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ABSTRACT Background Patients at high risk for cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplant (HCT) should receive CMV prophylaxis. Historically, ganciclovir has been the preferred agent. However, its side effect profile, particularly myelosuppression, is undesirable. Letermovir is a newer agent that is not myelosuppressive and has replaced ganciclovir as the preferred agent for CMV prophylaxis in high‐risk adult patients. Methods The primary objective was to compare the incidence of dose modifications or discontinuation of CMV prophylaxis between pediatric patients who received ganciclovir versus letermovir. Secondary objectives included comparing the use of granulocyte colony‐stimulating factor (G‐CSF) support and the incidence of CMV DNAemia. We reviewed records of all pediatric patients who received an HCT at our institution between 2000 and 2024 and received either ganciclovir/valganciclovir or letermovir for CMV prophylaxis. Results Between 2000 and 2024, 65 pediatric patients receiving prophylactic ganciclovir, valganciclovir, or letermovir were evaluated. The median age at transplant was 12.2 years. No patients receiving letermovir required dose modification or discontinuation as opposed to 14 (29.2%) patients receiving ganciclovir ( p = 0.014). After engraftment, 12 (25%) patients receiving ganciclovir required G‐CSF support compared to seven (41.2%) patients receiving letermovir ( p = 0.23). In the ganciclovir group, 10 (20.8%) patients experienced CMV infection versus one (5.9%) patient receiving letermovir ( p = 0.26). Conclusion Compared with those receiving letermovir, a significantly higher proportion of patients in the ganciclovir/valganciclovir group experienced dose modifications or discontinuation of CMV prophylaxis due to adverse effects. Letermovir shows great promise as a CMV prophylactic agent in pediatric HCT patients due to its favorable side effect profile.

OBJECTIVE This study aimed to develop an artificial intelligence (AI) model for automatically detecting Hounsfield unit (HU) values at the L1 vertebra in preoperative thoracolumbar CT scans. This model serves as a screening tool for osteoporosis in patients undergoing spine surgery, offering an alternative to traditional bone mineral density measurement methods like dual-energy x-ray absorptiometry. METHODS The authors utilized two CT scan datasets, comprising 501 images, which were split into training, validation, and test subsets. The nnU-Net framework was used for segmentation, followed by an algorithm to calculate HU values from the L1 vertebra. The model’s performance was validated against manual HU calculations by expert raters on 56 CT scans. Statistical measures included the Dice coefficient, Pearson correlation coefficient, intraclass correlation coefficient (ICC), and Bland-Altman plots to assess the agreement between AI and human-derived HU measurements. RESULTS The AI model achieved a high Dice coefficient of 0.91 for vertebral segmentation. The Pearson correlation coefficient between AI-derived HU and human-derived HU values was 0.96, indicating strong agreement. ICC values for interrater reliability were 0.95 and 0.94 for raters 1 and 2, respectively. The mean difference between AI and human HU values was 7.0 HU, with limits of agreement ranging from −21.1 to 35.2 HU. A paired t-test showed no significant difference between AI and human measurements (p = 0.21). CONCLUSIONS The AI model demonstrated strong agreement with human experts in measuring HU values, validating its potential as a reliable tool for automated osteoporosis screening in spine surgery patients. This approach can enhance preoperative risk assessment and perioperative bone health optimization. Future research should focus on external validation and inclusion of diverse patient demographics to ensure broader applicability.

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

Background: Despite the availability of effective vaccines and a recent decrease in annual deaths, coronavirus disease-2019 (COVID-19) remains a leading cause of death. Serological studies of anti-nucleocapsid (N) antibody response to infection provide insights into host immunobiology of adaptive immune response, which holds promise for identifying high-risk individuals for adverse acute and chronic COVID-19 outcomes. Hypothesis: Among participants previously infected with SARS-CoV-2, traditional vascular disease risk factors are associated with higher anti-N antibodies while vaccination is associated with lower anti-N antibodies. Methods: Among previously infected participants, anti-N antibodies were measured from dried blood spots collected between February 2021-February 2023 among 1,419 Collaborative Cohort of Cohorts for COVID-19 Research (C4R) participants with prior SARS-CoV-2 infection. We measured anti-N IgG antibodies reported as median fluorescence intensity (MFI) units; reactivity (i.e., seropositivity) was defined based on MFI above a validated threshold. Vascular disease risk factors were assessed via pre-pandemic in-person examination, questionnaires, and medical record review. Multivariable generalized linear models regressed anti-N reactivity (modified Poisson) or LN transformed MFI (linear). Results: Among 1,419 participants with prior infection, mean age (standard deviation) was 65.8(12.1) years, 61% were women, and 42.8% were self-reported from a race/ethnicity minority group. Participant reactivity to nucleocapsid peaked at 69% by 4 months post-infection and waned to only 44% ≥12 months after infection. After multivariable adjustment, higher anti-N antibody response was associated with older age, Hispanic (vs. White) or American Indian (vs. White) race/ethnicity, lower income and education, former smoking, and higher anti-spike antibody levels. Asian race (vs. White) and vaccination ( even after infection ) were associated with lower nucleocapsid reactivity; common cardiometabolic co-morbidities were not associated with anti-N reactivity or levels (Figures 1 and 2). Conclusions: Among participants previously infected with SARS-CoV-2, select sociodemographic and behavioral risk factors were associated with higher anti-N antibody levels while vaccination was associated with lower anti-N antibody levels. The observation that vaccination, even after infection, is related to lower anti-N antibody levels merits further investigation.

Introduction: Despite being healthier than the general population on arrival, immigrants to the US often face systemic barriers to healthy lifestyle behaviors and increased risk of cardiovascular disease (CVD). Self-efficacy has been associated with healthy diet and physical activity behaviors, but associations and construct validity have not been well studied in large samples of immigrant populations. Hypothesis: Self-efficacy for a healthy diet and physical activity will be associated with better dietary quality and intake and more physical activity, respectively. We also assessed the construct validity of measurement scales in this population. Methods: Set in southeast Minnesota and embedded with the Rochester Healthy Community Partnership, a 20-year community-based participatory research partnership, the Healthy Immigrant Community study enrolled Hispanic/Latinx and Somali immigrants into a randomized intervention to reduce obesity and CVD risks. Baseline assessments included biometric measures and self-reports of dietary intake, physical activity, and quality of life in English, Spanish, or Somali. Two self-efficacy items (“How confident are you that you can eat a healthy diet?”; “How confident are you that you can participate in regular exercise or physical activity?”) were rated as a percentage interval (0%=not at all confident; 25%; 50%=somewhat confident; 75%; 100%=very confident). Results: In total, 451 participants, 268 (59%) Hispanic/Latinx and 183 (41%) Somali, completed baseline assessments for this analysis. The mean age was 45 years (range=18-87), 59% were female, and 37% lacked health insurance over ≤12 months. Participants reporting more confidence to eat a healthy diet were more likely to eat fruits and vegetables as snacks ( p =<0.001), and less likely to drink fruit drinks or sports drinks ( p =0.02) or regular soda ( p =<0.001). Those reporting more confidence to be physically active were also reported higher levels of physical activity ( p =0.001). Validated self-efficacy scales had a wide distribution of scores, suggesting that the measures can be appropriately used among these immigrant communities. Conclusion: Higher self-efficacy for a healthy diet and physical activity were significantly associated with healthier eating and physical activity behaviors. Lifestyle interventions to reduce CVD risk may benefit from incorporating culturally tailored strategies to enhance self-confidence and support health equity in immigrant communities.

Background: Thrombo-inflammation is a hallmark of acute Covid-19, with higher thrombo-inflammatory markers during infection associated with adverse outcomes. We hypothesized that higher pre-pandemic biomarkers, reflecting a higher thrombo-inflammatory setpoint, might identify people at greater risk of severe manifestations of Covid-19. Hypothesis: Pre-pandemic inflammation markers are associated with risk of hospitalized or fatal (hereafter, “severe”) Covid-19 in a multi-ethnic US sample. Methods: From 2020-2023, C4R harmonized pre-pandemic measures and ascertained Covid-19 across 14 longstanding cohort studies. In 12 cohorts, we assessed biomarker data and covariates from the study visit closest to the pandemic for 6 analytes shown in the Table. HRs of severe Covid-19 by pre-pandemic biomarkers were estimated using cause-specific Cox regression, treating non-severe Covid-19 as a competing risk, and adjusting for pre-pandemic sociodemographic and clinical characteristics. Results: Biomarkers were measured a mean of 20 years before the pandemic with different sample sizes for each (Table footnote). Mean age at the start of the pandemic was in the 60s or 70s depending on the biomarker. The most represented race or ethnic groups were White and Black. The largest sample was for C-reactive protein, and there were 1,001 severe Covid-19 cases among 38,784 participants. In the adjusted models, considered individually, higher CRP, leukocyte count, factor VIII and fibrinogen, but not other markers, were associated with greater risk of severe Covid-19 (Table).Associations were robust across subgroups and time since biomarker measurement (example for C-reactive protein in Figure). Conclusions: In this prospective multi-study analysis of a multi-ethnic population, higher basal levels of thrombo-inflammation markers were associated with greater risk of severe Covid-19. Since we considered non-severe Covid-19 as a competing risk, associations may reflect factors related to progression to more serious Covid-19 illness.

Abstract Increased innate immune activity promotes neurodegeneration and contributes to progression in multiple sclerosis. This prospective case-control study aims to investigate thalamic microglia density on 18kDa translocator protein PET in patients with multiple sclerosis using a third-generation radioligand, 11C-ER176, and investigate the associations of 11C-ER176 PET uptake with imaging and clinical measures of progression in multiple sclerosis. Patients with multiple sclerosis (n = 50) and controls (n = 55) were prospectively enrolled and they underwent 11C-ER176 PET and MRI including diffusion MRI with neurite orientation dispersion and density imaging. Disease characteristics, expanded disability status scale and multiple sclerosis functional composite scores were obtained in patients with multiple sclerosis. Age at imaging (mean ± standard deviation: patients = 49.6 ± 12.9 years, controls = 48.2 ± 15.4 years, P = 0.63) and sex (female ratio; patients = 72%, controls = 65%, P = 0.47) were not different between the groups. Thalamus 11C-ER176 PET uptake was highest in patients with progressive multiple sclerosis (1.272 ± 0.072 standardized uptake value ratio), followed by patients with relapsing multiple sclerosis (1.209 ± 0.074 standardized uptake value ratio) and lowest in controls (1.162 ± 0.067 standardized uptake value ratio, P &lt; 0.001). Patients with thalamic lesions had higher thalamus 11C-ER176 PET uptake than those without thalamic lesions in both relapsing multiple sclerosis and progressive multiple sclerosis (P &lt; 0.001). In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with lower thalamic volume (r = −0.45, P = 0.001), higher mean diffusivity (r = 0.56, P &lt; 0.001), lower neurite density index (r = −0.43, P = 0.002), lower orientation dispersion index (r = −0.40, P = 0.005) and higher free water fraction (r = 0.42, P = 0.003) in the thalamus. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake also correlated with higher mean diffusivity (r = 0.47, P &lt; 0.001) and lower neurite density index (r = −0.36, P = 0.012) in the corpus callosum. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with worse expanded disability status scale scores (r = 0.33, P = 0.02), paced auditory serial addition test scores (r = −0.43, P = 0.003) and multiple sclerosis functional composite z-scores (r = −0.46, P = 0.001). Microglia density in the thalamus is highest in patients with progressive multiple sclerosis and is associated with imaging biomarkers of neurodegeneration and clinical disease severity. As a signature imaging biomarker of progression in multiple sclerosis, effectively reflecting the global disease burden, 11C-ER176 PET may aid development and efficacy evaluation of therapeutics targeting microglia.

Abstract INTRODUCTION Biomarkers play a crucial role in understanding Alzheimer's disease (AD) pathogenesis and treatment effects. However, comparing biomarker measures without standardization and appreciating their magnitude relative to the disease can be challenging. METHODS To address this issue, we propose the CentiMarker approach, similar to Centiloid, which provides a standardized scale between normal (0) and nearly maximum abnormal AD (100) ranges. We applied this scale to cerebrospinal fluid (CSF) biomarkers in dominantly inherited AD and sporadic AD cohorts. RESULTS CentiMarkers facilitated the interpretation of disease abnormality, demonstrating comparable changes and distributions of AD biomarkers across disease stages. CentiMarkers make the treatment effect more comparable than their original scales across various biomarkers. DISCUSSION The versatility of CentiMarkers makes it a valuable tool for standardized biomarker comparison in AD research, enabling informed cross‐study comparisons and contributing to accelerated therapeutic development. Adoption of the CentiMarker scale could enhance biomarker reporting and advance our understanding of AD. Highlights Comparing fluid biomarkers without appreciating their magnitude relative to the disease can be challenging. We propose a CentiMarker metric to standardize biomarker measures from normal (0) and nearly maximum abnormal AD (100) ranges. CentiMarkers make the treatment effect more comparable across various biomarkers than when using the original scales.

The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra’s dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that urethral neuroendocrine cells (UNECs), and the serotonin they synthesize, protect the bladder from bacterial colonization. We tested the hypothesis that serotonin initiates urethral contraction to expel ascending bacteria. We identified transient receptor potential cation channel subfamily A member 1, a noncanonical lipopolysaccharide receptor, in human and mouse UNECs and localized the serotonin receptors (HTR) 2B and 3, as well as the calcium-activated chloride channel anoctamin 1 (ANO1) to the pacemaker cells of the human and mouse urethra, the interstitial cells of Cajal (ICCs). HTR2B or ANO1 activation is sufficient for urethral contraction and is required for serotonin-induced mouse urethral contraction. Our results support the hypothesis that the urethra actively surveils its environment and responds to an ascending pathogen by evoking UNECs and ICC to induce urethral contraction and pathogen expulsion.