Citations

Abstract Background Some data suggest that neuroinflammation may be associated with pro‐inflammatory states in the body. Systemic, proinflammatory cytokines (TNFα, IL‐1, IL‐6, etc.) are produced by a variety of comorbidities. Neuroinflammation has been shown to be associated with the accumulation of amyloid in the brain (Becher, Heneka). We hypothesized that systemic cytokine production could be associated with neuroinflammation and thereby be related to brain amyloid accumulation. This study aims to evaluate the relationship between neuroinflammation, amyloid accumulation and systemic cytokines. Method 90 participants from the Mayo Clinic Study of Aging (MCSA) received a fasting cytokine panel over a 5‐year span where IL‐1, IL‐6, IL‐10, TNFa levels were measured. Participants were divided into four groups: cognitively unimpaired with normal levels of amyloid (CU A‐, n = 25), cognitively unimpaired with elevated amyloid (CU A+, n = 25), and mild cognitively impaired (MCI) with amyloid positive (MCI A+, n = 25), and Alzheimer's disease (AD) with elevated amyloid (AD A+, n = 15). To compare regional standardized uptake value ratio (SUVr) from neuroinflammation PET based on amyloid status (A+ vs A‐) and the four cytokines, Spearman's rank correlation and Fishers r‐to‐z transformations were used to assess pairwise group differences. Result Using Spearman's rank correlation and Fishers r‐to‐z transformations, no strong relationship was found between systemic inflammation and neuroinflammation. While comparing CUA‐ vs CUA+ in Figure 1, three regions (supplementary motor area, frontal superior medial lobe, and middle cingulate cortex) showed a significant difference ( p < 0.05). However, Figure 2 showed an overarching trend bias towards significance across most regions in IL10, IL6, and TNFa. Conclusion Although significant relationships between systemic inflammation, brain amyloid and neuroinflammation were limited, the data show an overarching trend bias in broad brain regions, suggesting that further analyses are needed, possibly with larger sample sizes, to assess the relationship of regional neuroinflammation and amyloid to systemic inflammation. Future analyses could also regress out factors like sex, age, and genotype to further proinflammatory cytokine research.

This economic evaluation estimates the implementation costs and cost per additional patient receiving the vaccine associated with each of the intervention strategies for increasing rates of human papillomavirus (HPV) vaccination in primary care practices.

BACKGROUND Among antiretroviral therapy–suppressed (ART-suppressed) people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the effect of sex on the inflammatory proteome, and whether age modifies these differences, remain unclear. METHODS Plasma inflammatory protein levels were assessed in ART-suppressed PWH from the Center for AIDS Research Network of Integrated Clinical Systems. The relationship between sex and plasma proteins — including 22 interferon-α response pathway proteins — was assessed, adjusting for confounders and assessing interactions by age. RESULTS Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age modified the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 but higher in women in those > 47 (interaction P < 0.001). Among the 131 proteins associated with mortality risk ( q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women. Women had decreased mortality than men ≤ 47 ( P < 0.001) but had similar mortality > 47 ( P = 0.84). CONCLUSION The menopausal transition appears to increase systemic type I interferon responses and inflammation in women with HIV, which may contribute to a loss of female advantage in mortality. FUNDING NIH National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases.

Abstract Introduction: Axi-cel, an autologous anti-CD19 CAR T-cell therapy has shown high and durable response rates and a manageable safety profile among R/R FL pts in the ZUMA-5 trial (Jacobson et al. 2022; Neelapu et al. 2024). Evidence from real-world data showed favorable early outcomes in a broader population using CIBMTR data, with comparable outcomes by ZUMA-5 eligibility, age, lines of therapy (LOT), and prior bendamustine (benda) use (Jacobson et al. 2023). This study investigated long-term outcomes and the association between age, performance status, comorbidities, and therapies given prior to infusion among R/R FL pts treated with axi-cel. Methods: Pts with R/R FL who received commercial axi-cel between 03/2021–10/2023 in the US were identified from the CIBMTR® registry; pts without consent, with prior non-transplant cellular therapy, and FL grade 3B or 3A/3B unspecified or unknown were excluded. Descriptive analyses were done among all pts and by age at infusion (&lt;65 vs ≥65 y), Karnofsky performance score (KPS), presence of hepatic, cardiovascular (CV), or moderate to severe pulmonary comorbidities, prior treatments (benda pre-leukapheresis, autologous hematopoietic stem cell transplant [autoHSCT]), and lymphodepletion (LD) therapy. Multivariable (MV) Cox and logistic regression were used to adjust for confounders. Results: In total, 238 pts from 68 centers were included (data cut-off October 2024). Median age at infusion was 61 yr (range, 29-83; ≥65 yr, 38%), and 79% were non-Hispanic White. KPS of pts was ≤70% (11%), 80% (35%), or 90-100% (54%); 2% had ECOG ≥2. Most (75%) had ≥1 clinically significant comorbidity (hepatic, 6%; CV, 15%; pulmonary, 18%). Median (min, max) prior LOT was 4 (1,13); 74% received benda pre-leukapheresis, and 6% had benda LD therapy. At a median follow-up of 24.1 months, objective response rate (ORR) was 96% (complete response [CR] rate, 91%). The 2-yr (95% CI) DOR, PFS, and OS were 70% (63-77), 64% (57-71), and 84% (78-89) respectively. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% and 18% of pts (any grade, 74% and 42%), respectively. Prolonged cytopenias by day 30 occurred in 14% of pts (neutropenia [10%] and thrombocytopenia [8%]) while 29% had clinically significant infections at 6 months. Second primary malignancies occurred in 16 pts (7%), with 7 (2%) being therapy-related myeloid neoplasm. The leading primary causes of death (n=34) were relapse/progression (10; 29%), organ failure (7; 21%), and infection 5 (15%). Cumulative incidence of non-relapse mortality at 2-yr was 9%. Outcomes were generally comparable among age, autoHSCT, and comorbidity subgroups. However, effectiveness outcomes differed by prior benda use (Yes vs No): ORR (95% vs 98%); CR (88% vs 98%); DOR (65% vs 89%), PFS (58% vs 84%), and OS (82% vs 91%) at 2 years. By LD therapy (single agent benda vs cyclophosphamide + fludarabine [Cy + Flu]): the ORR was 93% vs 96%; CR rate was 57% vs 93%. On MV analysis, prior benda use was associated with (OR/HR [95% CI]): worse CR (0.02 [&lt;0.01-0.43]), DOR (3.69 [1.51-9.02], and PFS (2.21 [1.12-4.38]). Pts given benda LD therapy had (OR/HR [95% CI]): worse CR rate (0.02 [&lt;0.01-0.16]), DOR (7.59 [2.33-24.72]), and PFS (4.89 [1.79-13.39]) compared to those who received Cy + Flu. CRS and ICANS were lower among those with prior benda use (Yes vs No): any-grade CRS (70% vs 87%); Grade ≥3 CRS (3% vs 8%); any-grade ICANS (36% vs 61%); and grade ≥3 ICANS (17% vs 25%). By LD therapy (single agent benda vs Cy + Flu): the Grade ≥3 CRS and ≥3 ICANS were 0% vs 5% and 7% vs 19% respectively. Any-grade ICANS was higher among those aged ≥ 65 yr vs &lt;65 yr (53% vs 35%). On MV analysis, pts who had prior benda use were less likely to have any-grade CRS (0.30 [0.12-0.75]), and any-grade ICANS (0.23 [0.11-0.50]. Pts ≥ 65 yr had higher any-grade ICANS (2.31 [1.18 – 4.50]). Summary/Conclusion: This long-term follow up of axi-cel in R/R FL shows durable responses and manageable safety similar to ZUMA-5. Outcomes among the elderly and those with comorbidities were generally comparable to the overall R/R FL population. Although benda use pre-leukapheresis was associated with less durable responses, we were unable to determine whether this association is limited to use close to axi-cel infusion, as data on timing of use was unavailable. The associations for benda LD should be interpreted with caution given the small sample size.

Abstract Description Infants are vulnerable to infectious diseases due to the immaturity of their immune system, including a delay in producing pathogen-targeting antibodies. Maternal immunization strategies have increased in use to protect infants from disease by vertical transfer of protective pathogen-specific antibodies. Late-onset sepsis (LOS) is a substantial contributor to neonatal mortality that results from a bloodstream infection at least 72 hours after birth. The implicated pathogen is often a member of the intestinal microbiome before systemic infection, suggesting translocation from the intestine as the path to the bloodstream. We hypothesized that maternal immunization of animals prior to pregnancy could protect nursing pups in a murine model of LOS. Following maternal immunization against Enterobacteriaceae taxa implicated in sepsis, we observed significantly decreased pup mortality following an oral challenge with Escherichia coli. This protection was associated with increases in antigen-specific IgG and IgA in both the mammary tissue of vaccinated dams and stomach contents of nursing pups. Interestingly, we did not observe differences in the infant microbiota following maternal vaccination, suggesting increased pathogen-specific IgG and IgA did not perturb the developing microbiota. This work suggests maternal immunization may be useful to protect offspring from enteric pathogens, and further supports the role of human milk and human milk factors in protection from LOS. Funding Sources Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) Topic Categories Vaccines and Immunotherapy (VAC)

Background: Post-treatment prognosis and monitoring are critical for determining the timing of salvage treatment in glioblastoma patients but has been challenging due to difficulties differentiating progression from treatment effects in conventional images. This exploratory study aimed to establish the correlation of radiomics image features from time series of amino acid tracer 18F-DOPA PET images, with outcomes, using machine learning and dimension reduction analysis. Methods: 18F-DOPA PET images were collected for a patient cohort with wild-type IDH and unmethylated MGMT who underwent dose-escalated radiation therapy. Quantitative features were derived from the high uptake region (T/N > 2.0) in pre- and post-radiation therapy follow-up 18F-DOPA PET images. A customized workflow was utilized for pre-selecting predictive features, followed by manifold learning. Machine learning algorithms were employed to establish associations between imaging features and remaining survival (RS), defined as the time between a follow-up scan and date of death. Results: The ML models exhibited 81–83% ROC_AUC in predicting RS evaluated on an independent test dataset. A RS map is proposed for monitoring tumor alterations through serial 18F-DOPA PET scans, demonstrating superior sensitivity and better correlation with survival compared to the RANO criteria. Conclusions: Our study demonstrates that ML models utilizing FU 18F-DOPA PET images have the potential to effectively predict future survival outcomes in patients with glioblastoma treated with dose-escalated radiation therapy. The capability to assess changes in tumor over time through imaging can potentially assist in patient stratification and the selection of salvage treatments, while also aiding in distinguishing treatment effects from genuine tumor progression.

Abstract Dobbs, WC, Almonroeder, TG, Carpenter, M, Schmitt, RE, Jacobson, AK, Luedke, JA, Roberts, BM, and Jagim, AR. Relationships between the Army Combat Fitness Test scoring structure and laboratory measurements of physical fitness in reserve officer training corps cadets. J Strength Cond Res 39(7): 798–808, 2025—The Army Combat Fitness Test (ACFT) assesses aerobic and anaerobic fitness capabilities in the U.S. Army. The aim of this study was to evaluate the association between raw and composite ACFT scores and laboratory-based measurements of fitness. Nineteen Reserve Officers' Training Corp cadets performed a battery of laboratory-based fitness testing. Tests included a movement screening (Fusionetics), countermovement jumps, and maximal isometric mid-thigh pulls on portable force plates to determine power and strength. A Wingate test involving maximal cycling for 30 seconds was used to determine peak and mean power. On a separate day, cadets completed body composition and a graded exercise test on a motorized treadmill to determine peak oxygen uptake (V̇ o 2 peak). Pearson correlations and partial corrections with 2000 bootstraps were used to compare ACFT scores (raw, composite, gender-neutral composite, and z -scores) with laboratory results. Significant associations were identified as 95% confidence intervals, not including zero. The results indicated that V̇ o 2 peak ( r = 0.61, [0.08–0.84]), body fat percentage ( r = −0.4, [−0.72 to −0.06]), and relative peak power ( r = 0.38, [0.02–0.68]) were associated with the total ACFT composite score when partialled by sex. All laboratory tests, except the movement screening, showed meaningful associations with total ACFT z -scores and gender-neutral ACFT scores ( r > 0.54). However, most relationships were eliminated when partialled out by sex, which may be due to a low sample size of women. This suggests the current scoring structure utilized for men is representative of aerobic and anaerobic fitness parameters and may be able to discriminate performance levels.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (&lt;3 vs 3-6 vs &gt;6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.