Explore the vast range of titles available.

The Young’s modulus and the secant modulus of a terpolymer-treated soil as a function of the polymer’s characteristics are discussed in the context of a more general inelastic property known as the toughness parameter. The soil chosen was a sample of the State of Qatar subsoil. The terpolymer, designated TPAM, was characterized by a backbone structure of acrylamide, anionic carboxylate, and cationic (3-acrylamidopropyl-trimethylammonium chloride) repeat units. The backbone unit ratio was estimated from 13C NMR analyses. TPAM was synthesized by straightforward NaOH hydrolyses of an acrylamide/cationic copolymer. The correlations between the NaOH molarity of the hydrolysis solution, with the corresponding ratio of the anionic and cationic units, were shown to have a significant influence on the value of the toughness parameter. It is speculated that controlling the anionic and cationic ratio of a terpolymer is a general approach to optimize the toughness parameter of treated soils. Measurements of the molecular weight of TPAM were made, and comments on the importance of this feature are given. The equivalent viscosity was also recorded. It is pointed out that the work is particularly relevant to the practical problem of subsoil pavement stabilization in which the terpolymer acts as a soil binder. Suggestions on further work are given.

To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's football and identify potential areas for injury prevention initiatives. Football is a high-velocity collision sport in which injuries are expected. Football tends to have one of the highest injury rates in sports. Epidemiologic data helps certified athletic trainers and other clinicians identify injury trends and patterns to appropriately design and institute injury prevention protocols and then measure their effects. During the 16-year reporting period, about 19% of the Division I, II, and III NCAA institutions sponsoring football participated in the Injury Surveillance System. The results from the 16-year study period show little variation in the injury rates over time: games averaged 36 injuries per 1000 athlete-exposures (A-Es); fall practice, approximately 4 injuries per 1000 A-Es; and spring practice, about 10 injuries per 1000 A-Es. The game injury rate was more than 9 times higher than the in-season practice injury rate (35.90 versus 3.80 injuries per 1000 A-Es, rate ratio = 9.1, 95% confidence interval = 9.0, 9.2), and the spring practice injury rate was more than 2 times higher than the fall practice injury rate (9.62 versus 3.80 injuries per 1000 A-Es, rate ratio = 2.5, 95% confidence interval = 2.5, 2.6). The rate ratio for games versus fall practices was greatest for upper leg contusions (18.1 per 1000 A-Es), acromioclavicular joint sprains (14.0 per 1000 A-Es), knee internal derangements (13.4 per 1000 A-Es), ankle ligament sprains (12.0 per 1000 A-Es), and concussions (11.1 per 1000 A-Es). Football is a complex sport that requires a range of skills performed by athletes with a wide variety of body shapes and types. Injury risks are greatest during games. Thus, injury prevention measures should focus on position-specific activities to reduce the injury rate. As equipment technology improves for the helmet, shoulder pads, and other protective devices, appropriate injury surveillance procedures should be performed to determine the effect of the new equipment on injury rates. A consistent evaluation of injury trends and patterns will assist decision makers in designing injury prevention techniques in areas that warrant the greatest attention and suggesting rule changes and modifications based on the data.

Background and objectives Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. Methods Plasma concentration–time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). Results Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. Conclusions Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.

Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration–time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2–2.7 m 2 ), sex, age (23–91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%.

Constant shear rate and dynamic rheological measurements have been used to investigate the effect of shear on the processes controlling the structural evolution (size and volume fraction of clusters and the extent of cluster–cluster cross-linking) during the gelation of colloidal silica sols. In the absence of shear, the storage and loss moduli (G′ and G″, respectively) initially increase slowly prior to gelation, indicating that cluster growth and network formation are initially proceeding slowly, but then the system evolves rapidly, with cluster growth occurring at a slightly faster rate than network formation. In contrast, sols presheared for 4 h prior to gelation exhibit rapid increases in both G′ and G″ immediately after cessation of the applied shear, reflecting significant differences in the evolution of the gel structure. On aging, the viscoelastic properties of the unsheared and presheared samples are similar, indicating that their structures are comparable on the length scales (several microns) being probed by the frequency range used here. However, their chemical and microstructural properties differ significantly, due to differences in the intercluster bonds. The effect of shear rate, initial pH, colloid particle size, and volume fraction on the structure of the resulting sols and gels is discussed.

In March 2024, ponatinib received accelerated FDA approval for the treatment of newly diagnosed Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph + ALL) in combination with chemotherapy based on the Phase 3 PhALLCON study (NCT03589326), which demonstrated a higher rate of minimal residual disease (MRD)‐negative complete remission (CR) at the end of induction (EOI) with ponatinib (34.4%) versus imatinib (16.7%; p = 0.002). Patients received ponatinib (30 mg QD with reduction to 15 mg QD upon achievement of MRD‐negative CR at EOI) or imatinib (600 mg QD) combined with 20 cycles of reduced‐intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; and maintenance: 11 cycles). Ponatinib pharmacokinetics (PK) were similar in patients in PhALLCON and patients in a previous population PK analysis. Bayesian re‐estimation of the previously developed population PK model adequately described PhALLCON PK data. Exposure–efficacy analyses did not identify a significant relationship between ponatinib exposure and the probability of MRD‐negative CR at EOI (p = 0.619), suggesting a consistent efficacy benefit across exposures. Ponatinib exposure was not a significant predictor of arterial occlusive events, venous thromboembolic events, thrombocytopenia, or lipase increase (p > 0.05). However, higher exposures were associated with a higher probability of hypertension (p = 0.0340) and alanine aminotransferase (ALT) increase (p = 0.0034). Dose reduction from 30 to 15 mg was predicted to decrease the odds of experiencing hypertension by 37.7% and ALT increase by 44.2%. Collectively, exposure–response analyses support a favorable benefit–risk profile of the approved ponatinib dosage (30 mg QD reduced to 15 mg QD upon achievement of MRD‐negative CR at EOI), combined with chemotherapy, for frontline treatment of Ph + ALL.

Background The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide–dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies. Methods Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd). Results At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p  = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p  = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%). Conclusions This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM. Trial registration ClinicalTrials.gov, NCT01564537

The ALK in Lung Cancer Trial of brigAtinib in First Line (ALTA‐1L) compared brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor‐naive patients with ALK+ non‐small cell lung cancer (NSCLC). A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure‐efficacy and exposure‐safety analyses in ALTA‐1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time‐independent) and dynamic (time‐varying) exposure metrics and efficacy (progression‐free survival [PFS], objective response rate [ORR], and intracranial ORR [iORR]) and safety outcomes (selected grade ≥2 and grade ≥3 adverse events [AEs]) were evaluated using logistic regression and time‐to‐event analyses. There were no meaningful differences in brigatinib PK in the first‐line and second‐line settings, supporting use of the previous population PK model for the first‐line population. Exposure‐response analyses showed no significant effect of time‐varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher iORR (odds ratio: 1.13, 95% confidence interval: 1.01–1.28, p = 0.049). Across the observed median exposure (5th–95th percentile) at steady state for 180 mg once daily, the predicted probability of iORR was 0.83 (0.58–0.99). AEs significantly associated with higher exposure were elevated lipase (grade ≥3) and amylase (grade ≥2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit‐risk profile of first‐line brigatinib 180 mg once daily (7‐day lead‐in dose at 90 mg once daily) in patients with ALK+ NSCLC.