Faculty Bibliography

High-resolution quantitative susceptibility mapping (QSM) combined with susceptibility source decomposition provides a powerful approach for investigating the magnetic susceptibility alterations in Alzheimer's disease (AD). In this study, ex vivo three-dimensional multi-echo gradient-echo (mGRE) images of 5xFAD and

BACKGROUND:Degenerative disc disease (DDD) with cartilaginous endplate degeneration and Modic type 1 or 2 changes is increasingly recognized as a source of chronic vertebrogenic and discogenic low back pain. Because the intervertebral disc and vertebral endplates function as a biological and biomechanical unit, regenerative strategies targeting both structures may better address the disc-endplate complex. CASE SERIES/METHODS:Thirteen consecutive patients with chronic refractory vertebrogenic and/or discogenic low back pain, MRI evidence of DDD with Modic type 1 or 2 changes, and failure of conservative management underwent combined intradiscal, peridiscal, and subchondral bone marrow aspirate concentrate (BMAC) injections under fluoroscopic guidance. Four patients had previously undergone basivertebral nerve radiofrequency ablation. The cohort included 6 men and 7 women with a mean age of 56.2 ± 17.5 years. Follow-up ranged from 4 to 15 months. Mean Visual Analog Scale scores decreased from 7.3 ± 2.0 at baseline to 2.1 ± 1.6 at latest follow-up, a mean reduction of 5.2 ± 1.8 points (72.7% ± 19.5%). All patients achieved at least 50% pain reduction and reported functional improvement. Twelve patients (92.3%) were satisfied or very satisfied, and all would recommend the procedure. No major procedure-related complications were observed. CONCLUSION/CONCLUSIONS:Combined intradiscal, peridiscal, and subchondral BMAC injections were associated with substantial pain reduction, functional improvement, high patient satisfaction, and no major complications in this small retrospective case series. Larger prospective controlled studies are needed to confirm these preliminary findings.

PURPOSE/UNASSIGNED:This treat-and-resect clinical study evaluated a specialized form of pulsed electric field (PEF) ablation's potential to modulate antitumor immunity in early-stage non-small cell lung cancer (NSCLC). Tertiary lymphoid structures (TLS) are lymphoid aggregates that recruit immune cells into the tumor microenvironment (TME) and serve as immunity-generating neighborhoods. TLS with germinal centers (GC) have strong prognostic value in most cancers and promote tumor control and responsiveness to immune-based therapies, but no commercially available therapeutics induce their formation. The Aliya System is a proprietary electrosurgical technology that delivers microsecond electrical pulses to tissue, achieving tumor clearance while maintaining stromal architecture. PATIENTS AND METHODS/UNASSIGNED:Treatment group patients received ablation immediately after diagnostic biopsy versus a biopsy-only control group. Herein, we report on exploratory endpoints examining immune modulation in blood and tumor samples collected from patients in both groups. RESULTS/UNASSIGNED:Histopathologic assessments revealed the presence of TLS with GC in resected tumors. Tissue cytokine assessments and single-cell RNA sequencing demonstrated upregulation of cytokines capable of recruiting and organizing TLS-associated lymphocytes, including CXCL13, and significant increases in GC-related immune populations, including class-switched memory B and plasma cells in ablated tumors versus preablation biopsies. Ablation group patients had more tumors containing TLS with GC (47%) versus control (24%). Ablation group patients exhibited enhanced systemic immunity, with increased serum high mobility group box 1 and circulating cytotoxic T cells. CONCLUSIONS/UNASSIGNED:This specialized PEF may orchestrate multiple simultaneous changes that promote a more immunologically active TME and represent a new approach for improving immunotherapeutic regimen responses in patients with NSCLC.

BACKGROUND:While many adults diagnosed with atopic dermatitis (AD) achieve disease control with standard treatments, a subset of patients remains refractory to optimal management. In these cases, misdiagnosis or the presence of concomitant conditions may be contributing to treatment failure. OBJECTIVE:To provide evidence-informed guidance for the diagnostic workup of presumed adult AD unresponsive to optimized treatment. METHODS:An expert multidisciplinary workgroup applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for issuing guidance on approaching suspected AD refractory to treatment by reviewing the indirect evidence, assessing the balance of benefits and harms, and reaching consensus. RESULTS:The workgroup developed a Good Practice Statement on the diagnostic workup of adults with presumed AD unresponsive to therapy. LIMITATIONS/CONCLUSIONS:This guidance is based on indirect evidence and expert consensus, as direct empirical data on diagnostic workup strategies for treatment-resistant AD are lacking. Applicability may vary depending on access to dermatologic and allergy specialist care. CONCLUSION/CONCLUSIONS:The Good Practice Statement supports consideration of diagnostic reassessment in cases of presumed AD in adults not responding to optimized treatment.

RATIONALE & OBJECTIVE/UNASSIGNED:Inflammation is associated with adverse kidney, cardiovascular, and mortality outcomes. Investigation of the metabolic milieu as it relates to inflammation may provide important insights into these disease processes. STUDY DESIGN/UNASSIGNED:Prospective cohort. SETTING & PARTICIPANTS/UNASSIGNED:African American Study of Kidney Disease and Hypertension (AASK), Atherosclerosis Risk in Communities (ARIC) study, and Boston Kidney Biopsy Cohort (BKBC) participants with available metabolomics and inflammatory protein data. PREDICTORS/UNASSIGNED:Baseline blood levels of 718 metabolites. OUTCOMES/UNASSIGNED:Baseline and longitudinal changes in blood levels of tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins 6, 8, and 10 (IL-6, IL-8, IL-10), uromodulin (UMOD), and epidermal growth factor (EGF). ANALYTICAL APPROACH/UNASSIGNED:Multivariable linear regression and linear mixed-effects models. RESULTS/UNASSIGNED:-diacetylornithine, which were associated with 2-year increases in TNFR1 and/or TNFR2, and 1,5-anhydroglucitol, where lower levels were associated with decreases in UMOD. In ARIC (n = 3,773) and BKBC (n = 413), replication of cross-sectional associations was excellent for TNFR1 (ARIC 83%; BKBC 85%) and TNFR2 (ARIC 64%; BKBC 79%) but poor for IL-8 (ARIC 3%; BKBC 3%). LIMITATIONS/UNASSIGNED:Metabolite data limited to baseline visit; potential for residual confounding. CONCLUSIONS/UNASSIGNED:Using an untargeted approach, multiple metabolites were cross-sectionally and longitudinally associated with inflammatory proteins in persons with chronic kidney disease.

Thrombotic risk in COVID-19 extends beyond acute illness, including in nonhospitalized individuals, suggesting that thrombo-inflammatory biology may persist during recovery. Longitudinal sampling with pre-infection baselines is needed to distinguish infection-associated signals from inter-individual variability and time-related drift in blood gene expression. To define coordinated, time-resolved whole-blood transcriptomic programs during SARS-CoV-2 convalescence using longitudinal within-person comparisons before and after infection, alongside COVID-19-naïve controls. Adults were sampled longitudinally with specimens collected before SARS-CoV-2 infection (T0) and at ~3 months (T1) and ~6 months (T2) post-infection; COVID-19-naïve controls were sampled across matched timepoints. COVID-19-naïve status was confirmed using a multiplex anti-nucleocapsid IgG assay spanning multiple variant antigens. Whole-blood RNA-seq (PAXgene) was analyzed with DESeq. 2 using models that incorporated time point and participant. To prioritize infection-linked changes, genes differentially expressed over time in controls were identified and excluded from comparisons between COVID-19 time points. Pathways were assessed by pre-ranked GSEA (MSigDB) and clustered with aPEAR. After excluding control-associated genes, COVID-19 convalescence remained associated with marked transcriptional remodeling (T1 vs. T0: 782 genes; T2 vs. T0: 655 genes; p < 0.05) and persistent pathway-level changes. Interferon-α and interferon-γ signatures were enriched at both T1 and T2, and a core set of interferon-associated genes remained elevated across convalescence. SARS-CoV-2 infection is followed by durable whole-blood immune-defense programs, including persistent interferon signaling, detectable up to 6 months post-infection. These sustained signatures support a model of prolonged post-infectious immune activation that may contribute to extended thromboinflammatory risk.

Nickel is a transition metal that is widely distributed in the environment. Nickel compounds are classified as Group 1 carcinogens (human carcinogens) by the International Agency for Research on Cancer (IARC). Despite extensive studies, the molecular mechanisms underlying nickel-induced carcinogenesis remain incompletely understood. Maternally Expressed Gene 3 (MEG3) is the first long non-coding RNA (lncRNA) identified as a tumor suppressor. Previous studies have shown that downregulation of MEG3 increases HIF-1α expression in human bronchial epithelial BEAS-2B cells chronically exposed to nickel. In the present study, we observed that MEG3 expression is markedly reduced in nickel-transformed cells. Dysregulation of Runt-Related Transcription Factor 2 (RUNX2) has also been implicated in multiple cancer types. Previous studies have demonstrated that RUNX2 is upregulated in nickel-induced malignantly transformed BEAS-2B cells. Consistent with these findings, we observed that chronic exposure of BEAS-2B cells to low-dose nickel increases both RUNX2 mRNA and protein expression, accompanied by elevated expression of mesenchymal markers and enhanced migratory and invasive capacities. Overexpression of MEG3 in nickel-transformed cells reduces RUNX2 protein levels and reverses the alterations of epithelial-mesenchymal transition (EMT) markers, resulting in decreased cell migration and invasion in nickel-transformed cells. Similarly, silencing RUNX2 reverses the expression of EMT markers and suppresses the migratory and invasive capacities of nickel-transformed cells. Notably, shRNA-mediated RUNX2 knockdown increases MEG3 expression, indicating reciprocal regulation between MEG3 and RUNX2 in nickel-transformed cells. Collectively, our findings demonstrate that MEG3 and RUNX2 form a reciprocally regulated signaling axis that contributes to EMT, thereby promoting migration and invasion in nickel-transformed cells. These results identify MEG3 and RUNX2 as interconnected biomarkers and potential therapeutic targets for cancer prevention and treatment, warranting further mechanistic investigation.

Ketogenic diet (KGD) combined with ketamine (KET) suppresses food restriction-evoked hyperactivity in activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) for more than 28 days, thereby improving weight retention and reducing anxiety, even after mice return to standard diet (SD) and are re-challenged with ABA (KGD + KET → SD, "KET + KGD group"). Suppression of these AN-like behavior is not sustained in mice fed KGD without KET (KGD → SD, "KGD-only group"). We hypothesized that the sustained efficacy of KET + KGD is associated with altered prevalence of certain synapses in the dorsal hippocampus that influence behavior. We compared the prevalence of excitatory and inhibitory synapses between KET + KGD (N = 7) versus KGD-only (N = 7) groups, using electron microscopy and GAD immunolabeling to distinguish GABAergic inhibitory synapses from non-GABAergic excitatory synapses. Pyramidal cell layer (PCL) was analyzed to assess the contribution by parvalbumin + subtype of GABAergic neurons known to reside there, while stratum lacunosum-molecular (SLM) was analyzed to assess inhibition by non-PV + GABAergic neurons known to reside there. In both PCL and SLM, the KET + KGD group exhibited greater correlation between GABAergic inhibition of PNs and weight retention. In SLM of the KET + KGD group, the areal density of excitatory synapses was less. Inhibitory synapses onto GABAergic dendrites (disinhibition which may also augment excitability) correlated negatively with hyperactivity for the KET + KGD group only. KET + KGD, but not KGD-only, may sustain ABA resilience by enhancing plasticity of both glutamatergic and GABAergic synapses. This jointly sustained plasticity underlying hippocampal excitability may be the cellular bases for KET + KGD treatment's suppression of AN relapses.

BACKGROUND:Electronic cigarette use, vaping, is common among young adults. The cardiovascular (CV) risk remains unknown. OBJECTIVES/OBJECTIVE:This study evaluated the association of long-term vaping with markers of CV risk in young adults. METHODS:We recruited 372 CV disease-free participants aged 18 to 49 years into 4 groups: vaping/never smoking, vaping/former smoking, vaping/current smoking (dual use), or never vaping/never smoking and measured systolic and diastolic blood pressure (SBP/DBP), endothelial function (Framingham reactive hyperemia index), and coronary artery calcification (CAC) (spatially weighted CAC score). We used multivariable-adjusted linear and log-linear regression to model associations of vaping with markers of CV risk. RESULTS:The median (Q1-Q3) age was 26 (21-33) years, and 50.5% were males. The median (Q1-Q3) years of vaping was 4 (2-6) years. After adjustment for age, gender, education, and body mass index, least squares mean differences (95% CI) for SBP/DBP in mm Hg were 4.79 (1.83-7.75)/2.88 (0.54-5.21), 1.60 (-1.65 to 4.85)/1.44 (-1.12 to 4.00), 1.10 (-1.86 to 4.06)/1.48 (-0.86 to 3.82), respectively, comparing vaping/never smoking, vaping/former smoking, and dual use to never vaping/never smoking. The corresponding least squares mean differences (95% CI) of SBP/DBP for greater than 100 vs fewer than 36 e-cigarette puffs/day were 4.84 (0.94-8.74)/3.57 (0.74-6.41) mm Hg. There was no association between vaping categories and Framingham reactive hyperemia index. For spatially weighted CAC score, there was an inverse association for the 3 vaping categories vs never vaping/never smoking. CONCLUSIONS:Long-term vaping in young adults was associated with higher blood pressure, with evidence of a dose-response by vaping intensity. Vaping alone or vaping plus smoking provided no risk reduction for hypertension compared to never vaping or smoking.

Long-acting growth hormone (LAGH) preparations have moved from development to routine clinical use over the past decade. Several products are now approved for paediatric growth hormone deficiency (GHD), selected non-GHD short-stature indications, and, in some regions, for adult GHD. The Growth Hormone Research Society convened an international workshop in October 2025 to reappraise the evidence base and refine clinical recommendations. Currently, data are available for up to 7 years of LAGH treatment in over 8,000 individuals. This remains substantially shorter and smaller than for daily GH. Across preparations, short- to mid-term efficacy appears comparable to daily somatropin, provided dosing is individualised and monitored appropriately. Approvals and pivotal trials include both, treatment initiation and switching from daily GH, depending on product and regional label. No new major safety signals have been identified in trials and real-world reports, although data on BMI trajectories require further evaluation. Injection-site reactions remain the most frequent adverse event and vary by formulation. Anti-drug-antibodies have been observed, yet evidence suggests they have limited clinical impact. Effects on glucose metabolism resemble those of daily therapy, but metabolically high-risk groups are under-represented in studies. Among cancer survivors, data on tumour recurrence and second neoplasms with LAGH are not yet available. Recommendations and practice points emphasised careful patient selection and counselling, product-specific dosing, and insulin-like growth factor-I (IGF-I) monitoring. Urgent knowledge gaps include transition care, long-term efficacy, adherence and safety in cancer survivors. Well-resourced registries are essential for addressing these gaps and supporting safe, effective, and patient-centred use of LAGH.