Citations

Abstract Background: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. Methods: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. Results: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p < 0.001) and had a higher prevalence of atrial fibrillation (77% vs 26%; p < 0.001). Their baseline National Institutes of Health Stroke Scale (NIHSS) scores were also higher (median 12 vs 9; p = 0.002). Before propensity score matching (PSM), anticoagulated patients had similar rates of favorable 90-day outcomes (mRS 0–1: 30% vs 37%, p = 0.1; mRS 0–2: 47% vs 50%, p = 0.41) but higher mortality (26% vs 17%, p = 0.008). After PSM, there were no significant differences in outcomes between the two groups. Conclusion: Anticoagulated patients undergoing MT for AIS due to DMVO did not show significant differences in 90-day mRS outcomes, reperfusion, or hemorrhage compared to non-anticoagulated patients after adjustment for covariates.

Objective Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. Design Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). Result We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. Conclusion Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

AbstractBackgroundThe potential association of long‐term oral corticosteroid (OCS) use with adverse events (AEs) in patients with bullous pemphigoid (BP) is not well characterized in a real‐world setting.ObjectivesTo evaluate the effect of OCS use and treatment duration on the incident AEs in patients with BP.MethodsThis retrospective cohort study used medical and pharmacy claims and patient enrollment data from IQVIA PharMetrics® Plus from 2006−2021. Eligible patients had a diagnosis of BP between 1 January 2006 and 30 June 2020 (≥2 claims for BP ≥ 30 days apart). Patients in the OCS cohort also had a claim for OCS use, ≥7.5 mg daily dose of prednisone or equivalent, and no claims for a nonoral systemic corticosteroid (CS) at any time during the study period. A control cohort of patients with BP not using OCS was also selected. Relative risk ratios were estimated between the incidence of AEs in OCS users with different exposure durations (short‐term, <30 days; medium‐term, 30−90 days; long‐term, >90 days) and nonusers by Poisson regression, after adjusting for age, sex, prior drug use, and baseline Charlson Comorbidity Index score within the follow‐up period.ResultsAt the 1‐year follow‐up, long‐term OCS users had a higher incidence of infections, cataract, osteoporosis, heart failure, depression or anxiety, and diabetes compared with OCS nonusers (p < 0.05). Furthermore, compared with nonusers, long‐term users had increased 1‐year risks (risk ratio; 95% confidence interval) for heart failure (2.27; 1.50−3.44), diabetes (2.05; 1.30−3.24), osteoporosis (1.72; 1.23−2.41), and infection (1.50; 1.13−1.99). Long‐term OCS users also had increased 1‐year risks for heart failure (2.00; 1.21−3.28) and osteoporosis (1.70; 1.16−2.50) compared with short‐term OCS users.ConclusionsLong‐term OCS use (≥7.5 mg) in patients with BP was associated with an increased risk of AEs. Study findings demonstrate a need for steroid‐sparing options with an improved safety profile.

AbstractThe objective of the current study is to develop a new method for tracking transplanted human induced pluripotent stem cells‐derived cardiomyocytes (hiPSC‐CMs) using magnetic resonance imaging (MRI). The CRISPR/dCas9 activation system is employed to overexpress ferritin heavy chain (FHC) in hiPSC‐CMs. The mRNA and protein expression of FHC in hiPSC and hiPSC‐CMs significantly increased after transfection. Iron chloride does not affect the cell viability in a concentration range from 0 to 2000 µm. hiPSCs overexpressing FHC (hiPSC‐ FHCOE) and hiPSC‐CMs overexpressing FHC (hiPSC‐CM‐FHCOE) significantly enhanced cellular uptake of iron chloride but with no changes in electrophysiological properties compared to hiPSC‐CM‐Control. Furthermore, hiPSC‐CM‐FHCOE presented robust contrast and lower T2* values, signifying their potential as highly effective candidates for cardiac MRI. Next, hiPSC‐CM‐FHCOE is injected into mouse hearts and after 3 days of transplantation, MR images are obtained. hiPSC‐CM‐FHCOE cells exhibited clear signals in the hearts with lower T2* and rapid signal decay. Collectively, data from this proof‐of‐concept study demonstrated that endogenous labeling with FHC in hiPSC‐CMs can be a potent strategy for enhancing the accuracy of cardiac MRI. This technology represents a significant step forward in tracking the transplanted hiPSC‐CMs in the hearts of live animals.

Study Design: Retrospective analysis of a prospective, multicenter registry. Objective: To assess whether upper or lower limb mJOA improvement more strongly associates with patient satisfaction after surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data: The modified Japanese Orthopaedic Association (mJOA) is commonly used to assess functional status in patients with CSM. Patients present with upper and/or lower extremity dysfunction, and it is unclear whether improvement in one and/or both symptoms drives postoperative patient satisfaction. Methods: This study utilizes the prospective Quality Outcomes Database (QOD) CSM data set. Clinical outcomes included mJOA and North American Spine Society (NASS) satisfaction. The upper limb mJOA score was defined as upper motor plus sensory mJOA, and the lower limb mJOA as lower motor plus sensory mJOA. Ordered logistic regression was used to determine whether upper or lower limb mJOA was more closely associated with NASS satisfaction, adjusting for other covariates. Results: Overall, 1141 patients were enrolled in the QOD CSM cohort. In all, 780 had both preoperative and 24-month mJOA scores, met inclusion criteria, and were included for analysis. The baseline mJOA was 12.1±2.7, and postoperatively, 85.6% would undergo surgery again (NASS 1 or 2, satisfied). Patients exhibited mean improvement in both upper (baseline:3.9±1.4 vs. 24 mo:5.0±1.1, P<0.001) and lower limb mJOA (baseline:3.9±1.4 vs. 24 mon:4.5±1.5, P<0.001); however, the 24-month change in the upper limb mJOA was greater (upper:1.1±1.6 vs. lower:0.6±1.6, P<0.001). Across 24-month NASS satisfaction, the baseline upper and lower limb mJOA scores were similar (pupper=0.28, plower=0.092). However, as satisfaction decreased, the 24-month change in upper and lower limb mJOA decreased as well (pupper<0.001, plower<0.001). Patients with NASS scores of 4 (lowest satisfaction) did not demonstrate significant differences from baseline in upper or lower limb mJOA (P>0.05). In ordered logistic regression, NASS satisfaction was independently associated with upper limb mJOA improvement (OR=0.81; 95% CI: 0.68-0.97; P=0.019) but not lower limb mJOA improvement (OR=0.84; 95% CI: 0.70-1.0; P=0.054). Conclusions: As the magnitude of upper and lower mJOA improvement decreased postoperatively, so too did patient satisfaction with surgical intervention. Upper limb mJOA improvement was a significant independent predictor of patient satisfaction, whereas lower limb mJOA improvement was not. These findings may aid preoperative counseling, stratified by patients’ upper and lower extremity treatment expectations. Level of Evidence: Level—III.

Racial, ethnic, and socioeconomic disparities exist in the prevalence and natural history of chronic liver disease, access to care, and clinical outcomes. Solutions to improve health equity range widely, from digital health tools to policy changes. The current review outlines the disparities along the chronic liver disease health care continuum from screening and diagnosis to the management of cirrhosis and considerations of pre-liver and post-liver transplantation. Using a health equity research and implementation science framework, we offer pragmatic strategies to address barriers to implementing high-quality equitable care for patients with chronic liver disease.

Abstract Background The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. NEJM 2020, Curigliano et al. Ann Oncol 2022). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS, time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a two-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in Austria, Chile, Greece, Italy, Japan, Poland, Portugal, Spain, the US, and several other European, APAC, and LATAM countries. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara O'Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-11.