sets of variables, nonparametric distribution, and presence of nonlinear correlations should be considered when deciding between these statistical methods.
Investigating gait-responsive somatosensory cueing from a wearable device to improve walking in Parkinson's disease.
Freezing-of-gait (FOG) and impaired walking are common features of Parkinson's disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson's disease and daily FOG were recruited. During 1 h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C, > 10 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD.
Unhelpful thoughts and distress regarding symptoms are associated with recovery from upper extremity fracture.
BACKGROUND: There is evidence that thoughts and emotions regarding symptoms are strongly associated with levels of comfort and capability for a given injury or disease. Longitudinal data from a large cohort of people recovering from an upper extremity fracture provided an opportunity to study how these mindset factors evolve during recovery. METHODS: Seven hundred and four adults (66% women, mean age 59 ± 21 years) recovering from upper extremity fracture completed two measures of reaction to symptoms (the Pain Catastrophizing Scale and the Tampa Scale of Kinesiophobia), a visual analog scale of pain intensity, and two measures of magnitude of incapability 1 week, 3 to 4 weeks, and 6 to 9 months after fracture. RESULTS: Exploratory factor analysis identified distinct groupings of questions addressing unhelpful thoughts and feelings of distress regarding symptoms. The number of distinct question groupings of mindset factors diminished over time. Variations in those groupings of mindset factors were associated with a notable amount of the variation in comfort and capability at all time points. Questions pertaining to unhelpful thoughts about symptoms had stronger associations with comfort and capability than questions measuring distress about symptoms, more so as recovery progressed. CONCLUSIONS: The need to integrate mental health into musculoskeletal is bolstered by the observation that mindsets-interpretation of symptoms in particular-are key contributors to comfort and capability.
Treatment of acute distal biceps tendon ruptures – A survey of the British Elbow and Shoulder Society surgical membership
Background: Acute distal biceps tendon ruptures result in weakness and deformity. While in other jurisdictions the rate of surgical repair has outpaced rises in incidence, UK practice for distal biceps tendon ruptures is unknown. The aim of this survey was to characterise current UK clinical practice. Methods: An online survey was sent to the surgeon members of the British Elbow and Shoulder Society. Questions covered respondent demographics, clinical decision making, surgical experience and willingness to be involved in future research. Results: A total of 242 surgeons responded; 99% undertook acute distal biceps tendon repairs with 83% repairing at least half of all distal biceps tendon ruptures, and 84% of surgeons would have their own, hypothetical, acute distal biceps tendon rupture repaired in their dominant arm and 67% for their non-dominant arm. Patient age, occupation and restoration of strength were the commonest factors underpinning a recommendation of surgical fixation. Most surgeons (87%) supported a national trial to study operative and non-operative treatments. Conclusions: UK upper limb surgeons currently advise surgical repair of acute distal biceps tendon ruptures for the majority of their patients. This is despite a paucity of evidence to support improved outcomes following surgical, rather than non-operative, management. There is a clear need for robust clinical evaluation in this area.
Symptoms of depression and catastrophic thinking attenuate the relationship of pain intensity and magnitude of incapability with fracture severity.
OBJECTIVE: The relative association of pain intensity and magnitude of incapability with pathophysiology, accounting for psychological factors, is incompletely understood. Using moderation analysis, we assessed the association of pain intensity and magnitude of incapability (dependent variables) with fracture severity (independent variable) and the influence of symptoms of depression and catastrophic thinking (moderators) at early and later stages of recovery. METHODS: A cohort of 731 patients recovering from a shoulder, elbow, or wrist fracture, completed self-reported measures of pain intensity, upper extremity capability, symptoms of depression, and catastrophic thinking between 2 and 4 weeks after injury and again between 6 and 9 months after injury. Fracture severity was rated by clinicians, and we used multivariable regression analysis to examine interaction effects of fracture severity, depression, catastrophic thinking, pain intensity, and magnitude of incapability at early and later stages of recovery. RESULTS: Symptoms of depression and catastrophic thinking attenuate the relationship between pain intensity and fracture severity at earlier and later stages of recovery. Symptoms of depression and catastrophic thinking also attenuate the relationship between the magnitude of incapability and fracture severity, but only at early stages of recovery. CONCLUSION: The relative divergence of pain intensity and magnitude of incapability from the level of fracture severity due to the moderating effects of unhelpful thinking and distress, signals a benefit to anticipating mental health opportunities during recovery after fracture. Fracture management can incorporate measures of unhelpful thinking and symptoms of distress to better address these opportunities and ensure comprehensive optimization of recovery. LEVEL OF EVIDENCE: Level IIc, prognostic.
Management and outcomes of femoral periprosthetic fractures at the hip data from the characteristics, outcomes and management of periprosthetic fracture service evaluation (COMPOSE) cohort study
Aims The aim of this study was to describe the management and associated outcomes of patients sustaining a femoral hip periprosthetic fracture (PPF) in the UK population. Methods This was a multicentre retrospective cohort study including adult patients who presented to 27 NHS hospitals with 539 new PPFs between 1 January 2018 and 31 December 2018. Data collected included: management strategy (operative and nonoperative), length of stay, discharge destination, and details of post-treatment outcomes (reoperation, readmission, and 30-day and 12-month mortality). Descriptive analysis by fracture type was performed, and predictors of PPF management and outcomes were assessed using mixed-effects logistic regression. Results In all, 417 fractures (77%) were managed operatively and 122 (23%) conservatively. The median time to surgery was four days (interquartile range (IQR) 2 to 7). Of those undergoing surgery, 246 (59%) underwent revision and/or fixation and 169 (41%) fixation alone. The surgical strategy used differed by Unified Classification System for PPF type, with the highest rate of revision in B2/B3 fractures (both 77%, 176/228 and 24/31, respectively) and the highest rate of fixation alone in B1- (55/78; 71%) and C-type (49/65; 75%) fractures. Cemented stem fixation (odds ratio (OR) 2.66 (95% confidence interval (CI) 1.42 to 4.99); p = 0.002) and B2/B3 fracture type (OR 7.56 (95% CI 4.14 to 13.78); p < 0.001) were predictors of operative management. The median length of stay was 15 days (IQR 9 to 23), 12-month reoperation rate was 5.6% (n = 30), and 30-day readmission rate was 8.4% (n = 45). The 30-day and 12-month mortality rates were 5.2% (n = 28) and 21.0% (n = 113). Nonoperative treatment, older age, male sex, admission from residential or nursing care, and sustaining the PPF around a revision prosthesis were significant predictors of an increased 12-month mortality. Conclusion Femoral hip PPFs have mortality, reoperation, and readmission rates comparable with hip fracture patients. However, they have a longer wait for surgery, and surgical treatment is more complex. There is a need to create a national framework for data collection for this heterogeneous group of patients in order to understand the outcomes of different approaches to treatment.