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Background Transcatheter edge‐to‐edge repair (TEER) and replacement (TTVR) have emerged as new modalities to treat patients with symptomatic significant tricuspid regurgitation. This study aimed to compare invasive hemodynamic and right ventricular (RV) changes and symptom improvement over 1 year. Methods Patients who underwent TEER/TTVR at Mayo Clinic (Rochester, MN, 2017–2024) were included. Hemodynamic profiles were described before and immediately after intervention, in addition to RV enlargement/dysfunction ≥moderate at 30 days and change in symptoms over time. Results Of 100 patients included (50 per group, median age 81 versus 80 years and female 62% versus 42%, in TTVR and TEER, respectively), all had ≥ moderate–severe symptomatic tricuspid regurgitation. Post intervention, mean right atrial pressure decreased in TEER (16 to 14 mm Hg, P <0.001), V wave decreased in both groups (to 16 mm Hg, P <0.001). RV enlargement was less prevalent in both cohorts at 30 days (60%–40% in TEER, P =0.01, and 72 to 58% in TTVR, P =0.07), yet prevalence of RV dysfunction decreased only in TEER (26 to 15%, P =0.17) as opposed to TTVR (31 to 44%, P =0.13). TTVR resulted in a higher stroke volume index and more complete tricuspid regurgitation elimination at 30 days. Both groups resulted in similar improvements in New York Heart Association class, with overall similar survival. Conclusions TEER was associated with a greater reduction in right atrial pressure and more favorable RV remodeling at 30 days, as opposed to TTVR, which achieved more complete and sustained elimination of tricuspid regurgitation with higher forward stroke volume.

OBJECTIVE Multisegmental pathological autofusion is a hallmark feature of ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH), creating a rigid, brittle spine highly susceptible to three-column fractures and devastating neurological injury. This study aimed to evaluate survival outcomes in this patient population and identify clinical and demographic predictors of mortality. METHODS Adults with DISH or AS who sustained a fracture and were admitted to a single tertiary care center for spinal fracture were retrospectively identified using ICD-10 diagnostic codes. Data were extracted on demographics, clinical presentation, fracture characteristics, and details of treatment. RESULTS A total of 383 patients (median age 78 years, 75.2% male) were included. Over a median follow-up of 17.3 months, overall mortality was 38.1%, in-hospital mortality was 5.2%, 30-day mortality was 5.7%, and 1-year mortality was 18.0%. Initial treatment consisted of external orthosis in 220 (57.4%) and surgery in 144 (37.6%), while 19 (5.0%) were left untreated. Patients who died were older (median 83 vs 74 years, p < 0.001), had a lower BMI (29.4 vs 32.3 kg/m 2 , p < 0.001), had higher frailty on the 5-item modified frailty index (mFI-5), and more commonly had congestive heart failure (CHF), cancer, functional dependency, and chronic kidney disease (CKD) (all p < 0.01). Mortality was not associated with fracture location, mechanism of injury, fracture number, or the presence of neurological deficits. Univariable time-to-event analysis showed that decreased survival was predicted by older age (HR 1.08, p < 0.0001), lower BMI (HR per kg/m 2 0.93, p < 0.0001), functional dependency (HR 2.05, p < 0.001), cancer (HR 1.55 p = 0.01), CKD (HR 1.48, p = 0.019), CHF (HR 2.18, p < 0.001), and higher mFI-5 score (HR per point 1.34, p < 0.001). On multivariable analysis, older age (HR 1.06 per year, p < 0.001), lower BMI (HR per kg/m 2 0.95, p < 0.001), and mFI-5 score (HR per patient 1.37, p < 0.001) remained significant independent predictors of mortality. Treatment modality did not predict mortality. CONCLUSIONS AS- or DISH-associated spinal fractures have a high associated mortality, regardless of mechanism or severity. Treatment modality did not affect odds of survival, suggesting that nonoperative management with an external orthosis may be an appropriate option, particularly in older and medically complex patients.

Abstract Background Optimal treatment following first-line immunotherapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study evaluated futibatinib, a pan-FGFR inhibitor, combined with pembrolizumab in previously treated patients with FGF19-expressing HCC. Methods Eligible patients were ≥18 years old with advanced HCC, prior systemic therapy, Child-Pugh A-B7 liver function, ECOG 0–2, and FGF19 overexpression. Patients received futibatinib 20 mg orally daily plus pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included overall survival (OS), objective response rate (ORR), quality of life, and safety. Results Between August 2021 and March 2024, 14 patients enrolled and 13 were evaluable. Median age was 72 years (range, 60–87), 53.8% were male, 92.3% had Child-Pugh A liver function, and all had received prior immunotherapy. Median progression-free survival was 15 weeks (95% CI, 9.0–NE), with a PFS6 rate of 23.1% (95% CI, 8.6–62.3%). ORR was 0% (95% CI, 0–24.7%), while stable disease was observed in 53.9% of patients. Median OS was 55.7 weeks (95% CI, 47.3–NE). Grade ≥3 adverse events occurred in 69.2% of patients, and grade ≥4 adverse events in 15.4%. One grade 5 event (acute-on-chronic kidney injury) was deemed unrelated to treatment. Common adverse events included hyperphosphatemia, fatigue, diarrhea, elevated transaminases, dry eye, nail changes, rash, and oral mucositis. Conclusions Futibatinib plus pembrolizumab demonstrated an acceptable safety profile but did not meet efficacy thresholds supporting further study in FGF19-expressing HCC. Effective post-immunotherapy treatment strategies remain an unmet need.

Cerebral amyloid angiopathy related inflammation (CAA-ri) is a rare neuroinflammatory condition that may present with a wide spectrum of clinical and radiographic findings. Classic imaging features include areas of asymmetric subcortical white matter hyperintensities due to vasogenic edema, together with the classic hemorrhagic lesions of cerebral amyloid angiopathy (CAA) including microhemorrhages, superficial siderosis, or convexity subarachnoid hemorrhage. We describe a case of CAA-ri appearing as fulminant leptomeningitis without other obvious radiographic features of CAA at presentation.

PURPOSE Detection of bone marrow disease has been a major component of rhabdomyosarcoma (RMS) staging with bilateral bone marrow aspirates/biopsies (BMAB) from the iliac crests considered the diagnostic gold standard. This study's goal was to determine if 2- 18 F-labeled fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) or PET/magnetic resonance imaging (MRI) may replace BMAB in RMS staging. METHODS Patients were recruited in Europe and North America. Medical records, FDG PET/CT or FDG PET/MRI (PET), and BMAB reports were collected retrospectively. Images were re-reviewed by nuclear medicine physicians at the patients' home institutions if PET reports indicated increased FDG uptake at bone/bone marrow sites or if tumor cells were detected in bone marrow samples. RESULTS PET imaging and BMAB were performed before chemotherapy and tumor resection in 301 patients with FDG-avid RMS. Bone marrow metastases were detected by PET and BMAB in 54, by PET only in 24, and by BMAB only in one of 301 patients with FDG-avid primary tumors. Absence of bone marrow metastases was confirmed by PET and BMAB in 222 of 301 patients. These observations translated into 98% sensitivity and 90% specificity for PET in detecting bone marrow metastases when BMAB was considered as gold standard. FDG-avid marrow disease was patchy (1-5 foci) in one third of cases. Patients with marrow disease indicated by PET and BMAB had more FDG-avid bone marrow foci, more metastatic sites, and lower survival than those with marrow disease indicated by PET only, suggesting more advanced disease stages. CONCLUSION Bone marrow sampling may be omitted in patients without evidence of FDG-avid bone marrow disease by PET. If there are FDG-avid bone marrow lesions, further investigation by MRI and/or biopsy should be considered.

The intestinal epithelium is exposed to diverse combinations of microbiota-derived compounds; however, the mechanisms by which the host integrates these signals remain poorly defined. Studying two highly abundant microbial metabolites, we identified the purine metabolite hypoxanthine as an effector metabolite that directly drives signaling and the short-chain fatty acid butyrate as a regulatory metabolite that conditions host responsiveness. Specifically, hypoxanthine activates the adenosine A1 receptor–TRPC4 axis in enterochromaffin (EC) cells, triggering calcium influx and serotonin release resulting in accelerated gastrointestinal transit locally and increased platelet activation systemically. In contrast, butyrate epigenetically upregulates specific G protein–coupled receptors and ion channels to enhance response to hypoxanthine and the neurotransmitters norepinephrine and dopamine. These findings define a cooperative signaling framework and highlight the role of EC cells as a distinct epithelial signaling hub that senses and integrates microbial metabolite signals to drive physiological responses. Our findings provide a mechanistic foundation for therapeutic strategies that leverage combinatorial microbial signaling.

Importance Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development. Observations Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear. Conclusions and Relevance In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.

Importance Recent case reports suggest that B antigen–containing blood products may be associated with anaphylactic transfusion reactions in recipients with preformed immunoglobulin E to galactose- α -1,3-galactose (alpha-gal). Objective To test the association of local alpha-gal syndrome (AGS) prevalence and allergic transfusion reaction (ATR) in patients with blood type O. Design, Setting, and Participants In this international, multicenter, retrospective cohort study at academic medical centers, sites were assigned to AGS high- or low-prevalence clusters based on the known geographic distribution of AGS. Data were collected on platelet or plasma transfusions and ATRs during 2020 to 2024. Consecutive patients receiving platelet or plasma transfusions were included. Exposures Patients with blood type O who received B or AB units and patients with blood type O who received O units (reference group) in AGS high- and low-prevalence clusters were compared. Main Outcomes and Measures Before data collection, the hypothesis was that if transfusion-related alpha-gal syndrome (TRAGS) is a true clinical entity, excess ATRs to group B or AB units would be detected in AGS high-prevalence regions exclusively. The main measure was the overall risk ratio (RR) for ATRs to B or AB plasma or platelets in AGS high- vs low-prevalence clusters. Results In total, 558 823 platelet and plasma transfusions at 40 sites in 5 countries were analyzed, of which ATRs occurred in 1744 transfusions (0.3%). In the US AGS high-prevalence cluster (9 sites), significantly more ATRs of any severity occurred among patients with blood type O who received B or AB units vs patients with blood type O who received O units (overall RR, 3.93; 95% CI, 2.96-5.21; P &amp;lt; .001). In contrast, in the primary analysis of the AGS low-prevalence cluster (15 sites), excess ATRs to B or AB units were not detected. In subgroup analyses among patients with blood type O receiving B units, the RR for moderate to severe ATRs was 9.14 (95% CI, 5.39-15.52; P &amp;lt; .001) in the AGS high-prevalence cluster vs 2.15 (95% CI, 1.34-3.47; P = .002) in the AGS low-prevalence cluster. Outside the US, a signal consistent with TRAGS was not detected. Conclusions and Relevance This cohort study provides provocative epidemiologic evidence that TRAGS may be a unique manifestation of AGS and a previously unrecognized risk associated with transfusion. In AGS high-prevalence regions, blood collectors and hospital transfusion services should consider approaches to preventing severe ATRs from B or AB plasma or platelet units.

Objectives: Women with a history of breast cancer are at increased risk of developing subsequent breast cancer, including ipsilateral recurrence and contralateral new primary breast cancer. This study evaluated the discriminatory performance of a mammogram-based artificial intelligence (AI) risk model for predicting subsequent breast cancer within one year after a negative screening mammogram. Methods: This enriched retrospective case–control study included women with a prior history of breast cancer who underwent screening digital breast tomosynthesis between January 2018 and December 2023 at three affiliated academic breast imaging centers. Digital breast tomosynthesis examinations classified as BI-RADS 1 or 2 were retrospectively analyzed using the ProFound AI® Risk model version 1.0 to estimate 1-year breast cancer risk. Patients were classified according to whether they developed subsequent breast cancer within one year of the index screening examination. Model discrimination was evaluated using receiver operating characteristic analysis. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated at an exploratory cutoff selected by maximizing the Youden index. Results: The study included 96 women (mean age, 65.3 ± 8.7 years), of whom 32 developed subsequent breast cancer within one year, and 64 did not. The mean AI risk score was significantly higher in the subsequent breast cancer group than in the control group (1.18 ± 0.59 vs. 0.49 ± 0.41; p < 0.001). The AI model demonstrated an AUC of 0.824 (95% CI: 0.728–0.921). At an exploratory cutoff of 0.39, sensitivity was 81.3%, specificity was 76.6%, PPV was 63.4%, and NPV was 89.1%. In separate exploratory analyses, the AUC was 0.790 (95% CI: 0.641–0.939) for ipsilateral recurrence and 0.860 (95% CI: 0.752–0.974) for contralateral new primary breast cancer. AI risk scores were not significantly correlated with tumor size or age at subsequent breast cancer diagnosis. Conclusions: In this enriched retrospective case–control study, higher mammogram-based AI risk scores were associated with subsequent breast cancer within one year after a negative screening examination. The model demonstrated discriminatory performance for both ipsilateral recurrence and contralateral new primary breast cancer; however, these analyses were exploratory. Because the cohort was enriched for subsequent breast cancer events, the reported predictive values are specific to the study sample and should not be extrapolated to routine surveillance populations. Larger prospective cohorts are needed to validate discrimination, calibration, and clinical utility.