Citations

Obstructive sleep apnea (OSA) is a common, heterogeneous disorder managed through a multidisciplinary pathway that connects recognition, physiologic testing, treatment selection, specialty referral, insurance coverage, and longitudinal reassessment. This narrative review provides a clinically oriented, system-level overview of the adult OSA care ecosystem in the United States for an international clinical audience, with particular emphasis on the evolving role of otolaryngology. We describe the organization and complementary functions of sleep physicians, otolaryngologists, dentists, and allied health professionals. We also outline the roles of polysomnography and home sleep apnea testing, along with major therapeutic pathways including positive airway pressure, oral appliance therapy, weight management, upper-airway surgery, and neurostimulation. Otolaryngology provides an important interface between physiologic diagnosis and airway-specific treatment by integrating anatomic evaluation, sleep-state airway phenotyping, intervention selection, and post-treatment reassessment. Recent advances in neurostimulation, pharmacologic weight management, wearable and home-based monitoring, airflow analysis, and artificial intelligence are expanding opportunities for accessible and phenotype-informed care. Important challenges include underdiagnosis, treatment attrition, fragmented transitions, variable coverage, and reliance on the apnea–hypopnea index. Although health-care structures differ internationally, multidisciplinary coordination, individualized treatment selection, and longitudinal reassessment provide broadly applicable principles for developing patient-centered OSA programs.

Single-cell studies have defined immune states in inflammatory bowel disease (IBD), but how adaptive receptor histories organize circulating immunity remains unclear. We generated a single-cell transcriptomic atlas of peripheral blood from 249 participants with Crohn's disease, ulcerative colitis, or non-IBD control status, including 182 with productive TCR and BCR recovery. Expanded TCR clonotypes marked inflammatory-memory and cytotoxic states, while distinct but similar paired TCRs shared inflammatory programs across participants. BCR lineage maturation linked IgA-associated mucosal and plasma B cell programs to somatic mutation and class switching, distinguishing maturation-associated biology from clonal expansion. Helper, regulatory, and cytotoxic T-cell programs covaried with B-cell states, and inferred interactions nominated reciprocal antigen-presentation and helper pathways. Repertoire-based machine learning distinguished diagnosis, inflammation, and contemporaneous six-month treatment-response status. Together, this atlas connects receptor architecture to coordinated systemic immune remodeling, establishes a foundation for repertoire-informed patient stratification, and prioritizes candidate mechanisms of IBD pathogenesis.

Abstract Background and Aims Fibroblast–neutrophil interactions are implicated in ulcerative colitis (UC) treatment resistance, but whether fibroblasts modify neutrophil inflammatory activity remains unclear. We investigated responses to fibroblast exposure, stromal depletion, and α5β1-directed treatment. Methods We integrated human and mouse colonic single-cell RNA sequencing (scRNA-seq), spatial protein profiling (CODEX), fibroblast–neutrophil coculture, and dextran sulfate sodium (DSS) mouse colitis with fibroblast activation protein (FAP) ablation or α5β1-directed treatment. Readouts included cellular representation and protein fluorescence via flow cytometry, neutrophil extracellular trap (NET)-associated elastase activity, RNA programs and epithelial responses using scRNA-seq. Results Inflamed UC tissue contained higher fractions of inflammatory fibroblasts and oncostatin M (OSM)- and CXCR4-associated neutrophils. Inflammatory fibroblasts had higher FAP–α5β1 module scores, and proximity to FAP-high fibroblasts was associated with higher neutrophil OSM and CXCR4 fluorescence. UC fibroblasts increased neutrophil OSM, CXCR4 and myeloperoxidase (MPO) fluorescence and NET-associated elastase activity relative to control fibroblasts, while α5β1-directed treatment attenuated these responses. Both mouse FAP ablation and α5β1 blockade in DSS colitis reduced histologic inflammation and overall neutrophil frequency. Ablation broadly reduced recovered neutrophil representation, whereas blockade increased OSM-positive and PADI4-positive percentages within neutrophils despite lower MPO fluorescence within these subsets. Both interventions were associated with lower epithelial chemokine scores but distinct absorptive and mucus/secretory responses. Conclusions Fibroblast exposure modifies neutrophil inflammatory phenotype and effector-associated activity, identifying candidate therapeutic pathways in UC. Evaluating these responses alongside neutrophil representation and tissue inflammation could inform pharmacodynamic assessment of stromal-directed therapies. Graphical Abstract What You Need to Know Background and Context Fibroblast–neutrophil interactions are associated with treatment resistance in ulcerative colitis. Whether fibroblast exposure modifies neutrophil inflammatory phenotype and effector activity, beyond its established recruitment role, remains unclear. New Findings UC fibroblasts increased neutrophil inflammatory proteins and NET-associated elastase activity; α5β1-directed treatment attenuated these responses. FAP ablation and α5β1-directed treatment reduced colitis and overall neutrophil frequency. α5β1-directed treatment lowered MPO within OSM-positive and PADI4-positive neutrophils despite higher marker-positive percentages. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but distinct barrier-associated and regenerative expression patterns. Limitations Cellular drug targets remain unresolved. Spatial associations and elastase activity do not establish direct contact, NET formation, or clinical efficacy. Clinical Research Relevance Fibroblast-associated pathways offer candidate therapeutic opportunities to modify neutrophil inflammatory phenotype and effector activity in UC. Coculture responses were pharmacologically modifiable, and stromal interventions reduced experimental colitis. Measuring neutrophil frequency, subset proteins, and effector activity alongside tissue inflammation could guide pharmacodynamic assessment. Clinical efficacy and treatment-selection utility require validation. Basic Research Relevance Human coculture provides experimental evidence that fibroblast exposure modifies neutrophil inflammatory proteins and NET-associated elastase activity. FAP+ stromal ablation and α5β1-directed treatment produced distinct patterns of neutrophil representation and subset proteins in colitis. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but differing barrier-associated and regenerative expression patterns. Together, these findings motivate mechanistic studies of how stromal recruitment cues, soluble signals, and matrix-associated interactions regulate neutrophil responses, and whether these changes contribute to reduced epithelial inflammation and tissue repair. Lay Summary Fibroblasts, support cells in the intestine, increased inflammatory activity in immune cells called neutrophils. Blocking a pathway involved in cell attachment reduced these responses in cultures. Targeting fibroblast-associated pathways also reduced experimental colitis, with changes in intestinal lining gene activity related to inflammation, barrier function, and repair. These findings suggest potential approaches to treating ulcerative colitis.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.

Abstract Objective. Four-dimensional CT (4DCT) enables visualization of dynamic wrist joint pathology but may be compromised by motion artifacts. Deep learning (DL)-assisted motion correction has the potential to enhance wrist 4DCT quality, but model development is hindered by scarce training data. To address this, we developed a model-based motion simulation framework that generated realistic 4DCT data with paired static ground truth images to demonstrate wrist motion correction using a physics-informed DL model trained with simulated data. Approach. Wrist motion was simulated by synchronizing rotational and translational movements of carpal bones and connective tissues. Elastic deformation guided by analytically-derived motion vector fields was applied to static wrist scans at neutral positions to create artifact-free images at multiple angular positions. Virtual motion-corrupted 4DCT images were produced via forward projection and reconstruction with synchronized gantry and wrist motion. Experimental data from 4DCT cadaver scans were collected to validate simulation quality. Low-intensity region score (LIRS), positivity, and entropy were used to assess simulated motion artifacts. A physics-informed motion correction network was adapted exclusively using simulated training data and subsequently deployed on simulated, real cadaveric, and in vivo 4DCT scans. LIRS and structural similarity index (SSIM) were used to evaluate motion correction quality. Wilcoxon signed-rank tests were conducted ( α = 0.05). Results. The simulation method created realistic motion artifacts compared to real scan reference ( p > 0.05). Motion artifacts were effectively mitigated across testing cases demonstrating generalizability. In simulated scans, LIRS improved from 0.55 ± 0.12–0.75 ± 0.04 and SSIM from 0.87 ± 0.08–0.95 ± 0.03 at bone regions (each p < 0.01). In experimental cadaveric scans, LIRS improved from 0.05 ± 0.01–0.31 ± 0.17 in marker regions and from 0.58 ± 0.19–0.77 ± 0.14 in bone regions (each p < 0.01). Significance. Our simulation method facilitates training DL-assisted motion correction algorithms by providing high-quality training data, effectively supporting 4DCT image quality enhancement.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

The effect of induced hypertension (iHTN) on functional outcomes in noncardioembolic acute ischemic stroke (AIS) with early neurological deterioration remains unclear. We performed a systematic review and meta-analysis evaluating the safety and efficacy of iHTN vs medical management. A literature search of PubMed/MEDLINE, Web of Science, Ovid Embase, and Scopus from inception through November 6th, 2025. The protocol was registered in PROSPERO (CRD420261282211). Studies evaluating iHTN within 72 h of AIS onset and reporting 90-day functional independence (modified Rankin Scale [mRS] 0-2) were included. Safety outcome was hemorrhagic transformation. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using random-effects model based on Restricted Maximum-Likelihood (REML) methods. Three studies were included, comprising 366 patients (iHTN, n = 180; control, n = 186). Mean age was 65.8 ± 11.8 years, 60.9% were men, and the mean initial NIHSS was 5.4 ± 3.5. Target systolic blood pressure (SBP) was a 15-25% increase from baseline SBP using phenylephrine. Functional independence at 90-days occurred more often in the iHTN group than in controls (68.8% vs 50.5%; RR = 1.37; 95% CI, 1.09-1.73; P = 0.007). Hemorrhagic transformation was uncommon and did not differ significantly between groups (3.3% vs 0.5%; RR = 2.08; 95% CI, 0.05-88.07; P = 0.70). In our study, phenylephrine-induced hypertension was associated with greater 90-day functional independence in selected AIS subtypes,without a significant increase in hemorrhagic transformation. However, the limited studies, predominance of retrospective designs, exclusively Asian cohorts, and heterogeneity in treatment protocols and populations warrant cautious interpretation and underscore the need for larger multicenter RCTs.

ABSTRACT Herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV) are associated with a range of clinical manifestations depending on the anatomical site of infection. HSV and VZV lesions often exhibit similar phenotypical characteristics, making clinical differentiation challenging. Detection and differentiation of HSV-1, HSV-2, and VZV are essential for diagnosis and treatment management. An automated multiplex real-time PCR assay, Alinity m HSV 1 & 2/VZV assay, was developed to detect and differentiate HSV-1, HSV-2, and VZV. The assay was validated for use with cutaneous and mucocutaneous lesion swab specimens collected in commercial viral transport media from symptomatic patients. The assay demonstrated a limit of detection of 5.90 TCID 50 /mL for HSV-1, 2.07 TCID 50 /mL for HSV-2, and 0.055 TCID 50 /mL for VZV. Testing with clinical swab specimens demonstrated greater than 95% clinical sensitivity and specificity for all three analytes. The Alinity m HSV 1 & 2/VZV assay provides a reliable and accurate method for detection and differentiation of HSV-1, HSV-2, and VZV in lesion swab specimens for improved diagnostic accuracy and patient management. IMPORTANCE Herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV) can cause skin and mucocutaneous lesions that often appear clinically similar, making accurate diagnosis difficult without laboratory testing. Rapid and reliable identification of the causative virus is important because patient counseling, treatment decisions, and infection management differ among these infections. In this multicenter study, a fully automated molecular assay was evaluated that simultaneously detects and differentiates HSV-1, HSV-2, and VZV from a single-lesion swab specimen. Testing of more than 1,200 clinical specimens demonstrated high sensitivity and specificity for all three viruses. The assay also offers a streamlined workflow with minimal hands-on time and rapid turnaround. These findings support the use of this multiplex assay as a practical diagnostic tool that can improve laboratory efficiency and provide clinicians with timely, accurate results to guide patient care.