Safety and use of late-turndown liver allografts to increase rate of transplantation.

BACKGROUND: The demand for liver transplants (LT) in the United States far surpasses the availability of allografts. New allocation schemes have resulted in occasional difficulties with allograft placement and increased intraoperative turndowns. We aimed to evaluate the outcomes related to use of late-turndown liver allografts. METHODS: A review of prospectively collected data of LTs at a single center from July 2019 to July 2023 was performed. Late-turndown placement was defined as an open offer 6 h prior to donation, intraoperative turndown by primary center, or post-cross-clamp turndown. RESULTS: Of 565 LTs, 25.1% (n = 142) received a late-turndown liver allograft. There were no significant differences in recipient age, gender, BMI, or race (all p > 0.05), but MELD was lower for the late-turndown LT recipient group (median 15 vs 21, p < 0.001). No difference in 30-day, 6-month, or 1-year survival was noted on logistic regression, and no difference in patient or graft survival was noted on Cox proportional hazard regression. Late-turndown utilization increased during the study from 17.2% to 25.8%, and median waitlist time decreased from 77 days in 2019 to 18 days in 2023 (p < 0.001). CONCLUSION: Use of late-turndown livers has increased and can increase transplant rates without compromising post-transplant outcomes with appropriate selection.

Targeting Rab7-Rilp Mediated Microlipophagy Alleviates Lipid Toxicity in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction, which progresses into heart failure and aberrant electrophysiology in diabetic patients. Dyslipidemia in type 2 diabetic patients leads to the accumulation of lipid droplets (LDs) in cardiomyocytes and results in lipid toxicity which has been suggested to drive DbCM. It is aimed to explore potential pathways that may boost LDs degradation in DbCM and restore cardiac function. LDs accumulation resulted in an increase in lipid toxicity in DbCM hearts is confirmed. Microlipophagy pathway, rather than traditional macrolipophagy, is activated in DbCM hearts. RNA-Seq data and Rab7-CKO mice implicate that Rab7 is a major modulator of the microlipophagy pathway. Mechanistically, Rab7 is phosphorylated at Tyrosine 183, which allows the recruitment of Rab-interacting lysosome protein (Rilp) to proceed LDs degradation by lysosome. Treating DbCM mice with Rab7 activator ML-098 enhanced Rilp level and rescued the observed cardiac dysfunction. Overall, Rab7-Rilp-mediated microlipophagy may be a promising target in the treatment of lipid toxicity in DbCM is suggested.

Angiopoietin-like protein 2 inhibits thrombus formation.

Acute myocardial infarction is mainly caused by a lack of blood flood in the coronary artery. Angiopoietin-like protein 2 (ANGPTL2) induces platelet activation and thrombus formation in vitro through binding with immunoglobulin-like receptor B, an immunoglobulin superfamily receptor. However, the mechanism by which it regulates platelet function in vivo remains unclear. In this study, we investigated the role of ANGPTL2 during thrombosis in relationship with ST-segment elevation myocardial infarction (STEMI) with spontaneous recanalization (SR). In a cohort of 276 male and female patients, we measured plasma ANGPTL2 protein levels. Using male Angptl2-knockout and wild-type mice, we examined the inhibitory effect of Angptl2 on thrombosis and platelet activation both in vivo and ex vivo. We found that plasma and platelet ANGPTL2 levels were elevated in patients with STEMI with SR compared to those in non-SR (NSR) patients, and was an independent predictor of SR. Angptl2 deficiency accelerated mesenteric artery thrombosis induced by FeCl3 in Angptl2-/- compared to WT animals, promoted platelet granule secretion and aggregation induced by thrombin and collogen while purified ANGPTL2 protein supplementation reversed collagen-induced platelet aggregation. Angptl2 deficiency also increased platelet spreading on immobilized fibrinogen and clot contraction. In collagen-stimulated Angptl2-/- platelets, Src homology region 2 domain-containing phosphatase (Shp)1-Y564 and Shp2-Y580 phosphorylation were attenuated while Src, Syk, and Phospholipase Cγ2 (PLCγ2) phosphorylation increased. Our results demonstrate that ANGPTL2 negatively regulated thrombus formation by activating ITIM which can suppress ITAM signaling pathway. This new knowledge provides a new perspective for designing future antiplatelet aggregation therapies.

Tracking single hiPSC-derived cardiomyocyte contractile function using CONTRAX an efficient pipeline for traction force measurement.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models to study the mechanisms underlying cardiomyopathies and cardiotoxicity. Quantification of the contractile function in single hiPSC-CMs at high-throughput and over time is essential to disentangle how cellular mechanisms affect heart function. Here, we present CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time. Three software modules enable: parameter-based identification of single hiPSC-CMs; automated video acquisition of >200 cells/hour; and contractility measurements via traction force microscopy. We analyze >4,500 hiPSC-CMs over time in the same cells under orthogonal conditions of culture media and substrate stiffnesses; +/- drug treatment; +/- cardiac mutations. Using undirected clustering, we reveal converging maturation patterns, quantifiable drug response to Mavacamten and significant deficiencies in hiPSC-CMs with disease mutations. CONTRAX empowers researchers with a potent quantitative approach to develop cardiac therapies.

Titration of Medications After Acute Heart Failure Is Safe, Tolerated, and Effective Regardless of Risk.

BACKGROUND: Guideline-directed medical therapy (GDMT) decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF (Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure), high-intensity care (HIC) in the form of rapid uptitration of heart failure (HF) GDMT was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses. OBJECTIVES: The authors sought to assess safety, tolerability, and efficacy of HIC according to the simple, powerful, and clinically translatable MAGGIC (Meta-Analysis Global Group in Chronic) HF risk score. METHODS: In STRONG-HF, 1,078 patients with acute HF were randomized to HIC (uptitration of treatments to 100% of recommended doses within 2 weeks of discharge and 4 scheduled outpatient visits over the 2 months after discharge) vs usual care (UC). The primary endpoint was the composite of all-cause death or first HF rehospitalization at day 180. Baseline HF risk profile was determined by the previously validated MAGGIC risk score. Treatment effect was stratified according to MAGGIC risk score both as a categorical and continuous variable. RESULTS: Among 1,062 patients (98.5%) with complete data for whom a MAGGIC score could be calculated at baseline, GDMT use at baseline was similar across MAGGIC tertiles. Overall GDMT prescriptions achieved for individual medication classes were higher in the HIC vs UC group and did not differ by MAGGIC risk score tertiles (interaction nonsignificant). The incidence of all-cause death or HF readmission at day 180 was, respectively, 16.3%, 18.9%, and 23.2% for MAGGIC risk score tertiles 1, 2, and 3. The HIC arm was at lower risk of all-cause death or HF readmission at day 180 (HR: 0.66; 95% CI: 0.50-0.86) and this finding was robust across MAGGIC risk score modeled as a categorical (HR: 0.51; 95% CI: 0.62-0.68 in tertiles 1, 2, and 3; interaction nonsignificant) for all comparisons and continuous (interaction nonsignificant) variable. The rate of adverse events was higher in the HIC group, but this observation did not differ based on MAGGIC risk score tertile (interaction nonsignificant). CONCLUSIONS: HIC led to better use of GDMT and lower HF-related morbidity and mortality compared with UC, regardless of the underlying HF risk profile. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies [STRONG-HF]; NCT03412201).

Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission.

Background: Explore the efficacy and safety of donor-derived CLL-1 chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory acute myeloid leukemia (R/R AML) bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission. Case presentation: An adult R/R AML patient received an infusion of donor-derived CLL-1 CAR-T cells, and the conditioning regimen bridging to allo-HSCT was started immediately after remission on day 11 after CAR-T therapy upon transplantation. Then, routine post-HSCT monitoring of blood counts, bone marrow (BM) morphology, flow cytometry, graft-versus-host disease (GVHD) manifestations, and chimerism status were performed. Result: After CAR-T therapy, cytokine release syndrome was grade 1. On day 11 after CAR-T therapy, the BM morphology reached complete remission (CR), and the conditioning regimen bridging to allo-HSCT started. Leukocyte engraftment, complete donor chimerism, and platelet engraftment were observed on days +18, +23, and +26 post-allo-HSCT, respectively. The BM morphology showed CR and flow cytometry turned negative on day +23. The patient is currently at 4 months post-allo-HSCT with BM morphology CR, negative flow cytometry, complete donor chimerism, and no extramedullary relapse/GVHD. Conclusion: Donor-derived CLL-1 CAR-T is an effective and safe therapy for R/R AML, and immediate bridging to allo-HSCT after remission may better improve the long-term prognosis of R/R AML.

Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence.

Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in aging and are targets of DNA damage response. Although we and others have demonstrated presence of short telomeres in genetic cardiomyopathic and heart failure cardiomyocytes, little is known about the role of telomere lengths in cardiomyocyte. Here, we demonstrate that in heart failure patient cardiomyocytes, telomeres are shortened compared to healthy controls. We generated isogenic human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) with short telomeres (sTL-CMs) and normal telomeres (nTL-CMs) as model. Compared to nTL-CMs, short telomeres result in cardiac dysfunction and expression of senescent markers. Using Hi-C and RNASeq, we observe that short telomeres induced TAD insulation decrease near telomeric ends and this correlated with a transcription upregulation in sTL-CMs. FOXC1, a key transcription factor involved in early cardiogenesis, was upregulated in sTL-CMs and its protein levels were negatively correlated with telomere lengths in heart failure patients. Overexpression of FOXC1 induced hiPSC-CM aging, mitochondrial and contractile dysfunction; knockdown of FOXC1 rescued these phenotypes. Overall, the work presented demonstrate that increased chromatin accessibility due to telomere shortening resulted in the induction of FOXC1-dependent expression network responsible for contractile dysfunction and myocardial senescence.

Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.

BACKGROUND: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. METHODS: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. RESULTS: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). CONCLUSIONS: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

Medical Decision-Making and Revascularization in Ischemic Cardiomyopathy.

Ischemic cardiomyopathy (ICM) is the most common underlying etiology of heart failure in the United States and is a significant contributor to deaths due to cardiovascular disease worldwide. The diagnosis and management of ICM has advanced significantly over the past few decades, and the evidence for medical therapy in ICM is both compelling and robust. This contrasts with evidence for coronary revascularization, which is more controversial and favors surgical approaches. This review will examine landmark clinical trial results in detail as well as provide a comprehensive overview of the current epidemiology, diagnostic approaches, and management strategies of ICM.

Cytokine-based models for efficient differentiation between infection and cytokine release syndrome in patients with hematological malignancies.

Although the efficacy of chimeric antigen receptor (CAR)-T cell therapy has been widely demonstrated, its clinical application is hampered by the complexity and fatality of its side effects. Cytokine release syndrome (CRS) is the most common toxicity following CAR-T cell infusion, and its symptoms substantially overlap with those of infection. Whereas, current diagnostic techniques for infections are time-consuming and not highly sensitive. Thus, we are aiming to develop feasible and efficient models to optimize the differential diagnosis in clinical practice. This study included 191 febrile patients from our center, including 85 with CRS-related fever and 106 with infectious fever. By leveraging the serum cytokine profile at the peak of fever, we generated differential models using a classification tree algorithm and a stepwise logistic regression analysis, respectively. The first model utilized three cytokines (IFN-ß, CXCL1, and CXCL10) and demonstrated high sensitivity (90% training, 100% validation) and specificity (98.44% training, 90.48% validation) levels. The five-cytokine model (CXCL10, CCL19, IL-4, VEGF, and CCL20) also showed high sensitivity (91.67% training, 95.65% validation) and specificity (98.44% training, 100% validation). These feasible and accurate differentiation models may prompt early diagnosis of infections during immune therapy, allowing for early and appropriate intervention.

Resolution of Severe Portopulmonary Hypertension With Inhaled Treprostinil and Liver Transplantation.

Portopulmonary hypertension is a rare condition with a poor prognosis. Prompt management is essential for liver transplantation eligibility, a potentially curative option. This report presents a case of severe portopulmonary hypertension that resolved with a conservative therapeutic regimen of tadalafil, macitentan, and inhaled treprostinil, which ultimately enabled successful liver transplantation. There was no recurrence of pulmonary hypertension after transplantation, and the patient was weaned off most pulmonary arterial hypertension therapies. This case report is the first to provide evidence that inhaled treprostinil is a safe and effective alternative to continuous intravenous prostacyclins in portopulmonary hypertension.

Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation.

Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre+) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre+ mice with DoIC, as compared to Csef/f/Cre- mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.

Advancing patient-centered research practices in a pragmatic patient-level randomized clinical trial: A thematic analysis of stakeholder engagement in Emergency Medicine Palliative Care Access (EMPallA).

BACKGROUND: Involving patient and community stakeholders in clinical trials adds value by ensuring research prioritizes patient goals both in conduct of the study and application of the research. The use of stakeholder committees and their impact on the conduct of a multicenter clinical trial have been underreported clinically and academically. The aim of this study is to describe how Study Advisory Committee (SAC) recommendations were implemented throughout the Emergency Medicine Palliative Care Access (EMPallA) trial. EMPallA is a multi-center, pragmatic two-arm randomized controlled trial (RCT) comparing the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. METHODS: A SAC consisting of 18 individuals, including patients with palliative care experience, members of healthcare organizations, and payers was convened for the EMPallA trial. The SAC engaged in community-based participatory research and assisted in all aspects from study design to dissemination. The SAC met with the research team quarterly and annually from project inception to dissemination. Using meeting notes and recordings we completed a qualitative thematic analysis using an iterative process to develop themes and subthemes to summarize SAC recommendations throughout the project's duration. RESULTS: The SAC convened 16 times between 2017 and 2020. Over the course of the project, the SAC provided 41 unique recommendations. Twenty-six of the 41 (63%) recommendations were adapted into formal Institutional Review Board (IRB) study modifications. Recommendations were coded into four major themes: Scientific, Pragmatic, Resource and Dissemination. A majority of the recommendations were related to either the Scientific (46%) or Pragmatic (29%) themes. Recommendations were not mutually exclusive across three study phases: Preparatory, execution and translational. A vast majority (94%) of the recommendations made were related to the execution phase. Major IRB study modifications were made based on their recommendations including data collection of novel dependent variables and expanding recruitment to Spanish-speaking patients. CONCLUSIONS: Our study provides an example of successful integration of a SAC in the conduct of a pragmatic, multi-center RCT. Future trials should engage with SACs in all study phases to ensure trials are relevant, inclusive, patient-focused, and attentive to gaps between health care and patient and family needs. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03325985, 10/30/2017.

Clinical research should involve patient and community stakeholder perspectives to make sure the study addresses questions important to the studied population. One way to do this is by creating a group of stakeholders who can advise on the conduct of a study. We assembled a Study Advisory Committee (SAC) for the Emergency Medicine Palliative Care Access (EMPallA) trial. The purpose of this clinical trial is to compare the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. This paper describes how the SACs involvement translated into direct impacts on the EMPallA trial. The trial research team held regular meetings with the SAC throughout the trial process. Their involvement led to many significant changes in the trial, such as  expanding recruitment inclusion criteria (Spanish-speaking patients), and including survey instruments to measure lonelines and caregiver burden. The SAC also devised strategies to overcome patient and caregiver recruitment and retention challenges, including the creation of patient-friendly materials and training for research coordinators. This study provides a successful example of how actively engaging patient and community stakeholders, through committee engagement, can promote patient priorities in all phases of a trial while facilitating patient recruitment and retention.

Association of eGFR and Albuminuria with Venous Thromboembolism.

BACKGROUND: CKD has been implicated as a risk factor of venous thromboembolism, but the evidence is limited to relatively healthy populations. The objective of this study was to discern whether parameters of kidney function and damage are associated with the occurrence of venous thromboembolism after hospitalization. METHODS: We conducted a retrospective study including 23,899 and 11,552 adult individuals hospitalized within Geisinger Health System and New York University (NYU) Langone Health from 2004 to 2019 and 2012 to 2022, respectively. A Poisson model was used to evaluate adjusted incidence rates of venous thromboembolism according to eGFR and albuminuria categories in each cohort. Cox proportional hazards models were used to analyze associations of eGFR and urinary albumin-to-creatinine ratio (UACR) with venous thromboembolism, and hazard ratios (HRs) were meta-analyzed across cohorts. RESULTS: Both lower eGFR and higher UACR were associated with higher risks of venous thromboembolism. In the Geisinger cohort, the incidence of venous thromboembolism after hospital discharge ranged from 10.7 (95% confidence interval [CI], 9.2 to 12.6) events per 1000 person-years in individuals in G1A1 (eGFR >90 ml/min per 1.73 m 2 and UACR <30 mg/g) to 27.7 (95% CI, 20.6 to 37.2) events per 1000 person-years in individuals with G4-5A3 (eGFR <30 ml/min per 1.73 m 2 and UACR >300 mg/g). A similar pattern was observed in the NYU cohort. Meta-analyses of the two cohorts showed that every 10 ml/min per 1.73 m 2 reduction in eGFR below 60 ml/min per 1.73 m 2 was associated with a 6% higher risk of venous thromboembolism (HR 1.06 [95% CI, 1.02 to 1.11], P = 0.01), and each two-fold higher UACR was associated with a 5% higher risk of venous thromboembolism (HR 1.05 [95% CI, 1.03 to 1.07], P < 0.001). CONCLUSIONS: Both eGFR and UACR were independently associated with higher risk of venous thromboembolism after hospitalization. The incidence rate was higher with greater severity of CKD. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_12_14_CJN0000000000000352.mp3.

Baclofen and the risk of fall and fracture in older adults: A real-world cohort study.

BACKGROUND: The growth of oral muscle relaxant prescriptions among older adults in the United States is concerning due to the drugs' adverse sedative effects. Baclofen is a gamma-aminobutyric acid agonist muscle relaxant that is associated with encephalopathy. We characterized the risk of fall and fracture associated with oral baclofen against other muscle relaxants (tizanidine or cyclobenzaprine) in older adults. METHODS: We designed a new-user, active-comparator study using tertiary health system data from Geisinger Health, Pennsylvania (January 2005 through December 2018). Older adults (aged ≥65 years) newly treated with baclofen, tizanidine, or cyclobenzaprine were included. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance the treatment groups on 58 baseline characteristics. Fine-Gray competing risk regression was used to estimate the risk of fall and fracture. RESULTS: The study cohort comprised of 2205 new baclofen users, 1103 new tizanidine users, and 9708 new cyclobenzaprine users. During a median follow-up of 100 days, baclofen was associated with a higher risk of fall compared to tizanidine (IPTW incidence rate, 108.4 vs. 61.9 per 1000 person-years; subdistribution hazard ratio [SHR], 1.68 [95% CI, 1.20-2.36]). The risk of fall associated with baclofen was comparable to cyclobenzaprine (SHR, 1.17 [95% CI, 0.93-1.47]) with a median follow-up of 106 days. The risk of fracture was similar among patients treated with baclofen versus tizanidine (SHR, 0.85 [95% CI, 0.63-1.14]) or cyclobenzaprine (SHR, 0.85 [95% CI, 0.67-1.07]). CONCLUSIONS: The risk of fall associated with baclofen was greater than tizanidine, but not compared to cyclobenzaprine in older adults. The risk of fracture was comparable among the older users of baclofen, tizanidine, and cyclobenzaprine. Our findings may inform risk-benefit considerations in the increasingly common clinical encounters where oral muscle relaxants are prescribed.

Cross-bispectrum connectivity of intracranial EEG: A novel approach to seizure onset zone localization.

Connectivity analyses of intracranial electroencephalography (iEEG) could guide surgical planning for epilepsy surgery by improving the delineation of the seizure onset zone. Traditional approaches fail to quantify important interactions between frequency components. To assess if effective connectivity based on cross-bispectrum -a measure of nonlinear multivariate cross-frequency coupling- can quantitatively identify generators of seizure activity, cross-bispectrum connectivity between channels was computed from iEEG recordings of 5 patients (34 seizures) with good postsurgical outcome. Personalized thresholds of 50% and 80% of the maximum coupling values were used to identify generating electrode channels. In all patients, outflow coupling between α (8-15 Hz) and ß (16-31 Hz) frequencies identified at least one electrode inside the resected seizure onset zone. With the 50% and 80% thresholds respectively, an average of 5 (44.7%; specificity = 82.6%) and 2 (22.5%; specificity = 99.0%) resected electrodes were correctly identified. Results show promise for the automatic identification of the seizure onset zone based on cross-bispectrum connectivity analysis.

High fat diet reveals sex-specific fecal and liver metabolic alterations in C57BL/6J obese mice.

Obesity is a major health concern that poses significant risks for many other diseases, including diabetes, cardiovascular disease, and cancer. Prevalence of these diseases varies by biological sex. This study utilizes a mouse (C57BL/6J) model of obesity to analyze liver and fecal metabolic profiles at various time points of dietary exposure: 5, 9, and 12 months in control or high fat diet (HFD)-exposed mice. Our study discovered that the female HFD group has a more discernable perturbation and set of significant changes in metabolic profiles than the male HFD group. In the female mice, HFD fecal metabolites including pyruvate, aspartate, and glutamate were lower than control diet-exposed mice after both 9th and 12th month exposure time points, while lactate and alanine were significantly downregulated only at the 12th month. Perturbations of liver metabolic profiles were observed in both male and female HFD groups, compared to controls at the 12th month. Overall, the female HFD group showed higher lactate and glutathione levels compared to controls, while the male HFD group showed higher levels of glutamine and taurine compared to controls. These metabolite-based findings in both fecal and liver samples for a diet-induced effect of obesity may help guide future pioneering discoveries relating to the analysis and prevention of obesity in people, especially for females.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.