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Multi-omics analysis of a pig-to-human decedent kidney xenotransplant.
No full textOrgan shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host\u27s blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A65, SPP16 (Osteopontin), and COLEC117, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival
State-Level Malpractice Factors and Imaging Utilization in Patients Presenting to the Emergency Department With Headache: A National Medicaid Analysis.
No full textCase Study of an Unusual Intracranial Mesenchymal Neoplasm.
No full textBACKGROUND AND IMPORTANCE: A 51-year-old woman with multiple sclerosis (MS) presented for MS management and follow-up, including repeat MRIs. On imaging, a slowly growing enhancing lesion was noted in the left posterior insula. Histopathology reported this tumor as a low-grade mesenchymal neoplasm, not elsewhere classified. The case reported here will add to the library of central nervous system tumors, which may help identify other previously unclassifiable tumors.
CLINICAL PRESENTATION: The lesion was inconsistent with MS plaques, and MRI and computed tomography angiography showed no signs of aneurysm. After evaluation, we recommended surgery to remove the lesion. Surgical excision posed a challenge as the dominant hemisphere posterior insula can be difficult to access. We used a trans-sylvian approach, sparing vasculature within the sylvian fissure with clean excisional margins. The trans-sylvian approach enabled minimal manipulation of brain tissue surrounding the lesion, including the receptive speech center. The patient recovered without complications. Postsurgical follow-up revealed no new neurological symptoms or deficits and no sign of tumor recurrence.
CONCLUSION: The trans-sylvian approach we used to excise the tumor resulted in a favorable outcome for the patient. This case supports that the trans-sylvian approach, while technically more demanding, is feasible and potentially beneficial
XComposition: multimodal deep learning model to measure body composition using chest radiographs and clinical data.
No full textBackground: Body composition metrics such as visceral fat volume, subcutaneous fat volume, and skeletal muscle volume are important predictors of cardiovascular disease, diabetes, and cancer prognosis.
Purpose: We explore the use of deep learning to estimate body composition metrics from chest radiographs and a small set of easily obtainable clinical variables.
Materials and methods: A retrospective cohort of patients with concurrent noncontrast abdominal CT\u27s and frontal chest radiographs within 3 months of each other was selected. A multitask, multimodal, deep learning model using chest radiographs and clinical variables (age, sex at birth, height and weight extracted from electronic medical records) was trained to estimate the body composition metrics. Reference standard was body composition, including subcutaneous fat volume, measured on CT.
Results: Our final cohort consisted of 1118 patients (582 female and 538 male subjects) from 30 health systems across the United States with imaging performed from 2010 to 2024. The mean age at imaging was 67 years (SD: 17), mean height was 1.67 meters (SD: 0.2), and mean weight was 78 kg (SD: 20). Average values for visceral fat, subcutaneous fat, and skeletal muscle indices were 59.39 cm2/m2 (SD: 39.26), 88.13 cm2/m2 (SD: 58.52), and 44.81 cm2/m2 (SD: 15.49). The best-performing model achieved a Pearson correlation of 0.85 (95% CI: 0.81-0.88) for subcutaneous fat volume, 0.76 (0.65-0.80) for visceral fat volume, and 0.58 (0.49-0.67) for skeletal muscle volume with the multimodal model outperforming unimodal models (P = .0001 for subcutaneous fat volume). Mean absolute errors of the best performing models for subcutaneous and visceral fat volumes were 1054 cm3/m2 and 667 cm3/m2, respectively.
Conclusion: We introduced a multimodal deep learning model leveraging chest radiographs to estimate body composition. Our model can facilitate large-scale studies by estimating body composition using a chest radiograph and commonly available clinical variables
Emapalumab use in malignancy-associated hemophagocytic lymphohistiocytosis in the United States: The REAL-HLH study.
No full textMalignancy-associated hemophagocytic lymphohistiocytosis (mHLH), a hyperinflammatory syndrome, has poor prognosis and no standard therapy. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-gamma, is approved for treating primary hemophagocytic lymphohistiocytosis (pHLH). REAL-HLH, a retrospective chart review conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with at least 1 dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with mHLH. Overall, 51/105 (48.6%) patients did not meet the pHLH classification criteria and were categorized as presenting with secondary HLH; 17/51 patients had underlying malignancy (mHLH). At HLH diagnosis, median age (range) was 15.0 (3.0-27.0) years, 6/14 (42.9%) patients with available data had a positive Optimized HLH Inflammatory index indicating pathologic inflammation; 9/17 (52.9%) had infections, and 10/17 (58.8%) received emapalumab in an intensive care unit. Emapalumab was primarily initiated for treating refractory (10/17; 58.8%) or progressive (3/17, 17.7%) disease. Most patients received HLH-related therapies before (16/17; 94.1%) and/or concurrent with (15/17; 88.2%) emapalumab. Most key laboratory parameters improved, and some (fibrinogen [11/13; 84.6%], absolute neutrophil count [6/10; 60%], and CXCL9 [7/8; 87.5%]), normalized or stabilized per physician assessment, following treatment with emapalumab-containing regimens. Overall survival at the end of follow-up and 12-month survival probability from emapalumab initiation were 23.5% and 22.1%, respectively. In conclusion, emapalumab-containing regimens improved or normalized most laboratory parameters in patients with mHLH. Future studies are warranted to establish appropriate emapalumab dosing and utility in this high-risk population
Retrospective, Observational Study of Recovery in Pediatric Recurrent Concussions.
No full textRecurrent concussion (RC) studies, especially in young children, are limited and provide conflicting results. We studied 505 children sustaining concussions presenting to an outpatient concussion clinic over a 2-year period, ages 5-18, of which 207 were RCs. Recovery time was defined by days to return to play (RTP), return to learn (RTL), and headache recovery (HR). Recovery was not affected by age at first concussion. Neither loss of consciousness nor posttraumatic amnesia were more frequent in RC. The number of concussions was associated with prolonged HR
Local Tumor Control of Liver Tumors After Histotripsy: A Preliminary National Multicenter Study.
No full textPURPOSE: Histotripsy is a noninvasive, nonionizing, nonthermal method of treating liver tumors receiving US Food and Drug Administration (FDA) clearance in October 2023. This study aims to describe histotripsy as a method of achieving local tumor control (LTC) for primary and secondary liver tumors.
METHODS: All patients receiving histotripsy since FDA clearance (December 2023-December 2024) at four institutions (two academic; two private) with \u3e30 days of active follow-up were included. Patients were classified into palliative intent and complete treatment intent. LTC was assessed using contrast-enhanced imaging on the basis of modified response evaluation criteria in solid tumors (mRECIST) and standardized ablation criteria at postoperative days (POD) 30 and 90.
RESULTS: Forty-seven patients received intended complete treatment to 91 liver tumors. Three total complications were observed: two cases of skin irritation treated with topical ointment and one case of bacteremia. At 30 days, 95% (n = 86/91) of treated liver tumors were nonviable. Two patients (one each with hepatocellular carcinoma and hepatic adenoma) received repeat treatment between POD30 and POD90, both converted to complete response. Forty-four patients and 85 tumors achieved 90-day follow-up. Three patients demonstrated persistently viable disease at POD90, all who had demonstrated viable tumor at POD30. Thus, the calculated primary efficacy rate at POD90 was 94% (n = 80/85), and the secondary efficacy rate was 96% (n = 82/85). The two patients with viable disease had neuroendocrine (n = 1), breast, and colorectal metastases (n = 1). Control rates were similar between primary and secondary tumors on time-to-event analysis (log-rank
CONCLUSION: Histotripsy achieved high rates of LTC at 30 and 90 days in this preliminary multicenter cohort. Longer-term follow-up is needed to confirm stable results
Impella vs. IABP in Non-emergent High-Risk PCI: Outcomes and LVEF Recovery from a Large US EHR Study.
No full textINTRODUCTION: High-risk percutaneous coronary intervention (HR-PCI) involves patients with complex coronary disease, adverse hemodynamics, and/or severe comorbidities who are often ineligible for surgery. Mechanical circulatory support (MCS) may reduce procedural risk and facilitate complete revascularization. However, comparative data on outcomes and left ventricular ejection fraction (LVEF) recovery are limited. We hypothesized that the benefits of MCS-supported PCI observed in prior studies would extend to contemporary, real-world, non-protocolized all-comer datasets, where outcomes and LVEF recovery in patients undergoing non-emergent Impella- or intra-aortic balloon counterpulsation (IABP)-supported HR-PCI can be evaluated.
METHODS: We synthesized an MCS-specific cohort using de-identified electronic health record data (2017-2025). Adults undergoing non-emergent HR-PCI supported with cardiac unloading via a continuous, forward high-flow pump (Impella) or IABP were included. Admissions with emergent status, right heart failure, cardiogenic shock, or ST-elevation myocardial infarction, or those undergoing coronary artery bypass grafting, were excluded. Propensity score matching (1:1) adjusting for baseline differences was performed. Outcomes included all-cause mortality (7, 30, and 90 days) and 30-day, medical code-derived (cd) adverse events (acute kidney injury [cd-AKI] and cd-bleeding requiring transfusion). LVEF change within 1 year was assessed in a predefined subgroup.
RESULTS: Before matching, patients supported with Impella had more comorbidities, lower baseline LVEF, and more complex procedural characteristics than IABP-supported patients. After matching, baseline characteristics were balanced. Impella was associated with lower all-cause mortality at 30 days (12.7% vs. 16.6%) and 90 days (15.2% vs. 19.6%), and reduced cd-AKI (15.7% vs. 20.3%). In patients matched for baseline LVEF values and collection timing, both groups demonstrated LVEF improvement (+ 7% for Impella; + 3% for IABP).
CONCLUSION: In contemporary, non-protocolized, non-emergent HR-PCI, the use of Impella was associated with improved outcomes and greater LVEF recovery compared to IABP
Influence of Biological Sex on Participant Characteristics, Guselkumab Efficacy and Radiographic Progression in Active Psoriatic Arthritis: Post Hoc Analysis of Three Randomized Trials.
No full textINTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous disease, and clinical manifestations can differ between sexes. Sex-disaggregated baseline characteristics, guselkumab efficacy, and radiographic progression were assessed in a pooled cohort of randomized controlled trial (RCT) participants with active PsA.
METHODS: Post hoc analyses of DISCOVER-1 (N = 381), DISCOVER-2 (N = 739), and COSMOS (N = 285) assessed sex-related baseline characteristics differences. Week (W) 24 clinical response rates with guselkumab 100 mg at W0/W4/every 8W (Q8W) were compared between sexes using multivariate logistic regression. In DISCOVER-2, multivariate repeated-measures mixed models evaluated associations between sex and radiographic progression with guselkumab Q4W + Q8W through W100, and between early (W8) response in joint disease activity with guselkumab Q4W + Q8W and radiographic progression, stratifying by sex.
RESULTS: Females were older; had higher body mass index; longer PsA duration; less severe psoriasis; more prevalent enthesitis; and reported more fatigue, pain, and functional impairment. Analyses adjusting for sex-specific differences in baseline characteristics showed no significant sex impact on guselkumab clinical response. Through W100, males exhibited significantly greater radiographic progression than females in unadjusted and adjusted models. Early clinical improvement in joint disease activity with guselkumab afforded significantly less radiographic progression through W100 in males (p = 0.0288) and numerically less in females.
CONCLUSIONS: Despite being associated with significant differences in characteristics at baseline, sex had no independent effect on guselkumab clinical efficacy in this RCT cohort. The known independent association between male sex and radiographic progression was confirmed; males exhibited a stronger relationship between early improvement in joint disease activity and lower long-term rates of radiographic progression.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03162796, NCT03158285, NCT03796858