Showing papers by "Veterans Health Administration published in 2022"

Drug-Induced Acute Kidney Injury

Abstract: Medications are a common cause of AKI, especially for patients admitted to hospital wards and the intensive care unit. Although drug-related kidney injury occurs through different mechanisms, this review will focus on three specific types of tubulointerstitial injury. Direct acute tubular injury develops from several medications, which are toxic to various cellular functions. Their excretory pathways through the proximal tubules contribute further to AKI. Drug-induced AKI may also develop through induction of inflammation within the tubulointerstitium. Medications can elicit a T cell-mediated immune response that promotes the development of acute interstitial nephritis leading to AKI. Although less common, a third pathway to kidney injury results from the insolubility of drugs in the urine leading to their precipitation as crystals within distal tubular lumens, causing a crystalline-related AKI. Intratubular obstruction, direct tubular injury, and localized inflammation lead to AKI. Clinicians should be familiar with the pathogenesis and clinical-pathologic manifestations of these forms of kidney injury. Prevention and treatment of AKI relies on understanding the pathogenesis and judiciously using these agents in settings where AKI risk is high.

Fabrication of MSC-laden composites of hyaluronic acid hydrogels reinforced with MEW scaffolds for cartilage repair

Abstract: Hydrogels are of interest in cartilage tissue engineering due to their ability to support the encapsulation and chondrogenesis of mesenchymal stromal cells (MSCs). However, features such as hydrogel crosslink density, which can influence nutrient transport, nascent matrix distribution, and the stability of constructs during and after implantation must be considered in hydrogel design. Here, we first demonstrate that more loosely crosslinked (i.e., softer, ~2 kPa) norbornene-modified hyaluronic acid (NorHA) hydrogels support enhanced cartilage formation and maturation when compared to more densely crosslinked (i.e., stiffer, ~6-60 kPa) hydrogels, with a >100-fold increase in compressive modulus after 56 days of culture. While soft NorHA hydrogels mature into neocartilage suitable for the repair of articular cartilage, their initial moduli are too low for handling and they do not exhibit the requisite stability needed to withstand the loading environments of articulating joints. To address this, we reinforced NorHA hydrogels with polycaprolactone (PCL) microfibers produced via melt-electrowriting (MEW). Importantly, composites fabricated with MEW meshes of 400 m spacing increased the moduli of soft NorHA hydrogels by ~50-fold while preserving the chondrogenic potential of the hydrogels. There were minimal differences in chondrogenic gene expression and biochemical content (e.g., DNA, GAG, collagen) between hydrogels alone and composites, whereas the composites increased in compressive modulus to ~350 kPa after 56 days of culture. Lastly, integration of composites with native tissue was assessed ex vivo; MSC-laden composites implanted after 28 days of pre-culture exhibited increased integration strengths and contact areas compared to acellular composites. This approach has great potential towards the design of cell-laden implants that possess both initial mechanical integrity and the ability to support neocartilage formation and integration for cartilage repair.

A structured ICA-based process for removing auditory evoked potentials

Abstract: Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (EEG), reflect a combination of TMS-induced cortical activity and multi-sensory responses to TMS. The auditory evoked potential (AEP) is a high-amplitude sensory potential-evoked by the "click" sound produced by every TMS pulse-that can dominate the TEP and obscure observation of other neural components. The AEP is peripherally evoked and therefore should not be stimulation site specific. We address the problem of disentangling the peripherally evoked AEP of the TEP from components evoked by cortical stimulation and ask whether removal of AEP enables more accurate isolation of TEP. We hypothesized that isolation of the AEP using Independent Components Analysis (ICA) would reveal features that are stimulation site specific and unique individual features. In order to improve the effectiveness of ICA for removal of AEP from the TEP, and thus more clearly separate the transcranial-evoked and non-specific TMS-modulated potentials, we merged sham and active TMS datasets representing multiple stimulation conditions, removed the resulting AEP component, and evaluated performance across different sham protocols and clinical populations using reduction in Global and Local Mean Field Power (GMFP/LMFP) and cosine similarity analysis. We show that removing AEPs significantly reduced GMFP and LMFP in the post-stimulation TEP (14 to 400 ms), driven by time windows consistent with the N100 and P200 temporal characteristics of AEPs. Cosine similarity analysis supports that removing AEPs reduces TEP similarity between subjects and reduces TEP similarity between stimulation conditions. Similarity is reduced most in a mid-latency window consistent with the N100 time-course, but nevertheless remains high in this time window. Residual TEP in this window has a time-course and topography unique from AEPs, which follow-up exploratory analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject. We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFP/LMFP and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and may thus better isolate TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later response may be consistent with TMS-modulated alpha activity that is not site specific but is unique to the individual. TEP remaining after removal of AEP is unique and can provide insight into TMS-evoked potentials and other modulated oscillatory dynamics.

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

Abstract: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group.To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy.This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety.Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations.Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3

Abstract: Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal tubule epithelial cells. DDR1-induced BCR phosphorylation or BCR downregulation increased MCP-1 secretion, suggesting that BCR negatively regulates the levels of MCP-1. Mechanistically, phosphorylation or downregulation of BCR increased β-catenin activity and in turn MCP-1 production. Finally, we showed that DDR1-mediated STAT3 activation was required to stimulate the secretion of TGF-β. Thus, DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF-β. These findings identify DDR1 an attractive therapeutic target for ameliorating both proinflammatory and profibrotic signaling in kidney disease.

Impact of Perceived Social Support on Mental Health, Quality of Life, and Disability in Post–9/11 U.S. Military Veterans:

Abstract: This study examined the impact of perceived social support on mental health and psychosocial functioning in combat veterans after military deployment, including veterans with post-traumatic stress ...

Exploration of the Effects of Protective Person–Environment Factors Between Functional Impairments and Stress in Individuals With Multiple Sclerosis: Mediation and Moderation Analyses:

Abstract: Functional impairments can lead to stress in individuals with multiple sclerosis (MS). The study examined protective person and environment factors (i.e., positive cognitive stress appraisal, core ...

Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation.

Abstract: The interaction between neutrophils and endothelial cells is critical for the pathogenesis of vascular inflammation. However, the regulation of neutrophil adhesive function remains not fully understood. Intravital microscopy demonstrates that neutrophil DREAM promotes neutrophil recruitment to sites of inflammation induced by TNF-α but not MIP-2 or fMLP. We observe that neutrophil DREAM represses expression of A20, a negative regulator of NF-κB activity, and enhances expression of pro-inflammatory molecules and phosphorylation of IκB kinase (IKK) after TNF-α stimulation. Studies using genetic and pharmacologic approaches reveal that DREAM deficiency and IKKβ inhibition significantly diminish the ligand-binding activity of β2 integrins in TNF-α-stimulated neutrophils or neutrophil-like HL-60 cells. Neutrophil DREAM promotes degranulation through IKKβ-mediated SNAP-23 phosphorylation. Using sickle cell disease mice lacking DREAM, we show that hematopoietic DREAM promotes vaso-occlusive events in microvessels following TNF-α challenge. Our study provides evidence that targeting DREAM might be a novel therapeutic strategy to reduce excessive neutrophil recruitment in inflammatory diseases.

Cortical mu rhythms during action and passive music listening

Abstract: We are the first to report music-related mu enhancement in the absence of overt movements and the first to source-resolve mu activity during music listening. We suggest that music-related mu modulation reflects overt motor inhibition during passive music listening. This work is relevant for the development of theories relating to the involvement of covert motor system activity for predictive beat perception.

CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung transplantation

Abstract: Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, while a CD11b agonist, leukadherin-1, administered only to the donor lung prior to lung transplantation, abrogated CXCL2 production and PGD. The damage-associated molecular pattern molecule HMGB1 was increased in peripheral blood samples from patients undergoing lung transplantation after reperfusion and induced CXCL2 production in nonclassical monocytes via TLR4/MyD88. An inhibitor of HMGB1 administered to the donor and recipient prior to lung transplantation attenuated PGD. Our findings suggest that CD11b acts as a molecular brake to prevent neutrophil recruitment by nonclassical monocytes following lung transplantation, revealing an attractive therapeutic target in the donor lung to prevent PGD in lung transplant recipients.

The psychosocial needs of underserved breast cancer survivors and perspectives of their clinicians and support providers.

Abstract: Breast cancer survivors (BrCS) experience many psychosocial difficulties following treatment, leading to an increased risk of psychological distress compared to the general population. This is especially true for underserved BrCS whose unmet supportive care needs can result in worse physical and mental health outcomes. This qualitative study compared healthcare and support providers’ perceptions of BrCS’ needs to survivors’ perceptions of their own needs. Semi-structured in-depth interviews were conducted with 25 underserved BrCS and 20 cancer survivorship stakeholders identified using purposeful sampling. Using the constant comparison method and content analysis, data were analyzed via an iterative process of coding and discussion. Data were summarized according to three intermediate and proximal themes mentioned by both stakeholders and survivors: (1) psychosocial needs of cancer survivors, (2) support, and (3) benefit finding/positive feelings about cancer. Demographic data were analyzed by calculating descriptive statistics. There was consistency in providers’ and survivors’ perceptions of post-treatment mood changes, financial burden, familial stress, and physical changes. Providers and survivors differed in perceptions of BrCS’ preferred sources of care and support, effects of cancer treatment on body image, the effects of fear of cancer recurrence on follow-up care, and benefit finding. This study provides valuable insight into areas in which healthcare and support providers’ perceptions may differ from underserved BrCS’ lived experiences. Results from this study can be used to develop interventions and inform healthcare and support providers on how to provide high-quality care to underserved BrCS.

SRI-42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation.

Abstract: Glial activation with the production of pro-inflammatory mediators is a major driver of disease progression in neurological processes ranging from acute traumatic injury to chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Posttranscriptional regulation is a major gateway for glial activation as many mRNAs encoding pro-inflammatory mediators contain adenine- and uridine-rich elements (ARE) in the 3' untranslated region which govern their expression. We have previously shown that HuR, an RNA regulator that binds to AREs, plays a major positive role in regulating inflammatory cytokine production in glia. HuR is predominantly nuclear in localization but translocates to the cytoplasm to exert a positive regulatory effect on RNA stability and translational efficiency. Homodimerization of HuR is necessary for translocation and we have developed a small molecule inhibitor, SRI-42127, that blocks this process. Here we show that SRI-42127 suppressed HuR translocation in LPS-activated glia in vitro and in vivo and significantly attenuated the production of pro-inflammatory mediators including IL1β, IL-6, TNF-α, iNOS, CXCL1, and CCL2. Cytokines typically associated with anti-inflammatory effects including TGF-β1, IL-10, YM1, and Arg1 were either unaffected or minimally affected. SRI-42127 suppressed microglial activation in vivo and attenuated the recruitment/chemotaxis of neutrophils and monocytes. RNA kinetic studies and luciferase studies indicated that SRI-42127 has inhibitory effects both on mRNA stability and gene promoter activation. In summary, our findings underscore HuR's critical role in promoting glial activation and the potential for SRI-42127 and other HuR inhibitors for treating neurological diseases driven by this activation.

Simplifying Treatment Criteria in Chronic Hepatitis B: Reducing Barriers to Elimination

Abstract: Abstract Background Early, sustained hepatitis B virus (HBV) DNA suppression reduces long-term risks of hepatocellular carcinoma. Chronic hepatitis B (CHB) treatment criteria are complex. Simplifying criteria will improve timely linkage to therapy. We evaluated treatment eligibility patterns among US patients with CHB and propose stepwise simplification of CHB treatment criteria. Methods Using 2016–2020 Quest Diagnostics data, we evaluated treatment eligibility among patients with CHB (2 positive HBV tests [HBV surface antigen, HBV e antigen, or HBV DNA] ≥6 months apart) using American Association for the Study of Liver Disease (AASLD), European Association for Study of the Liver (EASL), Asian Pacific Association for Study of the Liver (APASL), and Asian American Treatment Algorithm (AATA) criteria. Results Among 84 916 patients with CHB, 6.7%, 6.2%, 5.8%, and 16.4% met AASLD, EASL, APASL, and AATA criteria, respectively. Among treatment-ineligible patients with CHB, proportion with significant fibrosis (aspartate aminotransferase platelet ratio index &gt;0.5) were 10.4%, 10.4%, 10.8%, and 7.7% based on AASLD, EASL, APASL, and AATA, respectively. In the proposed treatment simplification, the proportion of patients with CHB eligible for therapy increased from 10.3% for step 1 (HBV DNA &gt;20 000 IU/mL, elevated alanine aminotransferase [ALT] level) to 14.1% for step 2 (HBV &gt;2000 IU/mL, elevated ALT level), 33.5% for step 3 (HBV DNA &gt;2000 IU/mL, any ALT level), and 87.2% for step 4 (detectable HBV DNA, any ALT level). Conclusions A large proportion of patients with CHB not meeting established treatment criteria have significant fibrosis. Simplifying criteria to treat all patients with detectable HBV DNA will reduce complexity and heterogeneity in assessing treatment eligibility, improving treatment rates and progress toward HBV elimination.

A biomechanical investigation of lumbar interbody fusion techniques.

Abstract: The anterior, posterior, transforaminal, and circumferential lumbar interbody fusions (ALIF, PLIF, TLIF, CLIF/360) are used to treat spondylolisthesis, trauma, and degenerative pathologies. This study aims to investigate the biomechanical effects of the lumbar interbody fusion techniques on the spine. A validated T12-sacrum lumbar spine finite-element model was used to simulate surgical fusion of L4-L5 segment using ALIF, PLIF with one and two cages, TLIF with unilateral and bilateral fixation, and CLIF/360. The models were simulated under pure-moment and combined (moment and compression) loadings to investigate the effect of different lumbar interbody fusion techniques on range of motion, forces transferred through the vertebral bodies, disc pressures, and endplate stresses. The range of motion of the lumbar spine was decreased the most for fusions with bilateral posterior instrumentations (TLIF, PLIF, and CLIF/360). The increase in forces transmitted through the vertebrae and increase in disc pressures were directly proportional to the range of motion. The discs superior to fusion were under higher pressure, which was attributed to adjacent segment degeneration in the superior discs. The increase in endplate stresses was directly proportional to the cross-sectional area and was greater in caudal endplates at the fusion level, which was attributed to cage subsidence. The response of the models was in line with overall clinical observations from the patients and can be further used for future studies, which aim to investigate the effect of geometrical and material variations in the spine. The model results will assist surgeons in making informed decisions when selecting fusion procedures based on biomechanical effects.

Social Determinants of Health and Comorbidities Among Individuals with Atherosclerotic Cardiovascular Disease: The Behavioral Risk Factor Surveillance System Survey

Abstract: Individuals with atherosclerotic cardiovascular disease (ASCVD) often have a high burden of comorbidities. Social determinants of health (SDOH) may complicate adherence to treatment in these patients. This study assessed the association of comorbidities and SDOH among individuals with ASCVD. Cross-sectional data from the 2016 to 2019 Behavioral Risk Factor Surveillance System, a nationally representative US telephone-based survey of adults ages ≥18 years, were used. Cardiovascular comorbidities included hypertension, hyperlipidemia, diabetes mellitus, current cigarette smoking, and chronic kidney disease. Non-cardiovascular comorbidities included chronic obstructive pulmonary disease, asthma, arthritis, cancer, and depression. SDOH associated with being at or above the 75th percentile of comorbidity burden were analyzed using multivariable adjusted logistic regression models. The study population included 387,044 individuals, 9% of whom had ASCVD. The mean (SD) numbers of total, cardiovascular, and non-cardiovascular comorbidities were 1.97 (1.27), 1.28 (0.74), 0.69 (0.91) among those without ASCVD and 3.28 (1.62), 1.73 (0.91), and 1.54 (1.22) among those with ASCVD, respectively (P < 0.001 for all comparisons). Female gender, household income ≤$75,000, being unemployed, and difficulty accessing health care were significantly associated with a higher burden of comorbidities among those with ASCVD. The mean (SD) numbers of comorbidities for those with 0, 1, 2, and ≥3 of the aforementioned SDOH were 2.89 (1.45), 2.86 (1.47), 3.39 (1.58), and 4.01 (1.73), respectively (P < 0.001). Among persons with ASCVD, the burden of cardiovascular and non-cardiovascular comorbidities is directly proportional to SDOH in any given individual. Clinicians should address SDOH when managing high-risk individuals.