Faculty Bibliography

OBJECTIVES/OBJECTIVE:The COVID-19 pandemic highlighted an urgent need to more efficiently identify patients at highest risk for developing respiratory failure. We investigated whether plasma levels of lung injury biomarkers are associated with progression to respiratory failure among adults hospitalized with COVID-19 pneumonia without respiratory failure at admission. DESIGN/METHODS:This was a nested case-control study of COVID-19 patients enrolled in the Accelerating COVID-19 Therapeutic Interventions and Vaccines-3 (ACTIV-3)/Therapeutics for Inpatients with COVID-19 (TICO) platform trial who were on less than 20 L/min supplemental oxygen at enrollment. We compared baseline measurements of lung injury biomarkers between participants who progressed to respiratory failure or died by study day 10 (cases) and matched controls who did not progress to respiratory failure or death. Cases and controls were matched 1:1 on age, baseline oxygen requirement, immunomodulator use, and study arm. SETTING/METHODS:Hospitals enrolling in the ACTIV-3/TICO trials. PATIENTS/METHODS:Four hundred five cases and 405 matched controls. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Baseline levels of plasma interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor receptor, angiopoietin-2, soluble receptor for advanced glycation end-products (sRAGE), C-reactive protein (CRP), and surfactant protein D (SPD) were compared between cases and controls using matched logistic regression. Forward variable selection was used to identify biomarkers that were independently associated with progression to respiratory failure or death in a multivariate model. All lung injury biomarkers with the exception of SPD were significantly associated with progression to respiratory failure or death, with sRAGE demonstrating the highest odds ratio (OR) for each doubling of biomarker level (OR, 1.85; 95% CI, 1.61-2.12). In multivariate regression analysis, sRAGE, IL-6, and CRP were independently associated with progression, with sRAGE as the biomarker with the strongest association. CONCLUSIONS:Baseline levels of plasma lung injury biomarkers are significantly associated with progression to respiratory failure or death among hospitalized COVID-19 patients without respiratory failure at admission. These findings support the potential utility of measuring lung injury biomarkers in patients hospitalized without respiratory failure and should be tested in more heterogeneous patient groups including non-COVID-19 cohorts.

PURPOSE/UNASSIGNED:Eosinophil-related cutaneous adverse events (ercAE) are common after systemic cancer therapies and often affect health-related quality of life (HRQoL). In this study, we investigate the efficacy and safety of benralizumab for ercAE following systemic cancer therapies. PATIENTS AND METHODS/UNASSIGNED:This single-arm, single-center, open-label, phase II trial (NCT04552288) in patients with cancer and systemic therapy-associated ercAE was performed from September 2020 to October 2023. Benralizumab 30 mg was administered subcutaneously according to the approved dosing schedule, with 3 doses given every 4 weeks followed by 3 doses given every 8 weeks. The primary endpoint was clinical response (reduction in ercAE to Common Terminology Criteria for Adverse Events grade ≤ 1 by week 4). Secondary endpoints included HRQoL, rash body surface area (rash-BSA), eosinophil levels, and AE. RESULTS/UNASSIGNED:At baseline (N = 47), ercAE were attributed to phosphoinositide 3-kinase inhibitors in 47%, checkpoint inhibitors in 21%, tyrosine kinase inhibitors in 9%, and antibody-drug conjugates in 9%; ercAE were grade 2 and 3 in 49% and 51% of patients, respectively. Of the 42 patients evaluable for the primary endpoint, 76% of patients (n = 32/42) responded to treatment by week 4; median ercAE grade decreased from 2 to 1 (P < 0.0001). Patients exhibited improved HRQoL, reduced mean rash-BSA, and decreased peripheral eosinophils. All patients with ercAE following alpelisib (n = 18) or enfortumab vedotin (n = 4) responded by week 4 (both P < 0.05). Most AE were mild to moderate and likely unrelated to benralizumab. CONCLUSIONS/UNASSIGNED:Benralizumab demonstrated favorable efficacy and safety against grade 2/3 ercAE related to novel cancer therapies. Further investigation in larger placebo-controlled trials is warranted.

PURPOSE/OBJECTIVE:The term white dot syndromes (WDS) has historically grouped multiple non-infectious posterior uveitis (NIPU) entities based on a similar funduscopic appearance of "white dots." Despite decades of use, the clinical relevance of this umbrella terminology has been questioned. This perspective critically examines whether WDS remains a valid conceptual and diagnostic construct in the era of advanced retinal and choroidal imaging. DESIGN/METHODS:Perspective review. METHODS:Critical interpretation of the available literature on imaging and current pathophysiological evidence, combined with observations collected using cutting edge imaging technology (structural high-resolution optical coherence tomography (OCT), OCT angiography, and indocyanine green [ICG] angiography [ICGA]) for 6 of the NIPU classically considered as WDS: multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis with panuveitis (MFCPU), punctate inner choroiditis (PIC), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis (SC), and birdshot chorioretinitis (BSCR). RESULTS:Although these diseases share some overlapping clinical features, multimodal imaging reveals profound differences, with each entity having distinct anatomic features on multimodal imaging. OCT angiography (OCTA) demonstrate distinct patterns of tissue involvement-from photoreceptor/retinal pigment epithelium (RPE) injury in MEWDS, to Bruch's membrane disruption in MFCPU and PIC, to profound choriocapillaris ischemia in APMPPE and SC, and deep stromal choroidal infiltration in BSCR. ICGA further differentiates these entities by choroidal perfusion characteristics, distinguishing true vascular non-perfusion from other inflammatory reactions leading to tissue damage. Imaging-based hypotheses of immunopathogenesis suggest that these entities may arise from different immunopathogenic pathways-transient outer retinal inflammation (MEWDS), possible antigenic exposure from structural disruptions (MFCPU/PIC), primary inflammatory inner choroidal vascular occlusive process (APMPPE), a possible autoimmune or autoinflammatory choroidal ischemic mechanism (SC), and a likely Human Leukocyte Antigen (HLA)-A29-associated autoimmune response affecting the inner retina and choroid (BSCR) CONCLUSIONS: The label WDS, originally based on appearance alone, does not take into consideration major biological and prognostic differences among these NIPU. Current imaging-guided hypotheses of immunopathogenesis suggest that these conditions should no longer be grouped under a single classification. A paradigm shift toward disease-specific terminology is warranted to improve diagnostic precision, guide management, and reflect presumed pathophysiological diversity.

UNLABELLED:Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCLs derive from follicular B cells engaged in adaptive immune responses. By studying cooccurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extrafollicular trajectory. Using animal models and human specimens, we find that this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory, and a distinct, autoimmune B cell-like state. This trajectory is associated with sex-biased outcomes: Female patients and mice exhibit reduced survival compared with males in our cohorts. Further analysis links this disparity to enhanced X-chromosome-linked expression and functionality of Toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy. SIGNIFICANCE/UNASSIGNED:The findings in this article support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.

Lupus nephritis (LN) and diabetic nephropathy (DN) are leading causes of kidney failure, characterized by distinct yet overlapping patterns of glomerular injury. While histopathology remains central to diagnosis, it provides limited insight into the underlying molecular remodeling. Here, we applied matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to define the spatial N-glycan landscape across human kidney biopsies from healthy controls (HCs) and patients with DN or LN. Whole-biopsy analyses demonstrated that identical N-glycan species adopt distinct spatial distributions depending on the disease context. Healthy kidneys were enriched in bisected N-glycans, DN in biantennary and sialylated species, and LN in fucosylated and paucimannose N-glycans, reflecting divergent enzymatic and pathogenic pathways. Glomerulus-resolved analyses substantially enhanced discrimination among disease groups, revealing previously undetected differences and highlighting disease-specific molecular phenotypes that were masked at the whole biopsy level. Notably, glomeruli classified as histologically normal exhibited distinct N-glycan signatures across disease states, indicating that molecular remodeling occurs independently of the overt structural changes. Within biopsies, N-glycan class composition shifted systematically with glomerular injury, with DN displaying more uniform remodeling and LN demonstrating greater phenotypic heterogeneity. Mixed-effect modeling confirmed significant morphology-dependent differences while accounting for biopsy-level clustering. MALDI-IHC analysis further supported phenotype-specific molecular differences across the glomerular subtypes. Collectively, these findings establish glomerular N-glycan architecture as a major driver of glycomic divergence across kidney diseases and position spatial N-glycomics as a translational approach for defining disease-specific molecular signatures within intact renal tissues.

BACKGROUND:Inflammatory proteins detectable in blood reflect pathoanatomic injury patterns after traumatic brain injury (TBI). Identifying biomarkers of secondary neurologic and systemic injury may improve detection of patients at risk for clinical decline and chronic disability. This study examined the utility of acute and subacute inflammatory biomarkers to differentiate TBI diagnosis and severity, and predict 6-month outcomes. METHODS:-unit increase in biomarker level were reported. RESULTS:Ten biomarkers (c-reactive protein (CRP), serum amyloid A (SAA), interleukin (IL)-1ꞵ, IL-2, IL-4, IL-6, IL-10, IL-15, IL-17A, tumor necrosis factor (TNF)-α) differed significantly between GCS 3-12 vs. 13-15 TBI, CT-positive vs. CT-negative TBI, and GCS 3-12 TBI vs. OC, at both D1 and W2 (p < 0.001). IL-6, CRP, and SAA showed good discrimination of clinical TBI severity (D1/W2 area under-the-curve (AUC): 0.87/0.87, 0.82/0.88, 0.80/0.85, respectively), and moderate-to-good discrimination of radiographic TBI severity (D1/W2 AUC: 0.81/0.82, 0.78/0.83, 0.77/0.79, respectively). Five W2 biomarkers emerged as multivariable predictors of 6-month unfavorable outcomes (IL-15: AOR = 2.26 [1.14-4.49]; SAA: AOR = 1.91 [1.37-2.67]; IL-6: AOR = 1.80 [1.25-2.61]; IL-17A: AOR = 1.72 [1.24-2.39]; CRP: AOR = 1.40 [1.06-1.85]). CONCLUSIONS:Ten circulating inflammatory proteins were associated with TBI diagnosis and severity at D1 and W2. Of these, five biomarkers expressed subacute (W2) levels predictive of 6-month death/severe-disability, underscoring their potential for validation as a novel biomarker class and integration into TBI prognostic models. Distillation of pro- and anti-inflammatory biomarker cascades in TBI could facilitate precision medicine approaches for risk stratification and therapeutic modulation.

Since the introduction of the Vesical Imaging-Reporting and Data System (VI-RADS), MRI has become an important imaging modality in the management of patients with bladder cancer. Its excellent diagnostic performance for determining muscle invasion in bladder cancer has been supported by numerous prospective and retrospective studies. Nevertheless, there needs to be continued improvement of the diagnostic performance of VI-RADS and sustained efforts to address remaining unmet clinical needs within the field of bladder cancer. In this paper, we highlight several such areas, some of which are actively being investigated. These include (1) whether to use intravenous contrast media or not (multiparametric vs. biparametric MRI), (2) quantitative metrics to enhance assessment of muscle invasion, (3) anatomic locations that come with pitfalls in staging, (4) introduction of bladder MRI image quality, (5) neoadjuvant chemotherapy VI-RADS (nacVI-RADS) and other considerations needed in the treatment response assessment after systemic therapies, (6) need for wider adoption, training, and implementation, and (7) application of artificial intelligence.

Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been widely used in Ayurvedic medicine for its adaptogenic properties and therapeutic potential and has been investigated for its benefits related to sleep and stress management by Western medicine. However, concerns regarding its teratogenic and abortifacient effects have emerged following reports from the World Health Organization (WHO) and regulatory bodies. This systematic and ethnobotanical review critically evaluates these claims by assessing ashwagandha's toxicokinetics, toxicodynamics, and available safety data. A comprehensive literature review following PRISMA guidelines was conducted to identify studies on its reproductive toxicity, molecular interactions, and traditional usage. Historical ethnobotanical reports suggest potential abortifacient effects, but citation distortion and lack of primary source validation raise concerns regarding the validity of such claims. Toxicological studies in animal models demonstrate high tolerability, with no significant reproductive toxicity observed at doses relevant to human consumption. Human clinical studies also show no adverse effects on thyroid function, hormonal balance, or reproductive health. Altogether, evidence supporting significant teratogenic or abortifacient activity remains inconclusive. This review highlights the need for standardized, high-quality research addressing fertility and developmental outcomes in controlled conditions. Given the widespread use of ashwagandha as a dietary supplement ingredient and traditional medicine, a balanced and evidence-based approach is required to assess its safety, ensuring that regulatory actions are informed by robust scientific data rather than historical speculation.

INTRODUCTION/BACKGROUND:Survival outcomes among patients with World Health Organization grade III gliomas and IDH-mutant (IDHmt) gliomas treated with immunotherapy (IT) remain understudied, with most research focusing on grade IV (G4) glioblastomas or IDH wild-type (IDHwt) tumors. METHODS:A systematic literature search was conducted in PubMed/MEDLINE, SCOPUS, Embase, Google Scholar, and Science Direct databases following PRISMA guidelines. A random-effects meta-analysis was conducted to assess overall survival and 5-year mortality. Outcomes were compared across IT treatments and between historically designated grade III versus grade IV/GBM cohorts and explicitly reported IDHmt versus IDHwt glioma cohorts within each included study. RESULTS:A total of 21 studies involving 207 patients with grade III gliomas and 11 studies involving 115 patients with IDHmt gliomas were included. IT agents studied included dendritic cell and peptide vaccines (32 grade III, 45 IDHmt), immune checkpoint inhibitors (1 grade III, 39 IDHmt), oncolytic viruses (10 grade III, 20 IDHmt), modified lymphocyte therapies (1 grade III, 11 IDHmt), cytokine immunotherapy (47 IDHmt) and radioimmunotherapy (110 grade III). Most treated grade III (65.6%) and IDHmt (72.7%) gliomas were recurrent tumors. Across all immunotherapy agents, recurrent and newly diagnosed grade III glioma did not exhibit significant differences in overall survival (21.90 versus 29.71 months, p = 0.237), 5-year mortality (77.10% versus 60.89%, p = 0.481), or overall mortality at last follow-up (78.91% versus 70.37%, p = 0.553). Newly diagnosed IDHmt glioma had significantly greater overall survival than recurrent IDHmt glioma (43.13 versus 19.57 months, p = 0.005) and significantly lower 5-year mortality (10.26% versus 59.78%, p < 0.001). Between immunotherapy modalities, grade III glioma did not exhibit differences in overall survival compared to GBM in equivalent treated cohorts (p = 0.123). However, dendritic cell and peptide vaccines had a higher overall survival compared to all other immunotherapy agents in IDHmt glioma (p = 0.002), including when compared to IDHwt glioma in equivalent treatment arms (p = 0.044). CONCLUSION/CONCLUSIONS:Our study summarizes reported survival outcomes among patients with historically designated grade III and IDHmt gliomas treated with immunotherapy. Observed differences by histological grade, IDH status, and recurrence status are consistent with the established prognostic importance of these tumor features, and should not be interpreted as evidence that immunotherapy caused improved survival. Survival outcomes appeared more favorable in newly diagnosed IDHmt glioma and in IDHmt cohorts treated with dendritic cell or peptide vaccines; however, these findings are descriptive and hypothesis-generating given the predominance of single-arm studies, limited sample size, and potential confounding by baseline prognosis. Future prospective controlled trials are needed to determine whether specific immunotherapy approaches provide benefit in these glioma subgroups.

BACKGROUND:Transcriptome-wide association studies (TWAS) identify genetically regulated expression (GReX) components and can pinpoint causal genes in genome-wide association studies but are often limited by a single-cell context. OBJECTIVE:We hypothesized that modeling GReX across multiple conditions could enhance power to identify causal genes for complex inflammatory diseases. METHODS:We conducted TWAS on 400 transcriptomes under 8 proinflammatory cytokine stimulations in keratinocytes, modeling GReX for 18,599 genes against genome-wide association studies from 7 inflammatory skin diseases: atopic dermatitis, psoriasis, acne, alopecia areata, systemic sclerosis, systemic lupus erythematosus, and vitiligo. RESULTS:), and our method successfully captured >85% of all genes with colocalizing expression quantitative trait loci. Single-cell-resolution spatial profiling further demonstrated the modulation of TWAS signals in keratinocytes by close proximity to TNF/IL-17-expressing cells in psoriatic skin. CONCLUSION/CONCLUSIONS:Modeling gene expression across relevant cellular states substantially improves the power and resolution of TWAS.