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The NoLoCo Strategy for Essential Hypertension
Get PDFNinety-nine percent of all “essential” hypertension can be controlled by using the NoLoCo strategy, without causing any significant side-effects and without an increase in insulin resistance. NoLoCo stands for Norvasc (amlodipine), Lozol (indapamide), and Cozaar (losartan), but the medicines are considered and used in reverse order
Multimorbidity in Diverse Populations: Stratified Analysis of Race/Ethnicity, Age, Obesity, and Healthcare Costs
Get PDFThis research aims to fill an essential gap in understanding how Body Mass Index (BMI) cutoffs relate to multimorbidity across races in the United States (US). Given the significant and growing rates of obesity and multimorbidity, as well as the known differences in healthy fat distribution among different races, this is an important area of research. BMI is a widely used but imperfect measure of obesity, as it does not account for differences in body composition. However, it is still used as a diagnostic tool. It is vital to ensure that the cutoffs used to define obesity are appropriate for all populations, particularly given the racial disparities in multimorbidity rates. This proposed framework for evaluating BMI cutoffs across races for multimorbidity considered a range of measures, such as, including incidence rates of prevalent diseases, age, gender, type of patient visits, and type of health insurance to arrive at questioning the current World Health Organization (WHO) BMI cutoffs in the US. This research demonstrated that having the exact BMI cutoffs across all races does not serve all populations ideally through three assessments. First, it assessed differences in the prevalence of multimorbidity by race. It identified disease combinations shared by all races/ethnicities, shared by some, and those unique to one group for each age/obesity level. These findings demonstrated that despite controlling for age and obesity, there are differences in multimorbidity prevalence across races. Second, the study developed models to project total charges for the most common multimorbidity combinations in the US and evaluated the accuracy of these models across different racial and ethnic groups and multimorbidity patterns. The relationship between healthcare costs and multimorbidity varied for each racial group and depended on the specific combination of chronic conditions, age, and obesity status. Third, it assessed the relationship between BMI and healthcare burden across race and healthcare utilization among middle-aged patients in the US. It demonstrated that the relationship between BMI and healthcare burden varied across races within the same healthcare care utilization category. This research can improve health outcomes and reduce the risk of chronic diseases associated with obesity and multimorbidity, particularly among vulnerable populations. It will also be essential to consider the potential implications of any new BMI cutoffs on clinical practice and health policies related to obesity and multimorbidity in serving unique clinical needs. More work must be done to understand how multimorbidity, BMI, age, and healthcare burden associate across races
The Therapeutic Role of LM11A-31 (a p75NTR Modulator) in the Outcome of Ischemic Stroke and HIV-1 Pathogenesis
Get PDFThe objective of this research project is to explore the potential therapeutic role of LM11A-31 in both ischemic stroke and human immunodeficiency virus-1 (HIV-1) infection. There are limited treatment options for ischemic stroke, with tissue plasminogen activator (tPA) being the only effective medication and a narrow administration window, which is also accompanied with the high incidence of ischemic stroke in HIV-1 infected individuals. Therefore, it is critical to explore an effective therapeutic agent to address the urgent medical need. LM11A-31 is a p75 neurotrophin receptor (p75NTR) modulator and is orally bioavailable, and it can penetrate the intact blood-brain barrier (BBB). It is in phase II clinical trials for the treatment of mild to moderate Alzheimer’s disease. As p75NTR upregulation has been reported in both ischemic stroke and HIV-1 infection, LM11A-31 could be a potential therapeutic in these disease states. This study illustrated that pharmacological regulation of p75NTR with LM11A-31 or genetic knocking down p75NTR significantly improves the outcome of ischemic stroke in mice through mitigating cerebral infarction, edema, and hemorrhagic transformation. Additionally, this research revealed that modulation of p75NTR attenuates inflammatory and cell apoptosis markers, including NF-B, JNK/RhoA, Akt, GSK3, and Bcl-2/Bax. P75NTR modulation also improved the neurobehavioral function of animals, which were assessed using Catwalk analysis. This research also demonstrated that LM11A-31 improves HIV-1 pathogenesis in U1 macrophages via reducing viral replication, cytotoxicity, and pro-inflammatory markers, which was comparable to the positive control darunavir. Furthermore, LM11A-31 did not alter the protein level of Akt, Beclin-1, and oxidative stress enzymes, including SOD-1 and catalase. Overall, this study provides new insights into the efficacy of LM11A-31 in treating both ischemic stroke and HIV-1 infection. HIV-1-infected individuals are more suspectable to develop cerebrovascular diseases, including ischemic stroke, than non-infected individuals. Due to the limited ability of antiretroviral drugs to cross the BBB and achieve therapeutic concentration, LM11A-31 is a promising treatment for reducing HIV-1 pathogenesis, including neuroHIV-1, and cerebrovascular events. Further research is needed to investigate the safety and efficacy of LM11A-31 in dual animal models of ischemic stroke and HIV-1 infection before progressing to clinical trials
Development, Validation, and Testing of a Novel Ergonomic Backpack
Get PDFBackpacks (BP) are one of the most common means for carrying loads but the loading mechanics that result from carrying heavy loads can have implications across the body. It has been suggested that loads in a BP should not excess 10-15% of the user’s body weight (BW) but that is not always feasible. The loads in a BP are transferred to the body via the shoulder strap which induce a shear and compressive force which act externally on the spine and transfer loads through it to the lumbar. Additionally, the weight of the bag induces an external moment that further stresses the spine structures. The ergonomic backpack (EBP) was designed as a possible solution to the problematic loading conditions that are induced by load carriage and therefore improving load carriage efficiency and ergonomic performance. The term ergonomic performance was characterized by an accumulation of variables that could be used to evaluate backpack technology, including decreased shoulder and spine loads, reduction in paraspinal muscle involvement, reduction in oxygen consumption, reduction in lower extremity muscle effort, and improved comfort. The EBP utilizes several design features that alleviates spine and shoulder loading by redirecting and counterbalancing the external load from the backpack.
The objective of study 1 was to validate the design of the EBP. This was done by determining the strap tension-bag load relationship in the EBP compared to a traditional backpack using modified luggage scales which were configured to measure the tension in each strap. Additionally, the shoulder pressure-bag load relationship in the EBP compared to a traditional backpack using pressure sensors. Ten measurements of shoulder load and strap tension were taken in each backpack condition with five weight increments (0 kg to 11 kg). Shoulder loads were significantly reduced with the EBP (50%) at all weight increments (p
The objective of study 2 was to evaluate ergonomic performance while wearing the EBP compared to a traditional backpack during a walking task. The first aim was to measure paraspinal muscle response and the second aim was to measure oxygen consumption and lower limb muscle response. Fifteen healthy participants walked on a split-belt instrumented treadmill at 1.3 m/s in two backpack conditions, the EBP and a traditional backpack, with two loads (7 kg and 11 kg). A 3D motion capture system recorded electromyography and kinematic data, while the force treadmill recorded ground reaction forces. Kinetic and kinematic variable calculations were used to determine trunk angle and muscle powers at each major joint. Electromyography signals were processed and used to determine the muscle activity over the gait cycle. A metabolic cart recorded the volume of oxygen consumed during the walking trial. Results revealed significantly decreased trunk angle (more vertical trunk position), decreased paraspinal muscle activity, and decreased hip muscle power in the EBP compared to the traditional backpack (p
This body of work provides evidence that the EBP could provide the basis for design improvements that should be considered in improving backpacks for safer load carriage
Inhibition of KDM4 with QC6352 to Target High-Risk Neuroblastoma
Get PDFNeuroblastoma (NB) is a malignancy of improperly maturated nerve tissues of the sympathetic nervous system. It is the most diagnosed extracranial solid tumor of childhood, and it accounts for roughly up to 10% of all childhood malignancies and 15% of all childhood malignancy-related deaths. MYCN amplification, occurring in 20-25% of all NB patients and 50% of all high-risk NB patients, is the well-characterized genetic abnormality and is associated with ill-fated outcomes. Regrettably, in spite of the contemporary therapeutic advances and aggressive combinatorial treatments, the overall 5-year event-free survival rate is roughly 51% with a 5-year overall survival rate of nearly 63%. Unfortunately, close to 50% of high-risk NB patients develop disease relapses, which are largely incurable with no salvageable therapies so far. Recent evidence highlights that NB exhibits two cellular heterogeneities, namely adrenergic (ADRN) and mesenchymal (MES), which are tightly controlled by core regulatory circuitry-transcription factors (CRC-TFs). Driven by super-enhancers, these CRC-TFs, produce interrelated, feed-forward transcriptional loops that ultimately reinforce a specific gene expression program that defines the cellular state and identity of the cell. We showed that histone lysine demethylase subfamily 4 (KDM4) protein expression was higher in MYCN-amplified (MNA) NB cell lines and patient-derived xenografts (PDXs) compared with non-MNA counterparts. Additionally, genetic depletion of KDM4 correlated with reduced proliferation in vitro and in vivo. Interestingly, forced MYCN overexpression in MES-dominant NB cells facilitated MES to ADRN cellular state shift that was accompanied by induction of KDM4 proteins. Through various functional and genetic assays, we further validated the importance of the MYCN/KDM4/ADRN CRC-TF axis in maintaining the ADRN cellular state of NB. In view of these thrilling results, we opted to expand the clinical utility and examine the prospect of pharmacologic inhibition of KDM4 with QC6352, a selective and potent KDM4 inhibitor. Our data depicted that monotherapy QC6352 was selectively sensitive against MNA NB cells in vitro. Additionally, monotherapy QC6352 depicted satisfactory antitumor activities in high-risk cell line-based xenografts (NB1691), PDXs, and TH-MYCN/ALKF1178L transgenic mouse model in vivo. Molecularly, QC6352 reduced the mRNA and protein levels of oncogenic drivers and various ADRN CRC-TFs. Interestingly, QC6352 also decreased KDM4 expression at the translational protein level. Additionally, QC6352 culminated in favorable anticancer effects in vitro and in vivo, reflected by differentiation induction, apoptosis instigation, DNA damage, cell cycle cessation, and interestingly type-I interferon reactivation. Epigenomic-based investigations utilizing assay for transposase-accessible chromatin with sequencing (ATAC-seq) showed QC6352 reduced chromatin accessibility of MYCN and ADRN CRC-TFs, whereas chromatin immunoprecipitation with sequencing (ChIP-seq) and cleavage under targets and tagmentation (CUT&TAG) analyses showed KDM4 proteins were bound to genomic loci of MYCN and ADRN CRC-TFs, and QC6352 treatment promoted induction of the transcriptional repressive H3K9me3 mark. Lastly, combination therapy comprising QC6352 and standard-of-care chemotherapeutics (vincristine and irinotecan) led to 100% complete response in MNA NB xenografts without overt toxicity and accompanied by prolongation of survival. All in all, this research offers a solid proof-of-concept that pharmacologic inhibition of KDM4 with QC6352 may be translated from bench to bedside as a novel therapeutic tactic for high-risk MNA NB patients. Moreover, two orthogonal drug screens comprising CRISPR-Cas9 knockout (metabolism and kinase libraries), and high-throughput PRISM analysis highlighted enhanced anticancer effects between QC6352 and mammalian target of rapamycin (mTOR) inhibition. We demonstrated that combination of QC6352 and some mTOR inhibitors resulted in enhanced anticancer effects in vitro in several MNA and non-MNA NB cells. Functional genetic assays to validate the enhanced anticancer effects between dual KDM4 and mTOR inhibition failed. Lastly, combination of QC6352+rapamycin did not result in enhanced anticancer effects in SKNAS xenografts in vivo. Unless more in vivo work is performed, the present findings do not provide a compelling motivation to combine QC6352 with mTOR inhibition in the treatment of NB tumors
Studies on the Leukocyte-Associated Ig-Like Inhibitory Receptor-1 Signaling Pathway in T Lymphocytes
Get PDFInflammation is a natural process in which the immune system concertedly responds to pathogens and abnormal cell growth to protect the host. For an efficient/effective immune response that circumvents tissue atrophy, a delicate balance between stimulatory and inhibitory mechanisms is essential for the proper functioning of the immune system. Immuno-receptor Tyrosine-based Inhibitory Motif (ITIM)-bearing receptors in immune cells, including T lymphocytes, play a major role in preventing autoimmune responses. Leukocyte-associated Ig-like Inhibitory Receptor 1 (LAIR-1) is one of ITIM-bearing receptors. The mechanism by which LAIR-1 attenuates T-cell response has yet to be completely understood. In this study, I investigated a part of the mechanisms by which LAIR-1 transduces inhibitory signal to attenuate T cell activation. I investigated whether the LAIR-1 signaling complex contains SH2 domain-containing phosphatase (SHP)-1, SHP-2, C-terminal src kinase (Csk), and/or the protein tyrosine phosphatase, non-receptor 22 (PTPN22), whether these phosphatases are activated upon LAIR-1 and its ligand interaction, and whether SHP1 plays a role in LAIR-1 signaling and T cell activation.
I validated previous findings that suggested LAIR-1 stimulation by its natural ligand collagen suppresses T cell antigen receptor (TCR)-mediated T-cell activation. To study proximal LAIR-1 signaling, transformed human T cells (Jurkat) that overexpress LAIR-1 were treated with the constituent chain of collagen type II [α1(II)] to stimulate LAIR-1. LAIR-1 activation by α1(II) induced phosphorylation of both SHP-1 and SHP-2, as well as phosphorylation of LAIR-1. In addition, LAIR-1 stimulation by α1(II) recruited the phosphorylated form of SHP-1, the phosphorylated form of SHP-2, and PTPN22 to LAIR-1 in T cells. However, Csk was constitutively bound to LAIR-1 in T cells. These results indicate that upon ligand binding LAIR-1 forms a signaling complex with SHP1, SHP-2, Csk, and PTPN22 and activates SHP-1 and SHP-2 in human T cells. To determine the role of SHP-1 in LAIR-1 signaling, the expression of SHP-1 in Jurkat-LAIR1 cells was knocked down by stably expressing SHP-1-specific short hairpin RNA interference (shRNA). I found that expression levels of SHP-1 correlated with expression levels of LAIR1 in Jurkat-LAIR-1 cells, indicating a possibility that SHP1 and LAIR-1 regulate expression of each other in T cells as a feedback mechanism. Phosphorylation of SHP-2 was not inhibited in SHP-1- knockdown cells, indicating that SHP-2 activation by LAIR-1 is not affected by SHP-1. To investigate whether SHP-1 mediates LAIR-1 inhibitory signaling to suppress TCR signal transduction, control and SHP-1-knockdown Jurkat-LAIR-1 cells were treated with α1(II) followed by TCR stimulation by anti-CD3.
SHP-1-knockdown in Jurkat-LAIR1 cells resulted in ablation of ZAP70 and ERK phosphorylation regardless of LAIR-1 signaling and TCR signaling, indicating that SHP-1 is required for activation of ZAP70 and ERKs in T cells. Thus, SHP-1 may play a dual function; an intermediate for LAIR-1 to regulate signaling phosphoproteins and as a positive regulator of signaling pathways like the TCR to promote cellular activation and effector function. These results are insightful because they show that inhibitory receptors like LAIR-1 can engage multiple SH2 domain-containing phosphatases, some of which have a dynamic function that can positively and negatively regulate intracellular biochemical activities to modulate cellular behavior and hyperactive T-cell response to avoid autoimmunity
Suicide Screening Among Adolescents with a History of Mental or Physical Abuse- Evaluating the Effectiveness of Suicide Screening: A Scoping Review
Get PDFPurpose The purpose of this scoping review is to gather evidence on best practice for the administration of pediatric suicide screening in a variety of healthcare settings
Understanding the Host Cellular Response to Astrovirus Infection
Get PDFAstrovirus is a non-enveloped positive-sense single-stranded RNA virus that infects the small intestine and causes gastrointestinal disease in most hosts. However, in immunocompromised patients, astrovirus can infect the brain, causing encephalitis and death. Here, we characterize astrovirus induction of replication organelles and dysregulation of cellular processes. It is known that autophagy can play a key role in the viral lifecycle, from entry to egress, and can be either pro-virus or pro-host depending on the virus. RNA viruses often exploit autophagy machinery to create double membrane vesicles (DMVs) as sites of replication and to protect viral RNAs from detection by innate immune sensors. In these studies, we provide the first evidence that astrovirus exploits some, but not all autophagy machinery to assist in viral replication at DMVs. Astrovirus replication and DMV formation relies upon induction of PI3KC3 machinery, but not LC3 conjugation machinery. Astrovirus also disrupts lysosomal enzyme expression. These are the first studies describing astrovirus replication mechanism, and we have shown that the machinery involved may span species infected with astrovirus. We have also shown that astrovirus DMV formation likely originates from the endoplasmic reticulum (ER) and may affect ER stress pathways involved in normal cellular function. These results relate DMV formation to autophagosome biogenesis and suggest that ER stress could play a role in DMV biogenesis. Finally, we have shown that astrovirus replication results in cell cycle arrest during G1 phase of the cell cycle. This is beneficial to the viral life cycle, because G1 phase may provide an environment of growth for the replicating virus. In all, our studies have significantly grown the understanding of astrovirus replication mechanism and disruption of host cellular machinery. This has resulted in relating astrovirus to other positive strand RNA viruses and potentially finding common therapeutics for these viral infections
Shifting Emergency Department Utilization Patterns Among Vulnerable Populations During the COVID-19 Pandemic
Get PDFBackground: COVID-19 is a contagious respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of March 10, 2023, the virus infected nearly 104 million Americans. Many individuals were wary of seeking medical attention for issues unrelated to COVID-19 for fear of infection inside healthcare facilities. This hesitation caused a drop in emergency department (ED) visits for non-COVID-19 conditions. It is essential to ensure that individuals with critical healthcare needs receive the care they require and to mitigate the potential long-term consequences of delayed or deferred care. Objectives: The primary aim of this study is to examine how patterns of ED utilization shifted and may continue to shift for socially vulnerable populations during and beyond the COVID-19 pandemic. Accomplishing this entails understanding the broader baseline changes in ED utilization and then identifying patterns for vulnerable individuals. Insights from this step will be used to predict future ED utilization changes and assess downstream impacts on the healthcare system. Methods: An observational population-based cohort study design was chosen for this study. The onset of COVID-19 created a natural inflection point in time whereby changes in captured data could be examined. Electronic medical records from three large health systems in Tennessee was extracted from the Research Enterprise Data Warehouse (rEDW) from University of Tennessee Health Sciences Center (UTHSC), representing data from three Tennessee health systems: Methodist Le Bonheur (Memphis), University of Tennessee Medical Center (Knoxville), and St. Thomas Health (Nashville). These data included medical history, demographics, hospital procedures, diagnostic data, laboratory orders and results, and prescription medication information, and were adequate and equivalent pre- and post-COVID-19 cohorts for analyses. The data extract consisted of ED visits between March 2018 and March 2022. Results: This research revealed a significant overall decrease in ED utilization in the post-COVID-19 era. Vulnerable populations showed a significant reduction in mental health ED visits but an increase in substance-related concerns. Machine learning analysis highlighted a key predictor for ED volume in a census tract: the percent of single-parent households, indicating accessibility challenges. While the XGBoost model performed well overall (R2 = 0.96), it had limited applicability in Memphis MSA due to census tract heterogeneity. This study demonstrates the potential for accurate ED volume estimation using simplified models and census-level data. Conclusions: Emergency departments are critical to the US healthcare system and can be essential when dealing with life-threatening events and conditions. However, ED services can often be utilized for conditions that could be treated in an outpatient setting. This could impact cost and outcome issues in general; however, it becomes even more concerning amid a global pandemic. This study provides future researchers with insights, suggestions, and protocols for leveraging data and developing predictive tools for understanding emergency department utilization