Citations

Diffusion MRI (dMRI) enables assessment of white matter microstructural abnormalities in Alzheimer's disease (AD), and multisite datasets enable more robust modeling of non-biological variation that can confound analyses. The Alzheimer's Disease Neuroimaging Initiative (ADNI) includes over 10 dMRI protocols, necessitating robust methods to model protocol-related variability when pooling data. Here, we compared three harmonization approaches: (1) mixed-effects models, (2) ComBat-GAM, and (3) eHarmonize, a reference-based lifespan method. We assessed their ability to reduce protocol-related variability in diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD) while preserving associations with cognitive impairment (CI), and amyloid-beta (Aβ) and tau PET burden in 1,086 ADNI3/4 participants. All approaches yielded more closely aligned FA/MD distributions across protocols. Associations with clinical indicators of CI were highly consistent across approaches, whereas PET associations were less widespread and more variable. Overall, multiple strategies effectively modeled protocol-related variability while preserving AD-related associations.

Abstract INTRODUCTION We integrate visual and quantitative metrics in white matter and medial temporal lobe to examine relationships with neuropathology in a community cohort. METHODS Postmortem in situ MRI (T1, T2, DWI) was performed in 25 human brains, followed by visual ratings (Fazekas, MTA, ERICA, Koedam). Neuropathology included ADNC, LATE-NC, hippocampal sclerosis, PART, ARTAG, Lewy pathology, and CAA. RESULTS Increased Fazekas score was linked to aging, lower education, hypertension, higher basilar artery wall thickness, and greater Braak NFT stage. WMH volume also correlated with lacunes, Thal phase, and CERAD score that was not observed using Fazekas. Hippocampal volumes were lower in elderly, less educated people and were associated with higher atrophy scores and higher Braak NFT stage. Higher amygdala volume was only associated with higher CERAD score. DISCUSSION Quantitative MRI may detect neuropathologic associations more sensitively than visual ratings. Tau pathology is a key predictor of WMH burden and hippocampal atrophy.

Background: In the United States, rural residents face unique challenges that affect their overall cardiovascular health and mortality including access to care for acute cardiovascular conditions. We assessed differences in mortality and mode of care among adult patients diagnosed with acute myocardial infarction (AMI) based on geographical residence. Methods: Using data from the Medicare Provider Analysis and Review files, we identified adult patients aged 45 and older who were diagnosed with AMI between 2015 and 2019. Cox-proportional hazards regression models were constructed to determine the association between patient’s geographic residence (rural vs. urban) on 30- and 90-day all-cause mortality. Results: A total of 868,955 adult patients diagnosed with AMI were included in this study. Twenty-six percent of the sample resided in rural areas. Among rural residents with AMI, 46% were managed invasively with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery which was similar to 45% of urban residents. After controlling for age, race, sex, and comorbid conditions, rural residents had a higher risk of death compared to urban patients (aHR 1.04, p<0.001) at 30 and 90 days. In subgroup analyses, a similar pattern was observed among those who did not undergo invasive procedures (aHR 1.06, p<0.001), however, there was no differences in mortality at 30 days (aHR 0.99, p=0.30) and 90 days (aHR: 0.99, p=0.36) between rural and urban residents who were managed by PCI or CABG. Conclusion: Rural patients with AMI had a higher mortality risk than their urban counterparts, and this difference was driven by a higher death rate among those managed conservatively. Further investigation is needed to understand the underlying factors driving rural-urban disparities in mortality, particularly with non-invasive management of AMI.

Background: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. Methods: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. Results: Group A (“Advanced”) included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group A T ). Group M (“Mild”) included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6–13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group A T patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. Conclusions: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic Kras mutations are transdifferentiated to a duct-like phenotype that further progresses to become pancreatic intraepithelial neoplasia (PanIN) lesions, giving rise to PDAC. Although ADM formation is frequently observed in KrasG12D transgenic mouse models of PDAC, the exact mechanisms of how oncogenic KrasG12D regulates this process remain an enigma. Herein, we revealed a new downstream target of oncogenic Kras, cytokine CCL9, during ADM formation. Higher levels of CCL9 and its receptors, CCR1 and CCR3, were detected in ADM regions of the pancreas in p48cre:KrasG12D mice and human PDAC patients. Knockdown of CCL9 in KrasG12D-expressed pancreatic acini reduced KrasG12D-induced ADM in a 3D organoid culture system. Moreover, exogenously added recombinant CCL9 and overexpression of CCL9 in primary pancreatic acini induced pancreatic ADM. We also showed that, functioning as a downstream target of KrasG12D, CCL9 promoted pancreatic ADM through upregulation of the intracellular levels of reactive oxygen species (ROS) and metalloproteinases (MMPs), including MMP14, MMP3 and MMP2. Blockade of MMPs via its generic inhibitor GM6001 or knockdown of specific MMP such as MMP14 and MMP3 decreased CCL9-induced pancreatic ADM. In p48cre:KrasG12D transgenic mice, blockade of CCL9 through its specific neutralizing antibody attenuated pancreatic ADM structures and PanIN lesion formation. Furthermore, it also diminished infiltrating macrophages and expression of MMP14, MMP3 and MMP2 in the ADM areas. Altogether, our results provide novel mechanistic insight into how oncogenic Kras enhances pancreatic ADM through its new downstream target molecule, CCL9, to initiate PDAC.

Objective: To investigate patterns and trends of co-prescriptions of stimulants and sedatives within the last 6 years at a tertiary care center. Method: Patients 18 years of age and older who were dispensed at least one stimulant prescription from an institutional pharmacy between 1/1/2015 and 7/1/2021 were included. Prescription data for any co-prescribed sedative/hypnotic were collected. Results: Both the number of stimulant dispenses and the number of patients with stimulant dispenses increased significantly with yearly incidence rate ratios of 1.115 (95% CI [1.110, 1.119]) and 1.090 (95% CI [1.084, 1.096]), respectively. The number of patients with a stimulant dispensed who also had a benzodiazepine or “Z-drug” sedative-hypnotic dispensed at any point in the search timeframe increased significantly with incidence rate ratios of 1.077 and 1.092, respectively. The number of stimulant dispenses, number of patients with stimulant dispenses, and number of patients with a stimulant dispensed who also had both a benzodiazepine and Z-drug dispensed at any point in the search timeframe increased significantly more in Non-White than in White patients. Conclusions: The results confirm previous findings of increases in dispensing of stimulants over the past 6 years and report increased polypharmacy of stimulants and sedative-hypnotics.

Abstract Objective To describe the technique, safety profile, and outcome of computed tomography (CT)–guided atlanto-axial lateral articulation injections performed at our institution. Methods Consecutive cases of all CT-guided atlanto-axial injections performed from January 2017 to April 2022 at our institution were searched in the electronic medical records. Patient charts were reviewed for demographics, characterization of pain, potential altered anatomy, pain level before and immediately after the procedure, procedure technique, complications, and follow-up outcomes, if available. Results Forty-five injections in 40 different patients were included. The average age was 67.4 years, and 28 (70%) of the patients were female. Of the 45 injections, 43 (96%) were technically successful. The average change in pain score (0–10) from immediately before to immediately after the injection was –3.36 (SD = 2.87, range = –8 to +3). Of all injections, 14 (31%) had a postprocedural pain score of zero. In 2 cases (4%), patients reported an increase in pain score immediately after the injection. In 3 cases (7%), transient non–vertebral artery vascular uptake of contrast was documented during the procedure, which could be cleared with needle repositioning. There were no complications. Conclusion CT-guided atlanto-axial lateral articulation injection is a safe procedure with a high technical success rate. It allows for direct visualization of vital structures and provides an alternative option to the traditional fluoroscopic guidance, especially in cases of prior technically unsuccessful fluoroscopically guided injection or altered anatomy.

Abstract Multiple myeloma is a plasma cell malignancy that is still largely incurable, despite considerable progress in recent years. NF-κB is a well-established therapeutic target in multiple myeloma, but none of the currently available treatment options offer direct, specific pharmacologic targeting of NF-κB transcriptional activity. Thus, we designed a novel direct NF-κB inhibitor (IT848) as a drug candidate with strong potential for clinical translation and conducted comprehensive in vitro and in vivo mechanistic studies in multiple myeloma cell lines, primary multiple myeloma cells, xenograft models, and immunocompetent mouse models of multiple myeloma. Here, we show that IT848 inhibits NF-κB activity through inhibition of DNA binding of all five NF-κB subunits. IT848 treatment of multiple myeloma cell lines and patient samples inhibited proliferation and induced caspase-dependent and independent apoptosis. In addition to direct NF-κB inhibitory effects, IT848 treatment altered the redox homeostasis of multiple myeloma cells through depletion of the reduced glutathione pool, selectively inducing oxidative stress in multiple myeloma but not in healthy cells. Multiple myeloma xenograft studies confirmed the efficacy of IT848 as single agent and in combination with bortezomib. Furthermore, IT848 significantly improved survival when combined with programmed death protein 1 inhibition, and correlative immune studies revealed that this clinical benefit was associated with suppression of regulatory T-cell infiltration of the bone marrow microenvironment. In conclusion, IT848 is a potent direct NF-κB inhibitor and inducer of oxidative stress specifically in tumor cells, displaying significant activity against multiple myeloma cells in vitro and in vivo, both as monotherapy as well as in combination with bortezomib or immune checkpoint blockade.