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.

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 Within-Subjects Comparison of Clinical Outcomes for Patients' First and Second Concussions.

OBJECTIVES: To examine the difference between an individual's first and second concussion using a comprehensive, multidomain assessment including symptoms, neurocognitive, vestibular, ocular, and individual demographic and medical history risk factors associated with protracted recovery. SETTING: Concussion Specialty Clinic. PARTICIPANTS: Seventy-three patients (aged 13-21 years; 57% female) diagnosed with 2 separate concussions (380.5 ± 278.7 days between injuries) from August 2016 to August 2018. DESIGN: Retrospective within-subjects cohort study. MAIN MEASURES: ImPACT, PCSS, and Vestibular-Ocular Motor Screen (VOMS) at each visit. Patients were divided into "normal" (≤30 days) and "protracted" recovery (>30 days) for χ2 analyses. RESULTS: There were no differences between the first and second injuries in recovery time, VOMS, visual and verbal memory, or reaction time. Visual motor speed scores were higher at the second injury time point and reported sleep symptoms were higher at the first injury time point. In addition, participants reported to the clinic on average 3 days earlier for an evaluation for their second injury. Results from χ2 analyses indicated that female sex predicted protracted recovery (>30 days) from concussion at the first injury time point (OR = 4.1; 95% CI, 1.5-11.6; P = .006). CONCLUSIONS: The findings provide preliminary evidence that there is no clinical difference between patients' first and second concussions when both injuries were treated through a concussion specialty clinic.

Digital pathology is a practical alternative to on-site intraoperative frozen section diagnosis in thoracic surgery.

AIMS: Telepathology uses digitised image transfer to allow off-site reporting of histopathology slides. This technology could facilitate the centralisation of pathology services, which may improve their quality and cost-effectiveness. The benefits may be most apparent in frozen section reporting, in which turnaround times (TATs) are vital. We moved from on-site to off-site telepathology reporting of thoracic surgery frozen section specimens in 2016. The aim of this study was to compare TATs before and after this service change. METHODS AND RESULTS: All thoracic frozen section specimens analysed 4 months prior and 4 months following the service change were included. Demographics, operation, sample type, time taken from theatre, time received by laboratory, time reported by laboratory, TAT, frozen section diagnosis, final histopathological diagnosis and final TNM staging were recorded. The results were analysed with spss statistical software version 24. In total, there were 65 samples from 59 patients; 34 before the change and 31 after the change. Specimens included 51 lung, six lymph node, three bronchial, three chest wall and two pleural biopsies. Before the change, the median TAT was 25 min [interquartile range (IQR) 20-33 min]. No diagnoses were deferred. No diagnoses were changed on subsequent paraffin analysis. After the change, with the use of digital pathology, the median TAT was 27.5 min (IQR 21.75-38.5 min). This difference was not significant (P = 0.581). Diagnosis was deferred in one case (3.23%). There was one (3.23%) mid-case technical failure resulting in the sample having to be transported by courier, resulting in a TAT of 106 min. No diagnoses were changed on subsequent paraffin analysis. CONCLUSIONS: There was no significant difference in reporting times between digital technology and an on-site service, although one sample was affected by a technical failure requiring physical transportation of the specimen for analysis. Our study was underpowered to detect differences in accuracy.

On-Resin Macrocyclization of Peptides Using Vinyl Sulfonamides as a Thiol-Michael "Click" Acceptor.

Macrocyclization of linear peptides imparts improved stability to enzymatic degradation and increases potency of function. Many successful macrocyclization of peptides both in solution and on-resin have been achieved but are limited in scope as they lack selectivity, require long reaction times, or necessitate heat. To overcome these drawbacks a robust and facile strategy was developed employing thiol-Michael click chemistry via an N-methyl vinyl sulfonamide. We demonstrate its balance of reactivity and high stability through FTIR model kinetic studies, reaching 88% conversion over 30 min, and NMR stability studies, revealing no apparent degradation over an 8 day period in basic conditions. Using a commercially available reagent, 2-chloroethane sulfonyl chloride, the cell adhesion peptide, RGDS, was functionalized and macrocyclized on-resin with a relative efficiency of over 95%. The simplistic nature of this process demonstrates the effectiveness of vinyl sulfonamides as a thiol-Michael click acceptor and its applicability to many other bioconjugation applications.

Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens.

AIMS: We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS: We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients. RESULTS: T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS. CONCLUSIONS: Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

Efficacy Projection of Obiltoxaximab for Treatment of Inhalational Anthrax across a Range of Disease Severity.

Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax.

Model-based meta-analysis for development of a population-pharmacokinetic (PPK) model for Vitamin D3 and its 25OHD3 metabolite using both individual and arm-level data.

Clinical studies investigating relationships between D3 and 25OHD3 vary in dosing regimen, assays, demographics, and control of exogenous D3. This leads to uncertain and conflicting exposure-related associations with D3 and 25OHD3. To elucidate this parent-metabolite system, a PPK model was developed to predict mean D3 and 25OHD3 exposure from varied doses and administration routes. Sources of exposure variability related to metabolite baseline, weight, and assay type were explored. Specific search criteria were used in PUBMED to identify public source PK data pertaining to D3 and 25OHD3 in healthy or osteoporotic populations. Overall 57 studies representing 5395 individuals were selected, including 25 individual-level profiles and treatment-arm data. IV, oral, single and multiple dose data were used, with D3 and 25OHD3 dosing. A nonlinear mixed effects model was developed to simultaneously model PK dispositions of D3 and 25OHD3 (NONMEM v7.2), which were described by 2-compartment models with nonlinear and linear clearances, respectively. Proportional and additive assay variances were included on the 25OHD3 prediction. Unit-level random effects were weighted by treatment-arm size. D3 model estimates, relative to bioavailability were: maximum rate of metabolism ([Formula: see text], 1.62 nmol/h), Michaelis-Menten constant ([Formula: see text], 6.39 nmol/L), central volume of distribution ([Formula: see text], 15.5 L), intercompartmental clearance ([Formula: see text], 0.185 L/h), peripheral volume of distribution ([Formula: see text], 2333 L/h), and baseline concentration ([Formula: see text], 3.75 nmol/L). For 25OHD3 ([Formula: see text] = metabolite): [Formula: see text] = 0.0153 L/h, [Formula: see text] = 4.35 L, [Formula: see text] = 6.87 L, [Formula: see text] = 0.0507 L/h. Simulations of 25OHD3 concentration indicated an inverse relationship between 25OHD3 baseline and response, as well as a less than proportional 25OHD3 response. Estimation of assay bias parameters suggested that HPLC-MS and RIA produced similar measurement results, whereas CPBA and CHEMI are over-predictive of 25OHD3 concentration, relative to HPLC-MS.

A linearization approach for the model-based analysis of combined aggregate and individual patient data.

The application of model-based meta-analysis in drug development has gained prominence recently, particularly for characterizing dose-response relationships and quantifying treatment effect sizes of competitor drugs. The models are typically nonlinear in nature and involve covariates to explain the heterogeneity in summary-level literature (or aggregate data (AD)). Inferring individual patient-level relationships from these nonlinear meta-analysis models leads to aggregation bias. Individual patient-level data (IPD) are indeed required to characterize patient-level relationships but too often this information is limited. Since combined analyses of AD and IPD allow advantage of the information they share to be taken, the models developed for AD must be derived from IPD models; in the case of linear models, the solution is a closed form, while for nonlinear models, closed form solutions do not exist. Here, we propose a linearization method based on a second order Taylor series approximation for fitting models to AD alone or combined AD and IPD. The application of this method is illustrated by an analysis of a continuous landmark endpoint, i.e., change from baseline in HbA1c at week 12, from 18 clinical trials evaluating the effects of DPP-4 inhibitors on hyperglycemia in diabetic patients. The performance of this method is demonstrated by a simulation study where the effects of varying the degree of nonlinearity and of heterogeneity in covariates (as assessed by the ratio of between-trial to within-trial variability) were studied. A dose-response relationship using an Emax model with linear and nonlinear effects of covariates on the emax parameter was used to simulate data. The simulation results showed that when an IPD model is simply used for modeling AD, the bias in the emax parameter estimate increased noticeably with an increasing degree of nonlinearity in the model, with respect to covariates. When using an appropriately derived AD model, the linearization method adequately corrected for bias. It was also noted that the bias in the model parameter estimates decreased as the ratio of between-trial to within-trial variability in covariate distribution increased. Taken together, the proposed linearization approach allows addressing the issue of aggregation bias in the particular case of nonlinear models of aggregate data.

Gold(I)-promoted heterocyclization of internal alkynes: a comparative study of direct metallate 5-endo-dig cyclization versus a stepwise cyclization.

With cationic gold catalysts, internal alkynes bearing both propargylic acyloxy groups and tosylamide pronucleophiles were found to cyclize to give either five- or six-membered ring nitrogen heterocycles. A wide variety of gold catalysts, counterions, and solvents were examined to elucidate their effect on product distribution. In most cases, the direct 5-endo-dig cyclization was found to be the major pathway leading to good yields of dehydropyrrolidine products. Alkyne substrates bearing additional normal alkyl substituents at the propargylic position gave dehydropiperidines as the major product. This pathway is thought to proceed by way of a 1,2- Rautenstrauch rearrangement to produce a vinyl gold(I) carbene, which undergoes conjugate addition by the nitrogen pronucleophile. Structural and electronic factors were studied in the nitrogen pronucleophile and in the migrating acyloxy group. Each was found to have a minor effect on the product ratio.

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.

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.

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.

A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone.

OBJECTIVE: To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. METHODS: In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. CONCLUSION: In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.

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.

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.

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.

Alkene metathesis approach to ß-unsubstituted anti-allylic alcohols and their use in ene-yne metathesis.

The synthesis of ß-unsubstituted, anti-allylic alcohols using a catalytic Evans aldol reaction conjoined with a relay-type ring-closing alkene metathesis is reported. The metathesis step serves to remove a ß-alkenyl group, which facilitated the aldol step. The ß-substituted enals serve as acrolein surrogates. The products were employed in ene-yne cross metathesis.

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.

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.