Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world.

SUMMARY: Background: Neuropathic pain after spinal cord injury (SCI) is notoriously hard to treat. Mechanisms of neuropathic pain are unclear, which makes finding effective treatments challenging. Prior studies have shown that adults with SCI have body awareness deficits. Recent imaging studies, including ours, point to the parietal operculum and insula as key areas for both pain perception and body awareness. Cognitive multisensory rehabilitation (CMR) is a physical therapy approach that helps improve body awareness for pain reduction and sensorimotor recovery. Based on our prior brain imaging work in CMR in stroke, we hypothesized that improving body awareness through restoring parietal operculum network connectivity leads to neuropathic pain relief and improved sensorimotor and daily life function in adults with SCI. Thus, the objectives of this study were to (1) determine baseline differences in resting-state and task-based functional magnetic resonance imaging (fMRI) brain function in adults with SCI compared to healthy controls and (2) identify changes in brain function and behavioral pain and pain-associated outcomes in adults with SCI after CMR. Methods: Healthy adults underwent a one-time MRI scan and completed questionnaires. We recruited community-dwelling adults with SCI-related neuropathic pain, with complete or incomplete SCI >3 months, and highest neuropathic pain intensity level of >3 on the Numeric Pain Rating Scale (NPRS). Participants with SCI were randomized into two groups, according to a delayed treatment arm phase I randomized controlled trial (RCT): Group A immediately received CMR intervention, 3x/week, 45 min/session, followed by a 6-week and 1-year follow-up. Group B started with a 6-week observation period, then 6 weeks of CMR, and a 1-year follow-up. Highest, average, and lowest neuropathic pain intensity levels were assessed weekly with the NPRS as primary outcome. Other primary outcomes (fMRI resting-state and functional tasks; sensory and motor function with the INSCI AIS exam), as well as secondary outcomes (mood, function, spasms, and other SCI secondary conditions), were assessed at baseline, after the first and second 6-week period. The INSCI AIS exam and questionnaires were repeated at the 1-year follow-up. Findings: Thirty-six healthy adults and 28 adults with SCI were recruited between September 2020 and August 2021, and of those, 31 healthy adults and 26 adults with SCI were enrolled in the study. All 26 participants with SCI completed the intervention and pre-post assessments. There were no study-related adverse events. Participants were 52±15 years of age, and 1-56 years post-SCI. During the observation period, group B did not show any reductions in neuropathic pain and did not have any changes in sensation or motor function (INSCI ASIA exam). However, both groups experienced a significant reduction in neuropathic pain after the 6-week CMR intervention. Their highest level of neuropathic pain of 7.81±1.33 on the NPRS at baseline was reduced to 2.88±2.92 after 6 weeks of CMR. Their change scores were 4.92±2.92 (large effect size Cohen’s d =1.68) for highest neuropathic pain, 4.12±2.23 ( d =1.85) for average neuropathic pain, and 2.31±2.07 ( d =1.00) for lowest neuropathic pain. Nine participants out of 26 were pain-free after the intervention (34.62%). The results of the INSCI AIS testing also showed significant improvements in sensation, muscle strength, and function after 6 weeks of CMR. Their INSCI AIS exam increased by 8.81±5.37 points ( d =1.64) for touch sensation, 7.50±4.89 points ( d =1.53) for pin prick sensation, and 3.87±2.81 ( d =1.38) for lower limb muscle strength. Functional improvements after the intervention included improvements in balance for 17 out of 18 participants with balance problems at baseline; improved transfers for all of them and a returned ability to stand upright with minimal assistance in 12 out of 20 participants who were unable to stand at baseline. Those improvements were maintained at the 1-year follow-up. With regard to brain imaging, we confirmed that the resting-state parietal operculum and insula networks had weaker connections in adults with SCI-related neuropathic pain (n=20) compared to healthy adults (n=28). After CMR, stronger resting-state parietal operculum network connectivity was found in adults with SCI. Also, at baseline, as expected, right toe sensory stimulation elicited less brain activation in adults with SCI (n=22) compared to healthy adults (n=26). However, after CMR, there was increased brain activation in relevant sensorimotor and parietal areas related to pain and mental body representations (i.e., body awareness and visuospatial body maps) during the toe stimulation fMRI task. These brain function improvements aligned with the AIS results of improved touch sensation, including in the feet. Interpretation: Adults with chronic SCI had significant neuropathic pain relief and functional improvements, attributed to the recovery of sensation and movement after CMR. The results indicate the preliminary efficacy of CMR for restoring function in adults with chronic SCI. CMR is easily implementable in current physical therapy practice. These encouraging impressive results pave the way for larger randomized clinical trials aimed at testing the efficacy of CMR to alleviate neuropathic pain in adults with SCI. Clinical Trial registration: ClinicalTrials.gov Identifier: NCT04706208 Funding: AIRP2-IND-30: Academic Investment Research Program (AIRP) University of Minnesota School of Medicine. National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR002494; the Biotechnology Research Center: P41EB015894, the National Institute of Neurological Disorders & Stroke Institutional Center Core Grants to Support Neuroscience Research: P30 NS076408; and theHigh-Performancee Connectome Upgrade for Human 3T MR Scanner: 1S10OD017974.

Osteosarcoma is considered to be the most common primary malignant bone cancer among children and young adults. Previous studies suggest growth spurts and height to be risk factors for osteosarcoma. However, studies on the genetic cause are still limited given the rare occurrence of the disease. In this study, we investigated in a family trio data set that is composed of 209 patients and their unaffected parents and conducted a genome-wide association study (GWAS) to identify genetic risk factors for osteosarcoma. We performed a Bayesian gene-based GWAS based on the single-nucleotide polymorphism (SNP)-level summary statistics obtained from a likelihood ratio test of the trio data, which uses a hierarchically structured prior that incorporates the SNP-gene hierarchical structure. The Bayesian approach has higher power than SNP-level GWAS analysis due to the reduced number of tests and is robust by accounting for the correlations between SNPs so that it borrows information across SNPs within a gene. We identified 217 genes that achieved genome-wide significance. Ingenuity pathway analysis of the gene set indicated that osteosarcoma is potentially related to TP53, estrogen receptor signaling, xenobiotic metabolism signaling, and RANK signaling in osteoclasts.

Background: Alzheimer’s disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia. Methods: The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to three interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise, cognitive training, and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2 × 2 factorial phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n = 128). In this ACT Trial blood biomarkers study, we will enroll 120 ACT Trial participants with aMCI and measure blood biomarkers at baseline and at 3, 6, 12, and 18 months. The goals are to (1) determine the effect of interventions on blood biomarkers over 6 months, (2) evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months, and (3, exploratory) examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months. Discussion: This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among patients with aMCI subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia. Trial registration: ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.

Background: About 69% of Americans living with spinal cord injury (SCI) suffer from long-term debilitating neuropathic pain, interfering with the quality of daily life. Neuropathic pain is refractory to many available treatments—some carrying a risk for opioid addiction—highlighting an urgent need for new treatments. In this study, we will test our hypothesis that Spring Forest Qigong™ will reduce SCI-related neuropathic pain by improving body awareness. We will determine whether remotely delivered Qigong is feasible and we will collect data on neuropathic pain, and other reported associations with pain such as spasms frequency and/or severity, functional performance, mood, and body awareness. Methods: In this quasi-experimental pilot clinical trial study, adults with SCI will practice Qigong at home with a 45-min video, at least 3 × /week for 12 weeks. The Qigong practice includes movements with guided breathing and is individualized based on functional abilities, i.e., the participants follow along with the Qigong movements to the level of their ability, with guided breathing, and perform kinesthetic imagery by focusing on the feeling in the whole body as if doing the whole-body Qigong movement while standing. The highest, average, and lowest neuropathic pain ratings perceived in the prior week will be recorded weekly until the 6-week follow-up. The other outcomes will be collected at 5 time points: at baseline, midway during the Qigong intervention (6 weeks), after the Qigong intervention (12 weeks), after a 6-week and 1-year follow-up. Rate parameters for the feasibility markers will be estimated based on the participants who achieved each benchmark. Discussion: The University of Minnesota (UMN)’s Institutional Review Board (IRB) approved the study (IRB #STUDY00011997). All participants will sign electronic informed consent on the secure UMN REDCap platform. The results will be presented at academic conferences and published in peer-reviewed publications. Trial registration: ClinicalTrial.gov registration number: NCT04917107, (this protocol paper refers to the substudy), first registered 6/8/2021.

Although total plasma lipoproteome consists of proteins that have shown promises as biomarkers that can identify Alzheimer’s disease (AD), effect sizes are modest. The objective of this study is to provide initial proof-of-concept that the plasma lipoproteome more likely differ between AD cases and controls when measured in individual plasma lipoprotein fractions than when measured as total in immunodepleted plasma. We first developed a targeted proteomics method based on selected reaction monitoring (SRM) and liquid chromatography and tandem mass spectrometry for measurement of 120 tryptic peptides from 79 proteins that are commonly present in plasma lipoproteins. Then in a proof-of concept case–control study of 5 AD cases and 5 sex- and age-matched controls, we applied the targeted proteomic method and performed relatively quantification of 120 tryptic peptides in plasma lipoprotein fractions (fractionated by sequential gradient ultracentrifugation) and in immunodepleted plasma (of albumin and IgG). Unadjusted p values from two-sample t-tests and overall fold change was used to evaluate a peptide relative difference between AD cases and controls, with lower p values (< 0.05) or greater fold differences (> 1.05 or < 0.95) suggestive of greater peptide/protein differences. Within-day and between-days technical precisions (mean %CV [SD] of all SRM transitions) of the targeted proteomic method were 3.95% (2.65) and 9.31% (5.59), respectively. Between-days technical precisions (mean % CV [SD]) of the entire plasma lipoproteomic workflow including plasma lipoprotein fractionation was 27.90% (14.61). Ten tryptic peptides that belonged to 5 proteins in plasma lipoproteins had unadjusted p values < 0.05, compared to no peptides in immunodepleted plasma. Furthermore, 27, 32, 17, and 20 tryptic peptides in VLDL, IDL, LDL and HDL, demonstrated overall peptide fold differences > 1.05 or < 0.95, compared to only 6 tryptic peptides in immunodepleted plasma. The overall comparisons, therefore, suggested greater peptide/protein differences in plasma lipoproteome when measured in individual plasma lipoproteins than as total in immunodepleted plasma. Specifically, protein complement C3’s peptide IHWESASLLR, had unadjusted p values of 0.00007, 0.00012, and 0.0006 and overall 1.25, 1.17, 1.14-fold changes in VLDL, IDL, and LDL, respectively. After positive False Discovery Rate (pFDR) adjustment, the complement C3 peptide IHWESASLLR in VLDL remained statistically different (adjusted p value < 0.05). The findings may warrant future studies to investigate plasma lipoproteome when measured in individual plasma lipoprotein fractions for AD diagnosis.