Oregon Health & Science University

The ability to conceptualize numerical quantities is an essential human trait. According to the “Triple Code Model” in numerical cognition, distinct neural substrates encode the processing of visual, auditory, and non-symbolic numerical representations. While our contemporary understanding of human number cognition has benefited greatly from advances in clinical imaging, limited studies have investigated the intracranial electrophysiological correlates of number processing. In this study, 13 subjects undergoing stereotactic electroencephalography for epilepsy participated in a number recognition task. Drawing upon postulates of the Triple Code Model, we presented subjects with numerical stimuli varying in representation type (symbolic vs. non-symbolic) and mode of stimuli delivery (visual vs. auditory). Time-frequency spectrograms were dimensionally reduced with principal component analysis and passed into a linear support vector machine classification algorithm to identify regions associated with number perception compared to inter-trial periods. Across representation formats, the highest classification accuracy was observed in the bilateral parietal lobes. Auditory (spoken and beeps) and visual (Arabic) number formats preferentially engaged the superior temporal cortices and the frontoparietal regions, respectively. The left parietal cortex was found to have the highest classification for number dots. Notably, the putamen exhibited robust classification accuracies in response to numerical stimuli. Analyses of spectral feature maps revealed that non-gamma frequency, below 30 Hz, had greater-than-chance classification value and could be potentially used to characterize format specific number representations. Taken together, our findings obtained from intracranial recordings provide further support and expand on the Triple Code Model for numerical cognition.

Many patients with hepatocellular carcinoma (HCC) experience recurrence after curative-intent resection or ablation, with a poor prognosis. Real-world patterns of recurrence and the prognostic significance of early recurrence in U.S. clinical practice have not been well characterized. This retrospective observational study was designed to evaluate the impact of recurrence on overall survival (OS) among patients with HCC following initial curative-intent resection or ablation. We used the Surveillance, Epidemiology, and End Results cancer registry linked with Medicare claims (January 1, 2010–December 31, 2019). Eligible patients (≥66 years) diagnosed with HCC (2010–2017) had liver resection or ablation within 180 days of diagnosis. Patients were stratified by recurrence status using diagnosis- and treatment-based definitions of recurrence. Early or late recurrence was defined as within 1 year or after 1 year, respectively. Adjusted OS analyses used multivariable Cox regression models. A total of 1,146 patients were included. During a median overall follow-up of 35.2 months, 736 (64%) patients had a recurrence, of whom 380 (52%) had early recurrence (within 1 year). In the adjusted analysis, patients with recurrence had a 2.24-fold higher risk of death (95% confidence interval 1.85, 2.71; P < 0.001). Patients with early recurrence had a 1.39-fold higher risk of death (95% confidence interval 1.14, 1.68; P < 0.001) than those with late recurrence. Recurrence and the timing of recurrence are significant predictors of increased mortality risk for patients with HCC following initial curative-intent resection or ablation, highlighting the need for effective adjuvant therapies that may delay or avoid recurrences.

Background Hospitalizations involving opioid use disorder (OUD) are increasing. Addiction consultation services (ACS) initiate medications for opioid use disorder (MOUD) in hospital settings and arrange post-hospital follow-up for ongoing MOUD care. Engagement in MOUD following hospital discharge is hampered by challenges in timely access to MOUD. This protocol describes an open-label randomized comparative effectiveness trial comparing ACS treatment as usual (TAU) to a single injection of a 28-day formulation extended-release buprenorphine (XR-BUP) on MOUD engagement 34-days following hospital discharge. Methods Six U.S. hospitals with ACS capable of prescribing all MOUD (i.e., methadone, buprenorphine, and extended-release naltrexone) recruit and randomize hospitalized patients with OUD who have not been on MOUD in the fourteen days prior to hospitalization. TAU may consist of any MOUD other than XR-BUP. Participants randomized to XR-BUP may receive any MOUD throughout their hospital stay and receive a 28-day XR-BUP injection within 72-hours of anticipated hospital discharge. There is no intervention beyond hospital stay. Participants are followed 34-, 90-, and 180-days following hospital discharge. The primary outcome is engagement in any MOUD 34-days following hospital discharge, which we hypothesize will be greater in the XR-BUP group. Randomizing 342 participants (171 per arm) provides 90% power to detect difference in the primary outcome between groups with an odds ratio of 2.1. Safety, secondary, and exploratory outcomes include: adverse events, MOUD engagement on days 90 and 180, opioid positive urine drug tests, self-reported drug use, hospital readmissions and emergency department visits, use of non-opioid drugs, fatal and non-fatal opioid overdose, all-cause mortality, quality of life, and cost-effectiveness. Data are analyzed by intention-to-treat, with pre-planned per-protocol and other secondary analyses that examine gender as an effect modifier, differences between groups, and impact of missingness. Discussion Engagement in MOUD care following hospitalization in individuals with OUD is low. This randomized comparative effectiveness trial can inform hospital ACS in medication selection to improve MOUD engagement 34-days following hospital discharge. Trial registration NCT04345718.

Understanding the detailed mechanisms driving fibroblast migration within native tissue settings during pathophysiological events presents a critical research challenge. In this study, we elucidate how stromal cells migrate and contribute to the development of three-dimensional (3D) cellular aggregates within confined microcavities. Integrin α5β1 and β-catenin (β-cat) are central in guiding this collective migration and achieving optimal filling of the microcavity. When β-cat is suppressed, cells tend to migrate more sporadically, leading to less efficient cellular organization. Furthermore, we also detail the pivotal roles of Cx43 and N-cadherin (N-cad) in orchestrating collective migration and in shaping efficient cellular stacking. Suppressing gap junctions, especially Cx43, significantly impacts the extracellular matrix expression, integrin α5 and β1, and other elements in the 3D construct, emphasizing the importance of physicochemical cell–cell interactions. The distribution patterns of N-cad and focal adhesion kinase (FAK) further corroborate the essential roles in forming cell–cell junctions and FAK in establishing the foundational layer that underpins the cell stacking within the microcavity. Interestingly, neither Rho-associated protein kinase (ROCK) nor RhoA significantly alter the cell migration pattern toward microcavity. These findings provide fresh perspectives on fibroblast activities in 3D space, enriching our understanding and offering implications for advancements in wound healing and tissue engineering.

Imaging is critical to HCC management, including surveillance, diagnosis, staging, and treatment response assessment, which requires it be performed consistently at a high level. The Liver Imaging Reporting and Data System (LI-RADS) was developed to standardize the acquisition, interpretation, and reporting of liver imaging, but until now, has not addressed the essential component of exam quality and adequacy. In this manuscript, we discuss the concepts of quality and adequacy and their clinical significance in the setting of HCC diagnostic imaging and treatment response assessment. We describe prior and current efforts to improve image quality and adequacy. We review common sources of image degradation that need to be addressed and the rationale behind LI-RADS technical recommendations. Finally, we offer a glimpse into preliminary efforts to develop an adequacy scoring system and make a call to action for all stakeholders to contribute to this important goal.

Background Hepatic steatosis (HS) and 10‐year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 7.5% are associated with increased risk for cardiovascular events. Aim To assess underlying coronary artery disease (CAD) and major adverse cardiovascular event (MACE) among those with and without HS at different ASCVD risk. Methods We evaluated stable chest pain patients receiving coronary computed tomography (CT) in the PROMISE trial. HS and CAD endpoints were defined on coronary CT. MACE was defined as unstable angina, non‐fatal myocardial infarction, and all‐cause death. Multivariable Cox regression, adjusting for CAD characteristics, assessed the association of HS with MACE for ASCVD < 7.5%. Results One thousand two hundred and four of 3702 (32.5%) patients were at ASCVD < 7.5% and 20.3% (244/1204) of them had HS. Individuals with HS were younger (54.3 ± 5.2 vs. 55.8 ± 5.2; p < 0.001), more often males (40.2% [98/244] vs. 27.1% [260/960]; p < 0.001), had more risk factors/person (2.06 ± 0.89 vs. 1.93 ± 0.91; p = 0.047). CAD characteristics were similar between HS vs. non‐HS patients at ASCVD < 7.5% and ASCVD ≥ 7.5% (all p > 0.05). Patients with HS had greater MACE rate compared to non‐HS patients (ASCVD < 7.5%: 3.75%[9/244] vs. 1.5% [14/960]; p = 0.027 and ASCVD ≥ 7.5%: 4.7% [33/696] vs. 3.1% [56/1802]; p = 0.043). In patients without HS, MACE rate was higher in the ASCVD ≥ 7.5% vs. < 7.5% (3.1% [56/1802] vs. 1.5% [14/960]; p = 0.011). In patients with HS, MACE rates were not significantly different between ASCVD ≥ 7.5% vs. < 7.5% (4.7% [33/696] vs. 3.7% [9/244]; p = 0.484). In ASCVD < 7.5%, HS predicted MACE (aHR:2.34, 95%CI:1.01–5.43; p = 0.048), independent of CAD characteristics. Conclusions Individuals with HS at ASCVD < 7.5% risk had similar CAD characteristics as patients without HS at < 7.5% ASCVD risk, yet experienced comparable MACE rates as those at ASCVD ≥ 7.5%.

Background Despite the favorable prognosis of AJCC stage I/II melanoma patients, up to 20%–30% will develop metastases. Our objective is to predict long‐term risk (probability) of recurrence in early‐stage melanoma patients. Methods A Risk Score to predict long‐term recurrence was developed using Cox regression based on 2668 patients. Five clinicopathological risk factors were included. The association of the Risk Score with the risk of recurrence was evaluated using parametric models (exponential, Weibull, and Gompertz models) and compared to the Cox model using the Akaike information criterion. The discrimination of the model was measured by time‐dependent ROC analyses. A calibration curve was used to evaluate the agreement between predicted and observed recurrence probabilities. Results The bootstrap adjusted C‐index was 0.76 (95% CI, 0.74–0.79) overall and 0.87 (0.83–0.90) and 0.82 (0.78–0.85) at one and two years, respectively, and then remained above 0.70 up to 20 years. The Gompertz model for prediction of survival from the Risk Score showed the best performance and displayed good agreement with the Kaplan–Meier curves. The calibration curve of the Gompertz model showed a good agreement between predicted and observed 2‐, 5‐, and 10‐year risk of recurrence. Population‐level analysis demonstrated a significant association of Risk Score with risk of recurrence, with 10‐year risks of recurrence of 4.5%, 13.0%, and 33.7% in the first, second, and third tertiles, respectively. Conclusion We developed a Risk Score to predict long‐term risk of recurrence for early‐stage melanoma patients. A Gompertz survival model fit to the Risk Score allows for individualized prediction of time‐dependent recurrence risk.

While a live-attenuated Yellow fever (YF) vaccine is known to elicit durable immunity, antibody titers may wane after vaccination. This study evaluated the long-term immunity after vaccination against YF among individuals who reside in Korea and received vaccination with YF virus-17D prior to international travel. Serum was collected between December 2018 and December 2019 at the National Medical Center, Republic of Korea from YF vaccine recipients who were vaccinated more than five years prior to sample collection. Long-term immunity against YF was assessed using three serological assays: IgG enzyme‐linked immunosorbent assay (ELISA), immunofluorescence assay (IFA), and focus reduction neutralization test (FRNT). Sixty seven subjects were enrolled. The overall positivity rates for FRNT50, IFA and ELISA were 97.0%, 86.6% and 26.9%, respectively, in a time-variable, cross-sectional sample of the cohort. While 93.8% (15/16) of samples collected ≥10 years post-vaccination remained positive by FRNT50, a significant inverse correlation was observed between FRNT50 titer and interval after vaccination (r=-0.385, p=0.001). Humoral immunity against YF was well preserved among the Korean individuals who were more than five years post-vaccination. IFA testing yielded results similar to FRNT50 testing, which may justify further development of the IFA to screen for waning immunity among those with previous YF vaccination.

Background People who use drugs (PWUD) in rural communities increasingly use stimulants, such as methamphetamine and cocaine, with opioids. We examined differences in hepatitis C virus (HCV) testing and treatment history among rural PWUD with opioids, stimulants, and other substance use combinations. Methods PWUD were enrolled from ten rural U.S. communities from 2018 to 2020. Participants self-reporting a positive HCV result were asked about their HCV treatment history and drug use history. Drug use was categorized as opioids alone, stimulants alone, both, or other drug(s) within the past 30 days. Prevalence ratios (PR) were yielded using adjusted multivariable log-binomial regression with generalized linear mixed models. Results Of the 2,705 PWUD, most reported both opioid and stimulant use (74%); while stimulant-only (12%), opioid-only (11%), and other drug use (2%) were less common. Most (76%) reported receiving HCV testing. Compared to other drug use, those who reported opioid use alone had a lower prevalence of HCV testing (aPR = 0.80; 95% CI: 0.63, 1.02). Among participants (n = 944) who self-reported an HCV diagnosis in their lifetime, 111 (12%) ever took anti-HCV medication; those who used both opioids and stimulants were less likely to have taken anti-HCV medication compared with other drug(s) (aPR = 0.41; 95% CI: 0.19, 0.91). Conclusions In this pre-COVID study of U.S. rural PWUD, those who reported opioid use alone had a lower prevalence of reported HCV testing. Those diagnosed with HCV and reported both opioid and stimulant use were less likely to report ever taking anti-HCV medication.

Aquaporin-1 (AQP1) is a highly conserved water-channel protein, found to be expressed by astrocytes in adult humans and non-human primates (NHPs). Upregulation of cortical AQP1 expression occurs with cancer, injury, and neurodegenerative disease, but minimal information is available about the effects of normative aging on AQP1 expression. This study leverages tissues from the oldest-old rhesus macaques, some greater than 40 years of age, from the National Institute on Aging longitudinal study of caloric restriction (CR). We tested whether AQP1 levels are altered in the NHP brain as a function of diet group, sex, and age. Sections of formaldehyde-fixed prefrontal (PFC) and temporal (TC) cortices from 36 rhesus macaques (both sexes, 22 to 44 years, + / − CR) were immunochemically stained for AQP1, then the percent area of AQP1 staining was regionally measured using ImageJ free-ware. Results showed age-related regional increases of AQP1 expression, with no effect of diet group or sex. Specifically, in the PFC, AQP1 positively-stained area increased with age in multiple subregions. For the TC subregions, AQP1 area coverage was not affected by age, despite having average levels that were greater than in the PFC. The peak expression of AQP1 in astrocytes appeared in clusters across cortical layers in a subgroup of animals 30 + years old. Astrocytic AQP1 dysregulation may contribute to progressive risk of neuropathology with aging.

Purpose Colorectal cancer (CRC) significantly impacts patients’ physical well-being, often leading to distress and diminished quality of life (QOL). Body compassion (i.e., viewing one’s body with kindness, mindfulness, and common humanity) could be relevant to psychosocial adjustment to cancer but has yet to be explored within the cancer context. This study aimed to introduce a novel measure of body compassion and examine its associations with demographic, medical, and psychosocial variables among CRC patients. Methods Fifty-four patients with CRC completed a one-time survey assessing demographics, body compassion [Body Compassion Scale (BCS)], distress (HADS), loneliness (ULS-8), resilience (CD-RISC-10), and QOL (FACT-C). Descriptive and internal consistency reliability statistics characterized the BCS. Relationships with demographic, medical, and psychosocial variables were examined using correlations, t-tests, and hierarchical linear regressions. Results The BCS showed excellent internal consistency reliability (α = .94) (M = 82.1, SD = 19.0). Patients with metastatic CRC (vs. non-metastatic; BCS total MDiff = 12.2, CI95% [0.4, 24.0]; defusion MDiff = 5.0, CI95% [-0.4, 10.3]; common humanity MDiff = 5.7, CI95% [-0.5, 12.0]) and those in treatment (vs. not; BCS total MDiff = 14.1, CI95% [0.5, 27.6]; defusion MDiff = 6.2, CI95% [0.1, 12.3]) reported lower body compassion. Higher total body compassion was associated with lower distress (B = -0.235, CI95% [-0.32, -0.15]) and loneliness (B = -0.104, CI95% [-0.18, -0.03]), and higher resilience (B = 0.215, CI95% [0.12, 0.31]) and quality of life (B = 0.811, CI95% [0.50, 1.12]). Among the BCS subscales, defusion demonstrated the most robust associations with medical (time since diagnosis, current ostomy, current treatment, metastatic disease) and psychosocial variables [distress (β = -.334), loneliness (β = -.444), resilience (β = .585)]; acceptance showed strong associations with distress (β = -.310) and quality of life (β = .384). Conclusions Body compassion appears relevant to psychosocial adjustment to CRC treatment and survivorship and may be particularly germane for patients with high disease burden. Further research on body compassion in cancer is warranted, such as longitudinal and multi-method designs across cancer populations.

B-crystallin is an archetypical member of the small heat shock proteins (sHSPs) vital for cellular proteostasis and mitigating protein misfolding diseases. Gaining insights into the principles defining their molecular organization and chaperone function have been hindered by intrinsic dynamic properties and limited high-resolution structural analysis. To disentangle the mechanistic underpinnings of these dynamical properties, we ablate a conserved IXI-motif located within the N-terminal (NT) domain of human αB-crystallin implicated in subunit exchange dynamics and client sequestration. This results in a profound structural transformation, from highly polydispersed caged-like native assemblies into an elongated fibril state amenable to high-resolution cryo-EM analysis. The reversible nature of this variant facilitates interrogation of functional effects due to perturbation of the NT-IXI motif in both the native-like oligomer and fibril states. Together, our investigations unveil several features thought to be key mechanistic attributes to sHSPs and point to a critical significance of the NT-IXI motif in αB-crystallin assembly, polydispersity, and chaperone activity.

Background clinical guidelines recommend initiation of antiviral therapy as soon as possible for patients hospitalized with confirmed or suspected influenza. Methods A multicenter US observational sentinel surveillance network prospectively enrolled adults (aged ≥18 years) hospitalized with laboratory-confirmed influenza at 24 hospitals during October 1, 2022–July 21, 2023. A multivariable proportional odds model was used to compare peak pulmonary disease severity (no oxygen support, standard supplemental oxygen, high-flow oxygen/non-invasive ventilation, invasive mechanical ventilation, or death) after the day of hospital admission among patients starting oseltamivir treatment on the day of admission (early) versus those who did not (late or not treated), adjusting for baseline (admission day) severity, age, sex, site, and vaccination status. Multivariable logistic regression models were used to evaluate the odds of intensive care unit (ICU) admission, acute kidney replacement therapy or vasopressor use, and in-hospital death. Results A total of 840 influenza-positive patients were analyzed, including 415 (49%) who started oseltamivir treatment on the day of admission, and 425 (51%) who did not. Compared with late or not treated patients, those treated early had lower peak pulmonary disease severity (proportional aOR: 0.60, 95% CI: 0.49–0.72), and lower odds of intensive care unit admission (aOR: 0.24, 95% CI: 0.13–0.47), acute kidney replacement therapy or vasopressor use (aOR: 0.40, 95% CI: 0.22–0.67), and in-hospital death (aOR: 0.36, 95% CI: 0.18–0.72). Conclusion Among adults hospitalized with influenza, treatment with oseltamivir on day of hospital admission was associated reduced risk of disease progression, including pulmonary and extrapulmonary organ failure and death.