Citations

Tuberous sclerosis complex (TSC) is a highly variable autosomal dominant disease characterized by dysregulated organ development and growth. Benign tumors, termed hamartomas, may occur across organ systems but typically involve the kidney, brain, skin, heart, and lung. The diagnosis, surveillance, and clinical management of TSC requires a multidisciplinary approach, adopted by dedicated multispecialty centers worldwide. Nephrology involvement predominantly stems from the morbidity and mortality related to the prototypical kidney lesion, angiomyolipomas, whose presence and degree confers risk of CKD, hypertension, retroperitoneal bleeding, and possibly renal cell carcinoma. Surveillance of kidney structural lesions, kidney function, and BP may enable early interventions that limit kidney-related morbidity and mortality, such as mammalian target of rapamycin inhibitor therapy. We review the epidemiology, genetics, and pathogenesis of TSC and how these inform the evaluation, diagnosis, and clinical management of TSC from the vantage point of the treating nephrologist.

Background: Tracheal intubation and mechanical ventilation are facilitated by neuromuscular blocking agents. We investigated the effectiveness of subjective clinical evaluation of neuromuscular function on retroglossal area size, since it determines spontaneous ventilation adequacy following tracheal extubation. Secondarily, we correlated changes in retroglossal area and depth of neuromuscular block assessed during both respiratory phases using quantitative neuromuscular monitoring. Methods: Once mechanical ventilation was no longer needed, antagonists were used to reverse the neuromuscular block in 21 consenting patients; adequacy of reversal was assessed subjectively by delivering a sequence of four rapid (2 Hz) electrical stimuli (train-of-four, TOF) to a peripheral nerve and assessing attainment of four equal muscle contractions (TOF ratio = 1.0), signifying normal neuromuscular function. Retroglossal area during both inhalation and exhalation were measured pharyngoscopically at various phases of neuromuscular recovery, including at baseline after anesthesia induction but before neuromuscular block onset and at recovery before tracheal extubation; area changes were correlated with depth of quantitatively measured neuromuscular block. Results: Clinicians’ subjective evaluation of readiness for tracheal extubation failed to identify significant residual block in most patients who required rescue antagonism. Markedly decreased retroglossal areas (inhalation: 39.5% of baseline; exhalation: 20.1% of baseline) were present at extubation, and 11 out of 21 (52.4%) patients needed rescue antagonism. In contrast, in patients with neuromuscular recovery to the currently recommended threshold determined quantitatively (TOF ratio > 0.90), retroglossal areas were only 80% recovered but returned to near baseline values when the TOF ratio ≥ 0.95. Conclusions: Quantitative monitoring should guide the timing of tracheal extubation. Current definitions of the minimal threshold for adequate neuromuscular recovery (TOF ratio > 0.90) after mechanical ventilation in postoperative patients should be re-evaluated. A TOF ratio > 0.95 better correlates with return to normal (baseline) retroglossal area during both inhalation and exhalation.

Mesenchymal dendritic cell neoplasms represent a distinct category of hematologic malignancies that challenge traditional classifications of histiocytic and classical dendritic/Langerhans cell neoplasms. Historically grouped under the broader umbrella of dendritic cell neoplasms, these entities differ significantly in their ontogeny, histopathologic features, molecular alterations, and clinical behavior. They are categorized into three main subtypes including follicular dendritic cell sarcoma, fibroblastic reticular cell tumor, and EBV-positive inflammatory follicular dendritic cell sarcoma/fibroblastic reticular cell tumor. They originate from mesenchymal stromal cells, and genetic alterations activating the NF- κβ pathway are frequent in follicular dendritic cell sarcomas. Immunophenotypic characterization is critical to distinguish these from other hematologic malignancies including histiocytic and classical dendritic/Langerhans cell neoplasms and other solid (non-hematopoietic) cancers. This review recapitulates current knowledge on existing classifications, details their diverse ontogeny from classical dendritic cell neoplasms, and provides insights into their clinicopathologic characteristics to improve diagnostic accuracy. We detail two case studies that demonstrate the challenges involved in the histopathologic diagnosis of these rare tumors, necessitating a comprehensive workup. Integrating developmental biology into practical diagnostic algorithms is essential to improve recognition and classification of these underdiagnosed neoplasms, ultimately guiding timely management.

Henipaviruses are emerging zoonotic viruses that have caused deadly outbreaks in humans and livestock across several regions of the world. The fusion (F) protein of henipaviruses plays a critical role in viral entry into host cells and represents a key determinant of viral pathogenicity. This review provides a comprehensive analysis of current knowledge regarding trafficking, activation, as well as the role in particle assembly, of henipavirus F proteins. We discuss the unique characteristics of henipavirus F proteins compared to other paramyxovirus fusion proteins, with particular emphasis on their distinctive trafficking and activation mechanisms. Attention is also given to novel henipaviruses that have been detected in hosts other than bats, namely rodents and shrews. These viruses are sufficiently different that the International Committee on Taxonomy of Viruses has proposed a new genus for them, the Parahenipaviruses. We discuss how variations in F protein characteristics between Henipaviruses, Parahenipaviruses, and yet-unclassified henipa-like viruses might influence their trafficking and activation. Understanding these molecular mechanisms is crucial for developing effective therapeutic strategies against henipavirus infections and for predicting the emergence of novel henipavirus strains with pandemic potential.

Background/Objective: Noninvasive PET imaging-based assessment of PD-L1 expression is of high clinical value for better patient selection and treatment response rates to PD-L1 immunotherapies. Due to their shorter biological half-life and faster clearance from the blood pool, radiolabeled antibody fragments are an attractive alternative for imaging than their full-length IgG counterpart. This work investigated the radiosynthesis and in vitro cell uptake of anti-PD-L1-B11-nanobody radiolabeled with 44Sc (t1/2 = 4.04 h) as an alternative to anti-PD-L1-B11-IgG, better suited for longer half-life radioisotopes such as 89Zr (t1/2 = 78.41 h). Methods: The proteins were conjugated with p-SCN-Bn-DTPA and radiolabeled at room temperature with 44Sc, achieving a radiochemical yield of a RCY of 94.8 ± 3.1% (n = 3) for [44Sc]Sc-B11-IgG and 73.6 ± 12.1% (n = 3) for [44Sc]Sc-B11-nanobody, before purification. Results: Significantly higher uptake in the PD-L1+ cells than PD-L1KO cells was observed for both probes. However, high non-specific uptake, particularly of the radiolabeled B11-nanobody, was also observed which may negatively impact its potential as a molecular imaging probe. Conclusions: Due to the high non-specific uptake in vitro, the 44Sc radiolabeled nanobody was not progressed to further in vivo evaluation. These results should, however, not discourage future evaluations of other nanobody based probes radiolabeled with 44Sc, due to their well-matched biological and physical half-life.

Background/Objectives: Accurate assessment of spinal bone density is essential for evaluating bone health, particularly in preoperative planning. Conventional manual methods for Hounsfield unit (HU) measurements rely on single-slice measurements within the region of interest, limiting their precision and reproducibility in patients with severe vertebral deformities. We hypothesize that a novel deep-reasoning and learning model (DR-AI) can fully automate spinal bone density assessment volumetrically, with high correlations to spinal bone mineral density (BMD) obtained from dual-energy X-ray absorptiometry (DXA), as well as to the T- and Z-scores. Methods: A cross-sectional study was conducted on patients who had BMD assessment of their lumbar spine and lumbar CT scans within 1 year. The fully-automated DR model was utilized to analyze the soft-tissue window of the lumbar vertebrae CT scans. Spearman correlation coefficients were calculated to assess the strength of relationships between the computed volumetric HUs and the BMD, T-, and Z-scores from each vertebra. Results: 84 patients (67 females, mean age 74.1 ± 10.3 years; 17 males, mean age 68.1 ± 12.4 years) meeting inclusion criteria. Correlation analyses for L1 to L4 showed significant positive relationships (p < 0.0001), with the strongest correlation at L2 between HU and BMD (ρ = 0.75). Conclusions: the DR model for automated assessment of volumetric HUs offers a highly reliable, efficient, and precise alternative to DXA measurements.

Abstract Organoids, which are tiny, lab-grown 3D structures that mimic some organizational and functional properties of human organs, are slowly transforming the face of systems and developmental biology, biomedical research, pharmaceutical testing, environmental toxin testing, and healthcare. Significant investments are essential for the mass production, preservation, and distribution of organoids, with the aim to accelerate innovation and progress across multiple fields—much like the investments made in cell and biologics manufacturing over the past 2 decades.

Abstract Background Jamestown Canyon virus (JCV) is an emerging arboviral pathogen transmitted by mosquitoes in the United States and Canada. It is associated with neuroinvasive diseases and a wide spectrum of clinical presentations. Methods A retrospective chart review was conducted at the Mayo Clinic Health System in Northwest Wisconsin from January 2018 to December 2024, analyzing data from 12 hospitalized patients diagnosed with JCV infection. This study aimed to characterize the clinical, laboratory, imaging, and outcome profiles of the disease. The cohort included individuals aged 19 to 75 years, predominantly male (75%), with all patients reporting outdoor activity and 75% being pet owners. Results Only 27% of the patients recalled a mosquito bite. Among the cohort, 2 patients acquired an infection during the first trimester of pregnancy and subsequently delivered healthy infants. Coinfections with Borrelia burgdorferi were found in 33% of cases, while 16.7% of cases were seropositive to La Crosse virus. Magnetic resonance imaging of the brain was obtained in 5 patients and was nonspecific. Cerebrospinal fluid analysis demonstrated lymphocytic or monocytic pleocytosis in all cases where the test was performed. Conclusions All patients experienced clinical improvement, with only 1 developing lingering neurological symptoms in the form of brain fog. This study highlights the clinical heterogeneity of JCV infections and underscores the importance of including JCV in the differential diagnosis for patients residing in or traveling from endemic areas.