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Abstract Objective To evaluate whether postoperative intracranial pressure–lowering interventions reduce recurrence of lateral skull base spontaneous cerebrospinal fluid leaks after surgical repair. Data Sources Ovid MEDLINE, Embase, Cochrane CENTRAL, Web of Science Core Collection, and Scopus were searched from inception through April 7, 2025. Review Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines and included studies of adults with lateral skull base spontaneous cerebrospinal fluid leaks undergoing primary repair where postoperative intracranial pressure–lowering interventions were specified. Pooled recurrence rates were calculated by intervention type and compared with cohorts that did not receive intracranial pressure–lowering therapy. Results Thirty‐six studies including 687 patients (737 cases) met inclusion criteria. Six comparative cohorts (34 treated, 155 untreated) showed no significant difference in recurrence (risk ratio 1.16, 95% confidence interval [CI]: 0.14–9.76; I 2 = 0%). Across 82 intervention‐only cases, recurrence occurred in three (pooled proportion 0.10, 95% CI: 0.04–0.26; I 2 = 0%). Among 650 control‐only cases, 45 recurred (pooled proportion 0.09, 95% CI: 0.07–0.12; I 2 = 0%). No heterogeneity was observed across pooled analyses. Conclusion Available evidence does not support universal postoperative intracranial pressure–lowering therapy after lateral skull base spontaneous cerebrospinal fluid leak repair. Limited observational data suggest acetazolamide may be associated with lower recurrence, whereas lumbar drainage has not demonstrated sustained benefit. Given the heterogeneity in patient selection and intervention practices, postoperative management should be individualized. Future prospective studies are needed to better define the role of targeted therapy in high‐risk patients.

Abstract Introduction Hypoglossal nerve stimulators (HGNS) are used in patients with moderate-to-severe obstructive sleep apnea (OSA) who are unable to tolerate or do not respond to continuous positive airway pressure (CPAP) therapy. However, a subgroup of patients fail to achieve resolution of OSA with HGNS alone. Previous studies have shown that lower BMI, lower nadir oxygenation, decreased sleep latency, and higher VOTE score on drug-induced sleep endoscopy (DISE) predict better treatment outcome. We hypothesize that baseline diagnostic polysomnography (PSG) may further predict which patients will achieve successful therapeutic outcome with HGNS therapy. Methods We conducted a retrospective analysis of all adult patients who underwent HGNS implantation at Mayo Clinic Arizona between 2019-2025 and had a pre-implantation diagnostic PSG available for review. Treatment success was defined by Sher Criteria: >50% reduction in post-treatment apnea hypopnea index (AHI) to a final AHI of < 20/hr. Responders met Sher criteria and non-responders did not meet Sher criteria. Demographics, sleep questionnaire results, PSG variables, and VOTE score on DISE were collected and analyzed using Spearman’s rank correlation of reduction in AHI. Results Twenty-three patients (11M/12F, median age: 69[IQR:64,75] years) met inclusion criteria. Median baseline AHI was 24[IQR:19,37]/hr. Median post-implant AHI was 8 [IQR:3, 14]/hr. Responders (n=15, 65%) and non-responders (n=8, 35%) demonstrated median post-implant AHI of 4.5[IQR:2.3,7.3]/hr and 15.7[IQR:12.3,28.5]/hr, respectively. Treatment response was associated with less time with SpO2 < 88% (T88%) (21min [IQR:3,64] vs. 73[IQR:36,105mins]; p=0.023) and higher central apnea index (CAI) (1[IQR:0.1,3] vs. 0[IQR:0,1], p=0.03) on pre-implantation PSG. Conclusion In this small cohort of OSA patients, less nocturnal hypoxemia as defined by T88% and higher baseline central apnea index were predictors of better treatment response to HGNS therapy as measured by Sher criteria. We hypothesize that greater nocturnal hypoxemia likely reflects more severe airway obstruction during sleep. Our analysis also showed that responders had higher baseline CAI than non-responders, however we believe this association is not clinically significant and likely driven by one outlier (CAI 13/hr). Further analysis in a larger HGNS cohort is needed to confirm these findings. Data enrichment efforts and more sophisticated analyses are underway. Support (if any)

Abstract Background and aims Dementia represents a growing global health burden, with vascular dementia and Alzheimer's disease accounting for most cases through cumulative cerebrovascular damage. While periodontal disease (PD) is associated with cognitive decline, dental caries represents a distinct oral infection pathway characterized by bacterial invasion and infection, potentially contributing to vascular brain injury through microbial translocation, endothelial dysfunction, systemic inflammation, and cerebral microvascular damage. The relationship between dental caries and incident dementia within a vascular framework remains understudied. Methods We analyzed 6,542 participants from the Atherosclerosis Risk in Communities (ARIC) Study who received dental examinations at Visit 4 (1996–1998) and followed for incident dementia through 2023 using standardized surveillance (Figure-1). Cox proportional hazards models with competing risk accounted for death. Multivariable models adjusted for demographic factors, cardiovascular risk factors, BMI, physical activity, education, income, insurance status, APOE4 genotype, PD, and regular dental care. Results Mean age was 62.4 years; 54% female, 82% White, and 18% Black. Dental caries was present in 20%. Over median 25-year follow-up, individuals with dental caries demonstrated significantly higher cumulative dementia incidence (Gray’s test p<0.0001). After full adjustment, dental caries remained independently associated with increased dementia risk (adjusted HR 1.20, 95% CI 1.02–1.42), independent of PD and APOE4 status (Figure-2). Conclusions Dental caries was independently associated with increased incident dementia risk. These findings support a potential role for caries-related oral infection in vascular brain injury pathways relevant to vascular dementia and stroke-related cognitive impairment. Oral infection prevention may represent a modifiable target within cerebrovascular disease prevention strategies. Conflict of interest Alana E. Barton, Souvik Sen, Kevin Moss, James Selph, Ryan Demmer, Pamela L. Lutsey, Priya Palta, Kamakshi Lakshminarayan, Karly Pikel, Wayne Rosamond: nothing to disclose Figure 1 - belongs to Conclusions Figure 2 - belongs to Conclusions

Abstract Background and aims Systemic inflammation has been implicated in cognitive decline and dementia pathogenesis. Interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cardiovascular disease, may play a role in cerebrovascular and neurodegenerative processes. We examined the relationship between IL-6 levels and incident dementia risk using the Atherosclerosis Risk In Communities (ARIC) study. Methods ARIC study participants at Visit 4 (1996-1998) had IL-6 measurements and were followed for incident dementia over 25 years. IL-6 levels were dichotomized at the median value of 1.5 pg/mL. Incident dementia cases were identified through standardized surveillance. Cox proportional hazards regression calculated hazard ratios (HR) with 95% confidence intervals (CI), adjusting for age, race, gender, hypertension, diabetes, obesity, physical activity, smoking, alcohol use, education, income, insurance status, and ApoE-ε4 allele status. Results Participants (n=5,662; mean age 62.4±5.6 years, 55% female, 83% White, 17% Black) were followed for a median of 25 years. Those with IL-6 >1.5 pg/mL demonstrated significantly increased dementia risk versus IL-6 ≤1.5 pg/mL. The crude HR was 1.23 (95% CI 1.11-1.37). After adjustment, the association remained significant with HR 1.13 (95% CI 1.01-1.27). Kaplan-Meier survival curves showed progressive divergence between groups, with lower dementia-free survival in the higher IL-6 group, log-rank p<0.001. Conclusions Elevated mid-life IL-6 levels (>1.5 pg/mL) independently predict increased long-term dementia risk over 25 years, even after adjusting for cardiovascular and sociodemographic confounders. These findings support systemic inflammation's role in dementia pathogenesis and highlight IL-6 as a potential biomarker for dementia risk. Conflict of interest Karly Pikel, Natasha Carmichael, Alana E. Barton, Kevin Moss, Christine Downey, Ryan T. Demmer, Pamela L. Lutsey, Souvik Sen: Nothing to disclose Figure 1 - belongs to Conclusions

Compared with two-dimensional MR elastography (MRE), three-dimensional MRE demonstrated better test-retest repeatability, between–field-strength reproducibility, and between-day reproducibility at 3 T for measurement of liver stiffness in adults with severe obesity but failed more frequently.

Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

Abstract Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

Combined histopathological and metabolomic analysis of the same tissue specimen can reduce biological variability compared to independent analyses of similar samples. However, conventional workflows are incompatible: tissue fixation leads to metabolite loss through dilution and chemical reactions with fixative, while metabolomic extraction typically destroys the specimen. We propose a method that reconciles these conflicting requirements by enabling metabolite recovery from fixative while preserving tissue for histopathology. In this approach, tissue is initially fixed in a small volume of fixative; an aliquot of the fixative is then collected for nuclear magnetic resonance-based metabolomic analysis before additional fixative is added for standard processing. As a proof-of-concept, mouse kidneys from the same subject were analyzed using two protocols: standard perchloric acid extraction (ensuring complete metabolite recovery but destroying tissue) and metabolite extraction from fixative. Several metabolites were fully recoverable from the fixative, others partially, while some were lost due to chemical reactions. Despite some limitations, this strategy may be useful for analyzing precious specimens, such as human biopsies, that must remain intact for further studies. Moreover, using the same specimen for dual analyses reduces the number of animals required and enhances statistical robustness.

Introduction Asymptomatic individuals with negative Interferon-γ release assay (IGRA) and tuberculin skin test (TST) results are often labeled as tuberculosis-unexposed individuals. We hypothesize that flow cytometric (FC) detection of antigen-stimulated T-cells in peripheral blood can differentiate IGRA(-)/TST(-) individuals with and without prior potential M. tuberculosis (Mtb) exposure. Methods We used FC multiparameter profiling of T-cell activation markers in TST/IGRA-negative individuals at risk for Mtb exposure and in unexposed controls. Results We studied 54 IGRA(-)/TST(-) subjects, including 27 individuals at risk for prior Mtb exposure. While quantitative IGRA results were negative in all patients, FC profiling of CD3/CD4 + IFN-γ + HLA-DR + T-cells after stimulation with a pool of Mtb-specific region of difference-1 (RD1) peptides, mycobacterial (PPD and MTB300), or Candida antigens, statistically differentiated between unexposed and potentially exposed individuals (P<0.05). ROC analysis showed PPD and RD1 peptides responses had AUCs >0.7 (sensitivity of 55.5–74% and specificity of 66.6–85.1%). The presence of a polyfunctional RD1-reactive CD3/CD8 + IFN-γ + TNF-α + T-cell subset also significantly differentiated these groups (AUC 0.66). Other T-cell markers demonstrated no significant differences. Conclusions FC detection of antigen-specific IFN-γ + HLA-DR + CD4+T-cells and IFN-γ + TNF-α + CD8 + T-cells can differentiate IGRA(-)/TST(-) individuals at risk of Mtb exposure from unexposed controls. Further validation is needed to determine whether this immunoprofiling approach can improve detection of Mtb infections and identification of unexposed individuals for future biomarker studies and vaccine trails.

Abstract SETD2 is frequently mutated or deleted in clear cell renal cell carcinoma (ccRCC). Loss of SETD2 could create synthetic lethal dependencies that confer therapeutic vulnerabilities. In this study, we demonstrated that SETD2 deficiency promotes cytoplasmic mitochondrial DNA (mtDNA) leakage, leading to basal activation of cGAS-STING inflammatory signaling and increased apoptotic priming. This inflammatory state upregulated the BH3-only protein NOXA, constrained myeloid cell leukemia 1 (MCL-1) function, and enforced a synthetic lethal dependency on the antiapoptotic protein BCL-xL. Pharmacologic inhibition of BCL-xL further amplified cGAS-STING signaling in SETD2-deficient cells through sublethal mitochondrial outer membrane permeabilization, resulting in increased mtDNA release and robust NOXA induction. Elevated NOXA neutralized the compensatory MCL-1–mediated survival signaling, triggering apoptosis. In contrast, SETD2-proficient ccRCC cells exhibited minimal cGAS-STING activation and failed to induce NOXA following BCL-xL inhibition, rendering them resistant. Genetic ablation of cGAS, STING, IRF3, or NOXA rescued sensitivity to BCL-xL inhibition, confirming that mtDNA-driven innate immune signaling is required for this dependency. In vivo, BCL-xL inhibition suppressed tumor growth and prolonged survival in SETD2-deficient xenograft models. Collectively, these findings establish a mechanistic link between SETD2 loss, mtDNA-driven innate immune activation, and enforced BCL-xL dependence in ccRCC, revealing a therapeutically targetable vulnerability in SETD2-deficient tumors. Significance: SETD2 deficiency, which is associated with worse prognosis in kidney cancer, promotes mitochondrial DNA-driven cGAS-STING signaling and NOXA-mediated apoptotic priming, creating a therapeutically targetable dependency on BCL-xL in kidney cancer.