Computer Hexapod-assisted Orthopaedic Surgery for the Correction of Multiplanar Deformities throughout the Lower Limb.

Introduction: Computerised hexapod-assisted orthopaedic surgery (CHAOS) is a method by which complex multiplanar, multilevel deformity can be corrected with a high degree of accuracy utilising minimally invasive techniques within a single operative event. This study's aim was to report the reliability, accuracy and magnitude of correction achieved, alongside patient-reported outcomes and risk factors for complications when using the CHAOS technique throughout the lower limb. Materials and methods: Retrospective review of medical records and radiographs for consecutive patients who underwent CHAOS for lower limb deformity correction at a tertiary centre between 2012 and 2020. Results: There were 70 cases in 56 patients, with the site of surgery being the femur in 48 cases, proximal tibia in 17 and distal tibia in 5 cases. Multiplanar correction was performed in 43 cases, and multilevel osteotomy was undertaken in 23 cases. Fixation was undertaken with intramedullary nailing (IMN) in 49 cases and locked plates in 21.The maximum corrections were 40° rotation, 20° coronal angulation, 51° sagittal angulation and 62-mm mechanical axis deviation (MAD). Deformity correction was mechanically satisfactory in all patients bar one who was undercorrected requiring revision. The mean patient global impression of change (PGIC) score was 6.2 out of 7.Overall complication rate was 12/70 (17%). Complications from femoral surgery included two nonunions, one case of undercorrection, one case of stiffness, one muscle hernia and one pulmonary embolism. Complications from tibial surgery were one compartment syndrome, one pseudoaneurysm of the anterior tibial artery requiring stenting, one transient neurapraxia of the common peroneal nerve, one locking plate fatigue failure, one seroma and one superficial wound infection. Conclusion: Computerised hexapod-assisted orthopaedic surgery can be used for accurate correction of complex multilevel and multiplanar deformities of both the femur and tibia. The risk profile appears to differ between femoral and tibial surgeries, and also to that of traditional circular frame correction. Patients remain highly satisfied with both the functional and symptomatic outcomes. How to cite this article: French JMR, Filer J, Hogan K, et al. Computer Hexapod-assisted Orthopaedic Surgery for the Correction of Multiplanar Deformities throughout the Lower Limb. Strategies Trauma Limb Reconstr 2024;19(1):9-14.

Bayesian estimation in NONMEM.

Bayesian estimation is a powerful but underutilized tool for answering drug development questions. In this tutorial, the principles of Bayesian model development, assessment, and prior selection will be outlined. An example pharmacokinetic (PK) model will be used to demonstrate the implementation of Bayesian modeling using the nonlinear mixed-effects modeling software NONMEM.

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus.

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model-based meta-analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG-based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate-level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti et al. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE.

Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient-level placebo (Standard-of-Care) data to enable model-informed drug development.

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo-controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints. Herein, we characterized longitudinal disease activity in the SLE population and the sources of variability by developing a latent disease trajectory model for SLE component endpoints (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI], Physician's Global Assessment [PGA], British Isles Lupus Assessment Group Index [BILAG]) and composite endpoints (Systemic Lupus Erythematosus Responder Index [SRI], BILAG-based Composite Lupus Assessment [BICLA], and Lupus Low Disease Activity State [LLDAS]) using patient-level historical SoC data from nine phase II and III studies. Across all endpoints, in predictions up to 52 weeks from the final disease trajectory model, the following baseline covariates were associated with a greater decrease in SLE disease activity and higher response to placebo + SoC: Hispanic ethnicity from Central/South America, absence of hypocomplementemia, recent SLE diagnosis, and high baseline disease activity score using SLEDAI and BILAG separately. No discernible differences were observed in the trajectory of response to placebo + SoC across different SoC medications (antimalarial and immunosuppressant such as mycophenolate, methotrexate, and azathioprine). Across all endpoints, disease trajectory showed no difference in Asian versus non-Asian patients, supporting Asia-inclusive global SLE drug development. These results describe the first population approach to support a model-informed drug development framework in SLE.

Variable or variate? A conundrum in pharmacometrics exposure-response models.

Key elements of scientific writing-consistency and clarity-can be compromised in case of inaccurate use of methodological terms, especially in complex and multidisciplinary scientific fields. Such is the case in reports of pharmacometrics exposure-response analyses with the use of the terms univariate/multivariate and univariable/multivariable. This perspective outlines the issues in the use of these terms, clarifies their definitions, provides examples, and makes recommendations for authors, reviewers, and journals in the fields of clinical pharmacology and pharmacometrics.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Distal biceps repair through a single incision with the use of a knotless cortical button device: Mid-term results.

Background: Distal biceps rupture presents with an increasing incidence and evidence suggests that although a surgical repair is not mandatory, it results in superior functional outcomes when compared to non-operative management. As implant technology has advanced, several devices have been utilised and studied in managing this pathology. We present our single-centre experience with the use of the ToggleLoc Ziploop reattachment device, a knotless cortical button implant, using a single-incision technique. Methods: Retrospective series of 70 consecutive distal biceps tendon repairs, at a mean follow-up of 45.6 months after surgery, using a standardised single implant, single-incision technique, and post-operative rehabilitation programme. Results: There was one (1.4%) re-rupture in our patient cohort. The range of motion was complete in all patients except for one patient who had symptomatic heterotopic ossification, causing limitation in pronation. Complications were minor with the commonest being transient neuropraxia of the lateral cutaneous nerve of the forearm. The mean Oxford elbow score was 46.9 out of 48, and the patient global impression of change scale was 7 out of 7 in 77% of cases. Conclusion: Our data support this technique and implant combination when dealing with acute and chronic distal biceps tendon rupture.

International Survey of Practice for Prophylactic Systemic Antibiotic Therapy in Hip and Knee Arthroplasty.

(1) Background: Prophylactic systemic antibiotics are acknowledged to be an important part of mitigating prosthetic joint infections. Controversy persists regarding optimal antibiotic regimes. We sought to evaluate current international antibiotics guidelines for total joint arthroplasty (TJA) of the hip and knee. (2) Methods: 42 arthroplasty societies across 6 continents were contacted and their published literature reviewed. (3) Results: 17 societies had guidelines; of which 11 recommended an antibiotic agent or antibiotic class (10-cephalosporin; 1-cloxacillin); 15 recommended antibiotic infusion within an hour of incision and 10 advised for post-operative doses (8-up to 24 h; 1-up to 36 h; 1-up to 48 h). (4) Conclusions: Prophylactic antibiotic guidelines for TJA are often absent or heterogenous in their advice.

Virtual Trauma Meeting as a Component of Undergraduate Orthopaedic Education.

INTRODUCTION: Virtual teaching has proven effective for medical students during the COVID-19 pandemic. This study is the first to describe an undergraduate orthopaedic teaching strategy in the format of virtual trauma meetings (VTM). METHODS: Clinical medical students from the Universities of Bristol and Cardiff were invited to attend five VTM between October and November 2020. These were delivered by consultants and speciality doctors via Zoom software. An 11-item feedback form was distributed after each session to assess the relevance of teaching material, student confidence in asking and answering questions, and if students would benefit from further sessions. Several open-ended questions were designed to evaluate aspects of the session that were most useful, which orthopaedic topics were of high priority and if they had any suggestions for improvement. Our initial aim was to assess student acceptance of the virtual format. Several months later pre-recorded material was uploaded onto YouTube and post hoc questionnaires were analysed. RESULTS: A total of 50 students attended, with a median of 11±6 attending per session, producing a total of 26 feedback responses. Among the responders, there were 10 males and nine females and 63% of the students were in their third year. 100% of students felt comfortable asking questions and 96% felt comfortable answering questions. X-ray interpretation and management of fractures were the highest priority subjects. The majority of students considered the interaction between senior and junior doctors most valuable, and the most common improvement suggested was the inclusion of polls or OSCE-styled questions. CONCLUSIONS: VTM could be a useful resource to enhance undergraduate trauma and orthopaedic (T&O) education by providing student-focused material in an open learning environment.

Pharmacometric modeling and machine learning analyses of prognostic and predictive factors in the JAVELIN Gastric 100 phase III trial of avelumab.

Avelumab (anti-PD-L1) is an approved anticancer treatment for several indications. The JAVELIN Gastric 100 phase III trial did not meet its primary objective of demonstrating superior overall survival (OS) with avelumab maintenance versus continued chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer; however, the OS rate was numerically higher with avelumab at timepoints after 12 months. Machine learning (random forests, SIDEScreen, and variable-importance assessments) was used to build models to identify prognostic/predictive factors associated with long-term OS and tumor growth dynamics (TGDs). Baseline, re-baseline, and longitudinal variables were evaluated as covariates in a parametric time-to-event model for OS and Gompertzian population model for TGD. The final OS model incorporated a treatment effect on the log-logistic shape parameter but did not identify a treatment effect on OS or TGD. Variables identified as prognostic for longer OS included older age; higher gamma-glutamyl transferase (GGT) or albumin; absence of peritoneal carcinomatosis; lower neutrophil-lymphocyte ratio, lactate dehydrogenase, or C-reactive protein (CRP); response to induction chemotherapy; and Eastern Cooperative Oncology Group performance status of 0. Among baseline and time-varying covariates, the largest effects were found for GGT and CRP, respectively. Liver metastasis at re-baseline predicted higher tumor growth. Tumor size after induction chemotherapy was associated with number of metastatic sites and stable disease (vs. response). Asian region did not impact OS or TGD. Overall, an innovative workflow supporting pharmacometric modeling of OS and TGD was established. Consistent with the primary trial analysis, no treatment effect was identified. However, potential prognostic factors were identified.

Performance Validity Testing in Patients Presenting to a Specialty Clinic With a Mild Traumatic Brain Injury.

OBJECTIVE: To evaluate predictors of performance validity testing (PVT) and clinical outcome in patients presenting to a specialty clinic with a mild traumatic brain injury (mTBI). SETTING: An outpatient mTBI specialty clinic. PARTICIPANTS: Seventy-six (47% female) patients aged 16 to 66 (mean = 40.58, SD = 14.18) years within 3 to 433 days (mean = 30.63, SD = 54.88, median = 17.00) of a suspected mTBI between 2018 and 2019. DESIGN: A cross-sectional, observational study comparing patients who passed PVT (n = 43) with those who failed (n = 33). A logistic regression (LR) was conducted to evaluate factors that predicted failed PVT. Independent-samples t tests and general linear model were used to evaluate PVT groups on clinical outcomes. The LR with a receiver operating characteristic (ROC) curve was conducted to evaluate embedded validity indicators. MAIN MEASURES: Performance validity testing, computerized neurocognitive testing, vestibular/oculomotor screening, symptom reports. RESULTS: At their initial clinic visit 43% of patients failed PVT. PVT failure was predicted by presence of secondary gain (odds ratio [OR] = 8.11, P = .02), while a history of mental health predicted passing of PVT (OR = 0.29, P = .08). Those who failed PVT performed significantly worse on computerized neurocognitive testing (P < .05) and took an average of 33 days longer to return to work (P = .02). There was no significant difference (P = .20) in recovery time between failed/passed PVT groups when covarying for those who sustained a work injury. Word memory learning percentage less than 69% and design memory learning percentage less than 50% accurately classified patients who failed PVT (area under the ROC curve = 0.74; P < .001). CONCLUSION: Secondary gain was the best predictor of failed PVT. Patients presenting for mTBI evaluation and rehabilitation who fail PVT demonstrate worse performance on cognitive testing and take longer to return to work post-injury, but recover in a similar time frame compared with those who pass PVT. Clinicians should be cautious in discounting patients who yield invalid test results, as these patients appear to be able to achieve recovery in a treatment setting.

A model-based analysis to guide gonadotropin-releasing hormone receptor antagonist use for management of endometriosis.

AIMS: To identify linzagolix doses, an oral GnRH receptor antagonist, that effectively lower oestradiol (E2) to relieve endometriosis-related pelvic pain without compromising bone health. METHODS: Integrated statistical, pharmacokinetic-pharmacodynamic and systems pharmacology models were developed from Phase 1 and 2 clinical trial data in healthy volunteers and patients, receiving linzagolix 25-200 mg daily or placebo, and analysed simultaneously. The main outcome measures were pelvic pain scores for dysmenorrhoea, nonmenstrual pelvic pain (NMPP), uterine bleeding and lumbar spine bone mineral density (BMD). RESULTS: Linzagolix pharmacokinetics were described by a 2-compartment model with sequential zero/first-order absorption process (CL/F: 0.422 L/h). E2 changes over time were well described as a function of linzagolix 24-hour AUC (AUC50 : 1.68 × 105 ng h/mL). For a Caucasian reference patient, a change in E2 from 50-20 pg/mL at 24 weeks increased the odds of relief of dysmenorrhoea 1.33-fold and NMPP 1.07-fold (95% CI: 1.22-1.47 and 1.02-1.12, respectively) and decreased bleeding days by 1.55 (95% CI: 1.39-1.72). A previously validated quantitative systems pharmacology BMD model was adjusted to the clinical data. The mean week 24 lumbar spine BMD change from baseline ranged from -0.092% in the 50 mg dose, -1.30% in the 100 mg dose group and -2.67% in the 200 mg dose group. DISCUSSION: The previously-reported E2 target range (20-50 pg/mL) to balance efficacy and safety endpoints was confirmed. Linzagolix once daily doses between 75-125 mg daily were expected to meet endometriosis-associated pain, efficacy, and BMD loss targets in Caucasian patients.

Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor.

This analysis was conducted to assess exposure-response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (Cavg ) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between Cavg and incidence of ALT-related and AST-related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT-related and AST-related AEs. These results support the US Food and Drug Administration-approved dose (400 mg two times/day without initial loading dose).

Adverse reaction to metal debris due to fretting corrosion between the acetabular components of modular dual-mobility constructs in total hip replacement: a systematic review and meta-analysis.

Modular dual-mobility (MDM) constructs can be used to reduce dislocation rates after total hip replacement (THR). However, there are concerns about adverse reaction to metal debris (ARMD) as a result of fretting corrosion between the metal liner and shell. This systematic review reports outcomes following THR using MDM components. It was registered with PROSPERO and conducted in line with Cochrane and PRISMA recommendations.Sixteen articles were included overall, with meta-analysis performed on relevant subsets using a random intercept logistic regression model. Estimated median incidence of ARMD requiring revision surgery within study follow-up period was 0.3% (95% CI 0.1 - 1.8%, from 11 cohort studies containing 1312 cases).Serum metal ion levels were mildly raised in 7.9% of cases, and significantly raised in 1.8%, but there was no correlation with worse clinical hip function scores within studies. Dislocation rate was 0.8%. Revision rate was 3.3%.There are mixed reports of wear on the backside of the metal liner from the acetabular shell and screw heads. Both implant design and component malseating are implicated, but currently it is unclear to what extent each factor is responsible.Studies were poor quality with high risk of confounding, especially from trunnion corrosion. We have made recommendations for further work. In the meantime, surgeons should be aware of the potential risk of ARMD when considering using an MDM prosthesis, and, if selecting one, must ensure proper seating of the liner and screws intraoperatively. Cite this article: EFORT Open Rev 2021;6:343-353. DOI: 10.1302/2058-5241.6.200146.

Cerebral amyloid angiopathy distribution in older people: A cautionary note.

INTRODUCTION: Radiolabeled ligands for fibrillar amyloid beta (Aß) peptides are used in positron emission tomography (PET) for dementia diagnosis. Current ligands do not discriminate parenchymal amyloid plaques from cerebral amyloid angiopathy (CAA). METHODS: We undertook neuropathological examination of 65 older people (81.6 ± 7.96 (mean ± SD) years, 27F/38M): 15 with neuropathological diagnosis of AD, 25 with neuropathological diagnosis of other neurodegenerative dementias (Lewy body dementia and Parkinson disease dementia), and 25 without significant neurodegenerative pathology. RESULTS: We observed CAA in non-Alzheimer's dementia (non-AD dementia) and control brains, of comparable extent to those with neuropathologically confirmed AD. Aß-positive vessel density did not differ significantly between non-AD dementia and control groups. Across all subjects there was a highly significant correlation between vessel Aß40 density and vessel Aß42 density (Spearman rho = 0.855, P < .001). CAA was absent or sparse in subcortical white matter across all patient groups. CONCLUSION: Our data indicate that CAA can be abundant in non-AD brains and raise a cautionary note regarding interpretation of amyloid PET imaging.

Use of Surgical Adhesive Tape to Maintain Tension on Intrafocal K-Wires for Easy Reduction and Fixation of Complex Intra-Articular Distal Radius Fractures.

Maintaining reduction during fixation of complex intra-articular distal radius fractures with dorsal comminution can be challenging. We describe an operative technique where reduction is achieved with temporary intrafocal Kirschner wires (K-wires), and held using surgical adhesive tape wrapped around the hand, whilst a volar plate is applied to achieve rigid fixation. This is a simple, inexpensive method used at our institutions which allows fixation of these fractures without the need for an operative assistant.