Defense Capacities Against Oxidative Stress in Diapause and Post‐Diapause Embryos of Artemia franciscana

ABSTRACT Embryos of Artemia franciscana survive harsh conditions in diapause and anoxia‐induced quiescence for years by undergoing deep metabolic transitions. During reactivation of metabolism, both the release of reactive oxygen species (ROS) from mitochondria and oxidative damage in mitochondria are low compared to mammalian mitochondria. Because antioxidant pathways can be important for avoiding oxidative stress upon metabolic reactivation in some cases, part of the low ROS efflux from A. franciscana mitochondria could be attributed to scavenging. Consequently, we analyzed activities of antioxidant enzymes and quantities of small‐molecule antioxidants in diapause versus post‐diapause embryos under steady‐state conditions. Functional capacities of most antioxidant enzymes (total superoxide dismutase [Cu/Zn‐SOD + Mn‐SOD], Mn‐SOD, and glutathione reductase [GR]) were higher in the post‐diapause state. These changes are understandable based on very elevated metabolic rates during post‐diapause, and the correspondingly higher defense capacities necessitated against ROS. Conversely, quantities of reduced glutathione (GSH), along with the total GSH pool (GSH + GSSG), were higher during diapause. The depressed metabolic rates during diapause predictably foster lower ROS generation (oxidative stress) to impact the GSH pool, so the standing quantity of reduced species in the pool is greater. However, our literature survey suggests that, overall, A. franciscana embryos do not possess abnormally elevated defenses against oxidative stress when compared to other hypoxia/anoxia‐tolerant species or even intolerant species. Thus, avoiding the actual generation of large ROS bursts after metabolic reactivation appears to be the more important contributor to protection of the embryos compared to ROS scavenging per se.

A Pilot Project to Evaluate the Benefit of Additional Support in Haematopoietic Cell Transplant (HCT) Research Data Management on Behalf of Anthony Nolan and BSBMTCT

ABSTRACT Background The participation of transplant centres in research studies that request detailed follow‐up data on included patients can be challenging due to the amount of time centre Data Managers have to complete additional requests. The Research Data Manager (RDM) Pilot Project was designed to support Anthony Nolan's longitudinal Patient/Donor project and provide real‐world evidence of the benefit of additional and dedicated data management resources in transplant centres. Objectives: For Anthony Nolan to continue advancing the field of donor selection, up‐to‐date and accurate follow‐up data is needed. This 12‐month pilot project aimed to demonstrate how on‐the‐ground support could improve access to outcome data. Study Design Following RDM placements at two participating centres, we reviewed the data quality and quantity collected, thus ensuring the methods used remain effective and are likely to result in successful and continuous data improvement. The cohort covered a broad timespan and included historical patient records, posing challenges in availability of prior data and long‐term follow‐up of discharged patients. Results Following the placements, over 400 patients now have the most up‐to‐date and complete patient clinical outcome data available within the EBMT/BSBMTCT registry database for any group to study, reducing the burden on these centres to complete research data requests for these individuals. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

Overlap between transitional care management after hospital discharge and alternative payment models

Abstract Care coordination is integral during posthospital transitions. The Centers for Medicare & Medicaid Services (CMS) has sought to promote post‐hospitalization care coordination through population‐based alternative payment models (APMs) and transitional care management (TCM) services. Both can be associated with benefits, but data are lacking about their overlap. Using 2018–2019 100% Medicare claims, we compared characteristics and quantified overlap across APM and TCM groups. Of 7,034,244 beneficiaries and 11,148,266 discharges, 41.6% were APM‐aligned and 14.5% involved TCM. TCM services were received in 19.7% of APM‐aligned discharges; among discharges involving TCM, 56.7% occurred among APM‐aligned beneficiaries. Relative to non‐APM beneficiaries, APM‐aligned beneficiaries receiving TCM were less likely to be from historically underserved populations, suggesting potential health disparity concerns. This early descriptive analysis offers novel evidence about TCM and APMs as major national policy investments, highlighting the need for future work on overlap and its effects on care coordination and patient outcomes.

MRI Safety Considerations for Permanent Magnet Implants in Muscle

ABSTRACT Background Permanent magnet implants are used with several medical and assistive devices, such as cochlear implants, dental attachments, and prosthetic control, but raise caution for MR imaging. Previous work has evaluated several magnet implants for position and magnetization stability, as well as for image artifacts under MRI. Yet, the intramuscular magnets used for prosthetic control still require evaluation for potential MRI conditionality. Purpose To investigate the position and magnetization stability of and image artifacts from 3‐mm‐diameter spherical permanent magnets ( B r  = 1.393 T, H ci  = 1.637 MA/m) implanted within muscle. Study Type Prospective longitudinal study. Animal Model Porcine; one animal, eight muscles. Field Strength/Sequence 0.55‐T, 1.5‐T/SE, GRE. Assessment Permanent magnets and nonmagnetic controls were implanted into eight muscles and exposed to 1.5‐T MRI 36 days post‐implantation. All sites were examined histologically for evidence of implant migration (acute fibrotic response or fibrotic capsule disruption). Benchtop studies evaluated worst‐case demagnetization and image artifacts (artifact radius minus implant radius). The primary measure of position stability was histological examination interpreting characteristics of progressive skeletal muscle healing. Secondary position stability analysis was performed via CT imaging. Statistical Tests Unpaired one‐sided sign test with a significance level of 0.05. Demagnetization and imaging artifacts were summarized as maximums. Results Fibrotic capsules were similarly intact at permanent magnet and control sites (fibrotic capsule thicknesses: 20–550 μm [magnets], 20–220 μm [controls]). No effect of MRI exposure on implant migration was observed via secondary analysis ( p  = 0.965 [0.55‐T], p  = 0.996 [1.5‐T]). Maximum demagnetization was 2.1% under 0.55‐T exposure and 13.5% under 1.5‐T exposure, and maximum image artifact was 71 mm at both imaging strengths. Data Conclusion The permanent magnet implants used in this study were resistant to migration and substantial demagnetization under 0.55‐T and 1.5‐T MRI exposure and resulted in negligible image artifacts for critical organ imaging, suggesting that the presence of these implants does not preclude a patient from receiving MR imaging up to 1.5T. Evidence Level N/A. Technical Efficacy Stage 5: Improvements in patient care.

Supply Chain Guardianship: Why Some Firms Intervene When Other Firms Commit Fraud

ABSTRACT In supply chains, firms often become aware of illegal actions committed by their partners, prompting the critical question: when and why do those who know become those who act? Drawing on industry examples of supply chain fraud, we introduce the concept of supply chain guardianship to study how firms respond to potential fraud committed by their supply chain partners. We identify key influences on supply chain guardianship and refine these insights into hypotheses, which we test across four behavioral experiments ( n  = 1000). Study A finds that the tone at the top of an organization can promote supply chain guardianship and that state moral disengagement is negatively correlated with it. Study B manipulates process moral disengagement and finds that it reduces guardianship behavior. Although the network position of the supply chain guardian emerges as important in industry examples, we do not find a significant effect in the experiments. We replicate and validate these findings in Studies C and D. This study offers an initial foundation for a behavioral theory of interfirm fraud responses in supply chains and offers practical insights into how firms can increase supply chain guardianship across macro‐, meso‐, and microlevels.

Porous Additively Manufactured PEKK Improves In Vitro Osteoblastic Performance Compared to PEEK

ABSTRACT Polyetheretherketone (PEEK) is a member of the polyaryletherketone (PAEK) family of semi‐crystalline thermoplastics that is increasingly considered as an alternative to metals for use in permanent implants. Another member of the PAEK family, polyetherketoneketone (PEKK), has many similar properties to PEEK, but can vary in its crystallization kinetics due to its varying terephthalic and isophthalic acid (T/I) ratios during manufacturing. We hypothesized that PEKK's differences in chemical structure may produce a better surface for cell adhesion, increasing in vitro osteoblastic performance when compared to PEEK. Solid and porous samples were printed under comparable conditions and cultured with MC3T3‐E1 mouse pre‐osteoblasts for up to 28 days. A laser confocal microscope was used to evaluate surface roughness of samples as one possible explanation for differences in in vitro performance. Micro‐CT was used to visualize the accuracy in printing of porous samples when compared to a digital model. PEKK samples were found to have significantly increased cell attachment, normalized alkaline phosphatase activity, and osteoblastic mineralization at multiple time points ( p  < 0.05). PEKK samples were also found to be significantly smoother than PEEK samples on the micron scale. Based on micro‐CT images, PEKK samples were found to more closely resemble the desired triply periodic minimal surface geometry than PEEK samples. This study suggests that PEKK should be considered in future studies investigating the biological performance of PEEK due to PEKK's encouraging in vitro biocompatibility.

High Demand Loading Conditions and Their Effect on Polyethylene Stresses in Lumbar Total Joint Replacement: Implications for Spine Wear Protocols

ABSTRACT The study aimed to compare contact stresses for a novel lumbar total joint replacement (LTJR) during a standardized duty cycle with elevated loading conditions. A finite element model (FEM) of an LTJR was developed, verified, and validated using the ASME V&V40 standard. Simulations were performed using LS‐Dyna. Increasing the axial loading for the 95th percentile male generally resulted in an increase in the peak contact pressures throughout the duty cycle. Specifically, contact pressure reached a maximum of 37.6 MPa. Despite this increase, the polyethylene peak contact stresses remained considerably lower than values previously documented during impingement. For 95th percentile male loading, the bearing mechanics of the LTJR design remained reasonably consistent with the 50th male loading scenario. Contact between the superior and inferior components remained confined to the intended hemispherical bearing surfaces, without evidence of impingement. The contact stresses in elevated loading scenarios fell below the levels associated with impingement loading. The polyethylene bearing stresses indicate that relative risks of wear and surface damage, including pitting, delamination, and fracture associated with a 95th percentile male, will be lower relative to the conditions from impingement testing. Clinical Significance: Our in silico approach to exploring elevated boundary conditions for spine wear testing will facilitate future test method development.

Osteoarthritis Gene Therapy: A 30‐Year Journey From Concept to Clinical Trials

ABSTRACT This manuscript summarizes over 30 years of research that began with the novel concept of using intra‐articular gene transfer to treat joint diseases. A notable milestone in this journey was the first‐in‐human transfer of an exogenous gene to a joint, accomplished by the ex vivo delivery of cDNA encoding the interleukin‐1 receptor antagonist (IL‐1Ra) to joints of patients with rheumatoid arthritis. Responding to lessons learned from this study and the prevailing clinical landscape we next developed an in vivo gene delivery system based on adeno‐associated virus (AAV) with osteoarthritis (OA) as the target disease. The safety and efficacy of this vector, sc‐rAAV2.5IL‐1Ra, was demonstrated in the joints of rats and horses leading to a successful IND application to the FDA. In this clinical trial (ClinicalTrials. gov Identifier: NCT02790723) sc‐rAAV2.5IL‐1Ra was injected at escalating doses into the knee joints of nine patients with OA who were followed for 1 year. This trial met its primary outcome measure, safety, and demonstrated that sustained expression of transgenic IL‐1Ra was possible after a single injection of the vector. Patient‐reported outcomes improved, but without a control group it is not possible to determine the influence of a placebo effect. This and other unresolved matters are addressed in a recently‐completed Phase Ib trial (ClinicalTrials. gov Identifier: NCT05835895). Beyond OA, sc‐rAAV2.5IL‐1Ra has potential therapeutic value in a variety of degenerative, inflammatory, fibrotic and autoimmune conditions. More generally, gene therapy holds much promise in the field of regenerative medicine, including regenerative orthopaedics. Trial Registration: (ClinicalTrials. gov Identifier: NCT02790723, NCT05835895).

Internal Density Calibration in the Proximal Humerus to Estimate Bone Stiffness for Stemless Shoulder Arthroplasty

ABSTRACT End‐stage osteoarthritis (OA) alters bone density in the humeral head, complicating implant fixation during stemless shoulder arthroplasty. Current preoperative assessments fail to consider the mechanical properties of bone directly supporting the humeral component. While in‐scan phantom calibration is used to determine volumetric bone mineral density (vBMD), phantoms are rarely used clinically. An internal density calibration method has been developed, but not yet applied in the proximal humerus. This study examined correlations between phantom and internal density calibration, and between vBMD and estimated stiffness in the proximal humerus. Nonpathologic cadaveric CT images containing a K 2 HPO 4 phantom were used to analyze a 10 mm region of interest below the anatomic neck. Phantom calibration was performed. Internal calibration used air (A), adipose (Ad), skeletal muscle (M), and cortical bone (C) in three combinations (AAdCM, ACM, AAdC). Finite element models (FEMs) were generated from each. Strong correlations were observed between phantom‐ and internally calibrated vBMD (AAdC R ² = 0.80; AAdCM R ² = 0.88; ACM R ² = 0.90), with ACM showing the lowest error (9.98%). Estimated stiffness and vBMD were strongly correlated across calibrations ( R ² = 0.61–0.66), with ACM showing the lowest error (5.46%). Findings support internal calibration for determining vBMD and FEMs for estimating stiffness in the proximal humerus.

Medication safety standards and the World Health Organization global patient safety challenge