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Introduction CD19 CAR T cell therapies are highly effective for several aggressive B-cell malignancies. Emerging data suggest that these therapies may lead to durable, treatment-free responses in multiple autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIMs), systemic sclerosis (SSc), and multiple sclerosis (MS). BMS-986353 (CC-97540) is an investigational CAR T cell therapy expressing the CD19-targeting CAR used in FDA-approved lisocabtagene maraleucel (liso-cel). BMS-986353 is manufactured using the NEX-TTM process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. Here, we report updated data on BMS-986353 in severe, refractory autoimmune diseases. Methods Two phase 1, multicenter, open-label studies are investigating BMS-986353 in patients (pts) with severe, refractory SLE, IIM, and SSc (CA061-1001; NCT05869955), and relapsing or progressive forms of MS (CA061-1006; NCT06220201). CAR T cells were manufactured using the NEX-T process and autoimmune-directed therapies were tapered before BMS-986353 infusion. Two to 9 d after lymphodepletion (3 d of fludarabine [30 mg/m2/d], cyclophosphamide [300 mg/m2/d]), a single infusion of BMS-986353 was administered. Pts were treated with 5 × 106 (MS only), 10 × 106, or 25 × 106 CAR+ T cells according to dose level. Pharmacokinetics were evaluated using droplet digital PCR to detect transgene copy numbers, and pharmacodynamics were measured using flow cytometry. Results As of Jul 12, 2024, 7 pts were treated with BMS-986353 (SLE, n=5; SSc, n=1; relapsing-remitting MS [RRMS], n=1). Seven pts were evaluable for safety; 4 pts were evaluable for efficacy (median follow-up of 167.5 d [range, 68-240]). All 5 pts with SLE had history of renal organ system involvement (BILAG category A) and disease refractory to multiple prior therapies (range 5-8); at screening, scores were (median [range]): SLE Disease Activity Index 2000 (SLEDAI-2K), 12.0 (7.0-22.0); Physician's Global Assessment (PGA), 2.3 (1.5-2.5). The pt with SSc was aged 43 y, and had history of progression of diffuse cutaneous SSc after 2 therapies and a modified Rodnan skin score of 18; the pt with RRMS was aged 33 y, and had history of active clinical disease despite 3 prior anti-CD20 therapies and an Expanded Disability Status Scale score of 3.0. Cytokine release syndrome was reported in 1 pt with SLE (grade [gr] 1) and 1 pt with SSc (gr 2), both resolved within 1 d. ICANS was reported in 1 pt with SSc (gr 1) and resolved in 1 d. Gr 3/4 transient lymphodepletion-related cytopenia occurred in 4 pts with SLE and 1 pt with MS. There were no prolonged gr ≥3 cytopenias or dose-limiting toxicities reported. In all efficacy evaluable pts, significant improvements in SLEDAI-2K (median, 4.0) and PGA (median, 0.55) were observed. dsDNA seroconverted and complements normalized for all pts who had abnormal values at screening. All pts remain off autoimmune-directed therapies without evidence of disease flare. Pts with SLE treated with 10 x 106 CAR+ T cell dose of BMS-986353 showed complete B-cell depletion and similar robust cellular expansion compared with pts with diffuse large B-cell lymphoma treated with liso-cel (TRANSFORM; NCT03575351) at the recommended phase 2 dose (RP2D; 100 x 106 CAR+ T cells). At the time of B-cell reconstitution following BMS-986353, re-emerging B cells were predominantly naive. Conclusions BMS-986353, a NEX-T investigational CD19-targeted CAR T cell therapy, has a more rapid manufacturing time and optimized phenotypic attributes. In pts with severe, refractory autoimmune diseases, BMS-986353 demonstrates a low rate of low gr CRS and ICANS events. Preliminary data suggest promising efficacy in pts with SLE despite discontinuation of all lupus therapies. Robust CAR T cell expansion comparable to the RP2D of liso-cel and complete B-cell depletion were observed after BMS-986353 at a dose of 10 x 106 CAR+ T cells despite being 1/10 of the RP2D of liso-cel. The studies continue to enroll pts in all autoimmune indications. Updated safety, efficacy, and translational data will be presented.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Background: The microvasculature of the human meniscus has been previously described by Arnoczky and Warren. However, to date, the qualitative and quantitative extra-articular vascular anatomy of the medial meniscus has not been characterized. Purposes: To perform a qualitative and quantitative anatomic study of the extra-articular medial meniscal vasculature and to introduce the novel “medial meniscal artery” (MMA), potentially providing future guidelines for the treatment of meniscal abnormalities. Study Design: Descriptive laboratory study. Methods: A total of 33 unpaired, frozen human cadaveric knees were dissected. The femoral artery was identified and cannulated using an angiocatheter. The arteries were perfused with a red acrylic paint solution, allowing for improved visualization. Artery dimensions and distances were measured using a digital caliper. Perfused specimens were imaged using computed tomography and segmented using 3D reconstruction software to identify vessels and repeat artery measurements digitally. Results: The MMA was consistently identified in all specimens. In 27 (82%) of 33 specimens, the MMA branched directly from the popliteal artery; in 5 (15%), the MMA shared a common trunk with the inferior medial genicular artery; and in 1 specimen (3%), the MMA shared a common branch with the inferior lateral genicular artery. The MMA was easily distinguishable from the superior, inferior, and middle genicular arteries, given its direct course to the medial joint line with terminal branches to the posterior horn of the medial meniscus and deep to the semimembranosus tendon. The MMA exhibited a consistently smaller vessel diameter relative to the genicular arteries. Conclusion: This is the first study to identify and quantitatively describe the MMA in the human knee. The MMA can be identified consistently on gross anatomic dissection in cadaveric donors of varying demographics. Further research is needed to identify and characterize the artery in vivo and to determine the MMA’s role in meniscus preservation surgery. Clinical Relevance: The findings of this study will provide future avenues of research toward understanding medial meniscus vascularization and the genesis of potential degenerative changes when vascularization is poor. This will help to further refine diagnostic and treatment options for meniscus revascularization and compartment preservation. Additionally, this study may help define safe zones in the knee during posterior approaches and expand the base of knowledge for emerging vascular procedures such as genicular artery embolization.

Background: Dilated Cardiomyopathy (DCM) is a major cause of heart failure (HF) and carries a high mortality rate. Drug treatment response for DCM-related HF patients is highly variable, with some patients having no response. A pharmacogenomic approach, genome-wide association study (GWAS) followed by biologically functional validation, can potentially identify genetic determinants of prognosis in DCM and might provide insight into novel biology of DCM pharmacotherapy. Methods: A GWAS was performed using DNA from 686 patients with recent onset DCM who were on standard HF therapy using change in left ventricular ejection fraction (LVEF) at a median of 6 months after initial diagnosis. Cultured human cardiac fibroblasts (HCFs) were used to functionally validate the GWAS findings in vitro . RNA-seq followed by pathway analysis after NAV3 knock-down (KD) using siRNA in HCFs were performed to explore potential biological mechanisms. Results: A genetic variant, rs11105445(G>A), identified from the GWAS, mapping to the neuron navigator 3 (NAV3) gene (rs11105445, p=2.37E-07; beta 2.74 ± 0.53) was associated with improvement in LVEF. Functional genomic experiments demonstrated that, both in LV tissue and in cultured fibroblasts, the minor allele A was associated with decreased transcription of NAV3 (pvalue: 0.0335 and 0.0432) suggesting that ↓NAV3 expression might be associated with improvement in LVEF. TGF-β1 can induce HCF transdifferentiation into myofibroblasts and we demonstrate that it also increases NAV3 expression. NAV3 KD which mimics the GWAS variant significantly suppressed TGF-β1 induced HCF transdifferentiation demonstrated by decreased expression of α-smooth muscle actin (ACTA2) and collagen I (COL1A1). RNA-seq after NAV3 KD followed by pathway analysis suggested that NAV3 exerted its effect by regulating ECM and cell cycle processes, especially G1/S transition. We demonstrate that NAV3 KD suppressed TGF-β1 induced G1/S arrest by regulating CDK4, CDK6 and INK4B (cyclin-dependent kinase inhibitor 2B/P15, CDK4 inhibitor). Conclusion: Decreased expression of NAV3 is associated with myocardial recovery in DCM, most likely due to its role in suppressing HCF differentiation by regulating TGF-β1 induced G1/S arrest. The role of NAV3 as a novel therapeutic target in DCM needs to be explored.

AimsDistal femoral osteotomies (DFOs) are commonly used for the correction of valgus deformities and lateral compartment osteoarthritis. However, the impact of a DFO on subsequent total knee arthroplasty (TKA) function remains a subject of debate. Therefore, the purpose of this study was to determine the effect of a unilateral DFO on subsequent TKA function in patients with bilateral TKAs, using the contralateral knee as a self-matched control group.MethodsThe inclusion criteria consisted of patients who underwent simultaneous or staged bilateral TKA after prior unilateral DFO between 1972 and 2023. The type of osteotomy performed, osteotomy hardware fixation, implanted TKA components, and revision rates were recorded. Postoperative outcomes including the Forgotten Joint Score-12 (FJS-12), Tegner Activity Scale score, and subjective knee preference were also obtained at final follow-up.ResultsA total of 21 patients underwent bilateral TKA following unilateral DFO and were followed for a mean of 31.5 years (SD 11.1; 20.2 to 74.2) after DFO. The mean time from DFO to TKA conversion was 13.1 years (SD 9.7) with 13 (61.9%) of DFO knees converting to TKA more than ten years after DFO. There was no difference in arthroplasty implant systems employed in both the DFO-TKA and TKA-only knees (p > 0.999). At final follow-up, the mean FJS-12 of the DFO-TKA knee was 62.7 (SD 36.6), while for the TKA-only knee it was 65.6 (SD 34.7) (p = 0.328). In all, 80% of patients had no subjective knee preference or preferred their DFO-TKA knee. Three DFO-TKA knees and two TKA-only knees underwent subsequent revision following index arthroplasty at a mean of 12.8 years (SD 6.9) and 8.5 years (SD 3.8), respectively (p > 0.999).ConclusionIn this self-matched study, DFOs did not affect subsequent TKA function as clinical outcomes, subjective knee preference, and revision rates were similar in both the DFO-TKA and TKA-only knees at mean 32-year follow-up.Cite this article: Bone Jt Open 2024;5(11):1013–1019.

Purpose To evaluate the available literature on the relationship between knee bony morphology and medial meniscus posterior root tears (MMPRTs) to determine which tibiofemoral morphologic risk factors may predispose the development of MMPRTs. Methods Embase, MEDLINE, and PubMed databases were searched to identify all relevant human clinical studies investigating knee morphologic features and MMPRTs. Shape features were compared between control groups and patients with MMPRTs. The methodological index for nonrandomized studies (MINORS) instrument was utilized to assess the methodological quality of included studies. Results Thirteen level III evidence studies and 1 level IV evidence study were included in this review (n = 2,181), with 895 patients in the MMPRT group and 1,286 in the control group. Tibial morphology features associated with an increased risk for MMPRTs included an increased medial tibial slope (6 studies), increased tibial torsion (1 study), increased medial meniscal slope (1 study), and shallower medial tibial plateau concavity (1 study). Varus mechanical alignment was found to increase the risk for MMPRTs (4 studies). Femoral morphology features associated with an increased risk for MMPRTs included an A‐type intercondylar notch (1 study), increased medial femoral condyle (MFC) angle (1 study), narrower intercondylar distance (1 study), narrower intercondylar notch width (1 study), shorter MFC distal offset distance (1 study), increased MFC width (1 study), increased MFC to medial tibial condyle width ratio (1 study), greater distance between the medial tibial eminence and MFC (1 study), and smaller femoral offset ratios of both the medial and lateral condyles (1 study). Conclusions Multiple tibiofemoral shape features, including a steeper slope of the medial tibial plateau, greater varus alignment, and a narrower intercondylar distance and notch width, were found to be predictive factors for MMPRTs. Level of Evidence Level IV, systematic review of Level III and IV studies.

Abstract Periprosthetic fractures of the lesser trochanter may migrate proximally and result in anterior mechanical irritation and impingement with hip flexion refractory to comprehensive conservative management. In such cases, patients may benefit from arthroscopic resection of the displaced lesser trochanteric fragment. We present a minimally invasive, arthroscopic approach with initial access through an air bursogram. This technique can be performed percutaneously, with standard access cannulas, without the need for additional disposable instrumentation or large cannulas. In such a way, reproducible arthroscopic instrumentation can be provided for safe and efficient fragment removal while remaining cognizant of the nearby medial neurovascular bundle. Technique Video video See video under supplementary data.

Background: Patients with persistent symptomatic iliopsoas tendonitis following total hip arthroplasty may benefit from iliopsoas fractional lengthening. We present an arthroscopic approach utilizing an air bursogram that provides safe and predictable access to the iliopsoas tendon for efficient tendon lengthening without violating the capsule or unintentional instrumentation of the nearby medial neurovascular bundle. Indications: Arthroscopic iliopsoas fractional lengthening is indicated for patients with clinical evidence of symptomatic iliopsoas tendonitis following total hip arthroplasty and have no radiographic evidence of frank acetabular malpositioning. A diagnosis of iliopsoas tendinitis amenable to surgical management can be established with substantial but nondurable relief following image-guided anesthetic injection to the iliopsoas bursa. Technique Description: Under fluoroscopic guidance, an air bursogram is employed in the anatomic plane of the iliopsoas tendon to accurately identify its course. This allows for hip portal placement with precise subsequent instrumentation. This technique is preferred in the setting of postarthroplasty anatomy because it avoids capsular violation and the challenge of working in an altered anatomic space with a nearby, medially based neurovascular bundle. Results: Arthroscopic and endoscopic approaches to iliopsoas release have been shown to provide excellent functional and patient-reported outcomes in >85% of patients, and several studies have shown that an arthroscopic approach not only provides a less invasive technique but also results in comparable or improved clinical outcomes with lower revision rates compared to open release or acetabular cup revision. Our technique for arthroscopic iliopsoas fractional lengthening using the air bursogram is both safe and reproducible and offers distinct advantages, including maintenance of an intact capsule, visual confirmation of the correct anatomic structure to be released, and percutaneous access with standard arthroscopic access cannulas without the need for hip distraction. Conclusions: Arthroscopic fractional iliopsoas lengthening is a minimally invasive and successful treatment option for patients with persistent groin pain after total hip arthroplasty, especially without substantial acetabular component malpositioning. This technique includes using an air bursogram to safely identify and navigate to the iliopsoas tendon without violating the hip capsule, thereby reducing the risk of inadvertent instrumentation of adjacent critical neurovascular structures. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.