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Steroid-Induced Ocular Hypertension in Mice Is Differentially Reduced by Selective EP2, EP3, EP4, and IP Prostanoid Receptor Agonists
Get PDFWe tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 microg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.This research was funded by the National Eye Institute, EY026177, and Santen Inc
The Impact of ADA Guideline Changes and Utilization Management on the Use of First-Line Antidiabetic Medication Classes for the Treatment of Type 2 Diabetes Mellitus in a Commercial Population
No full textPurpose: While metformin has a long track record regarding its efficacy and safety, newer classes like sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have also proven to not only be very effective in lowering A1c, but certain agents may provide additional cardiovascular, renal, and weight loss benefits as well. Recent 2023 American Diabetes Association (ADA) guidelines de-emphasized metformin as the de facto first-line pharmacologic agent in favor of selecting first-line agents based on patient-specific factors and treatment goals. Analysis of the prescription claims data can provide insight into the prescribing patterns of these newer agents over the past 2 years for any shifts in therapy in response to the changes in the guidelines. The objectives of this study is to compare the changes in utilization of different first-line antidiabetic classes in the treatment of Type 2 Diabetes Mellitus (T2DM), as monotherapy or combination therapy, in commercial population from January 1, 2021, and June 30, 2023.
Methods: This study is a retrospective analysis of prescription claims data identifying utilization of first-line antidiabetic classes. The classes of interest are biguanides, SGLT2, GLP-1, DPP-4, thiazolidinediones (TZD), and sulfonylureas (SU). Insulins and GLP-1 indicated for anti-obesity are excluded. The two study groups are plans with an initial metformin Step Therapy and plans with no utilization management in place. The primary objective will be to assess the changes in the proportion of 30-day supply claims for each class among the total antidiabetic utilizers from 2021 to 2023 between the two study groups. Key secondary objective include the difference in the proportion of non-metformin monotherapy for new antidiabetic utilizers. Another secondary objective is the difference between the proportion of utilizers for different type of combination therapy. Secondary endpoints will be reported as per utilizer per month (PUPM).
Results: Work-in-progress, N/A
Conclusion: Work-in-progress, N/
Impact of nicotine's autonomic effect on nicotine's discriminative stimulus
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Pharmacology & Neuroscience Award - 2nd PlacePurpose: As the leading cause of preventable death, tobacco smoking has inspired years of research into the mechanisms of addiction and pharmacological targets for smoking cessation. Nicotine, an active psychostimulant in tobacco, activates the brain's reward system and drives the addiction to smoking via dopaminergic neurons. Although some studies have suggested that the autonomic effects of psychostimulants may independently serve as cues for the release of dopamine in the brain, it has not been demonstrated behaviorally. A previous locomotor activity study in our lab showed that hexamethonium, a brain-impermeable nicotinic receptor antagonist blocks the locomotor stimulant effects of nicotine in mice. To further assess the impact of the autonomic effects of nicotine on behavior, we conducted a nicotine discrimination study. In this study, we subtracted nicotine’s autonomic effects from the overall subjective effect by using hexamethonium. Method: Using a two-lever drug discrimination operant chamber, six male Sprague-Dawley rats were trained to discriminate 0.1 mg/kg nicotine tartrate from saline by lever pressing. Subcutaneous injections of nicotine or saline for training occurred five minutes prior to the start of the training session. On test days, rats received hexamethonium (1, 2.5, 5, 10, 25, or 50 mg/kg) intraperitoneally 25 minutes prior to subcutaneous administration of nicotine at the training dose (0.1 mg/kg). Percentage of drug lever responses and response rate were recorded to measure antagonism and analyzed using repeated measures ANOVA. Results: Within the dose range of 10-50 mg/kg, hexamethonium partially antagonized nicotine’s discriminative stimulus effect by reducing the percentage nicotine-lever response to 42% of nicotine’s maximum discriminative stimulus effect. Conclusion: Although full antagonism was not observed, the partial antagonism of nicotine’s discriminative stimulus by a solely peripherally-acting antagonist shows that the autonomic effects of nicotine are a component of the overall subjective effect of nicotine that influences behavior and can be explored as a target for smoking cessation. More direct assays of reward, such as the self-administration assay will be required to affirm the autonomic contributions to the neurobiology of nicotine addiction.NID
Postural Sway in Back Pain Patients
No full textPurpose: Fall risk prediction is an active area of research due to the devastating impact of falls. Millions of Americans are injured by falls every year, with a significant portion suffering serious injuries such as head trauma and hip fractures (Bergen). Studies have demonstrated that postural sway (PS) is a crucial predictor of fall risk and indicator of several disease processes, which has prompted The University of North Texas Health Science Center (UNTHSC) to research the relationship between PS and other variables. Back pain (BP) has been proposed as one of these potential variables due to its prevalence and association with posture and balance. The purpose of our study is to analyze the relationship between BP and PS. Methods: Balance testing was collected as a vital at the UNTHSC Geriatrics and Family Medicine clinics. As part of the collection process, cooperating patients were instructed to stand quietly on a Bertec dual-balance force plate (Bertec, Columbus, Ohio) with their hands by their sides for 2 trials, each lasting 30 seconds and divided into 3 intervals of 10 seconds. In the first trial patients were instructed to open their eyes (eyes open condition), while in the second trial patients were instructed to close their eyes (eyes closed condition). A chart review was then conducted to gather patients with back pain that also had a balance assessment, while a healthy control group was established using data from previous PS collection projects at UNTHSC. The data was processed and analyzed using statistical analysis in Microsoft Excel. Results: The range for the center of pressure in the anterior posterior (COP AP) direction, which measures the movement of the COP AP, was found to be statistically significantly decreased for the BP group versus the control for the eyes open condition. No statistically significant relationships were identified for the eyes closed condition. Conclusion: These results demonstrate that during the eyes open trial BP patients exhibited less PS. We postulate that this is due to factors such as decreased lumbar proprioception and reduced motor control caused by BP, leading patients to depend more on their vision for positional sense. In contrast, the lack of statistical significance for the eyes closed condition may be attributed to the increased difficulty in maintaining balance without visual input, potentially masking the impact of BP on PS. Another consideration is that the BP patients could have been in pain and therefore concentrated more on not moving, which may have been easier during the eyes open condition than the eyes closed condition. Possible limitations of the experiment include the duration of the balance testing, as 30 seconds per trial may not have been enough time to adequately measure each condition, and the grouping of all BP patients into one group without considering the pain characteristics, intensity, and duration. We recommend that additional studies be conducted to address these factors, while considering other relevant confounding variables as well, with the ultimate goal of better understanding and preventing falls
Tracking the burden, distribution, and impact of Post-COVID conditions in diverse populations for children, adolescents, and adults (Track PCC): passive and active surveillance protocols
Get PDFBACKGROUND: Track PCC includes five geographic surveillance sites to conduct standardized population-based surveillance to estimate and track Post-COVID Conditions (PCC) by age, sex, race/ethnicity, geographic area, severity of initial infection, and risk factors among persons with evidence of SARS-CoV-2 infection (based on the Council of State and Territorial Epidemiologist [CSTE] case definitions for confirmed cases or laboratory-confirmed evidence of infection). METHODS: The study will estimate the incidence, prevalence, including temporal trends, and duration and severity of PCC symptoms, among children, adolescents, and adults. PCCs include a broad range of symptoms and conditions that continue or develop after acute SARS-CoV-2 infection or COVID-19 illness. Surveillance includes both passive and active components for diverse populations in Arizona, Indiana, and Utah as well as the Bronx Borough, NY, and part of Philadelphia County, PA. Passive surveillance will utilize electronic health records and health information exchanges within each site catchment area to longitudinally follow persons with COVID-19 to estimate PCC occurring at least 30 days after acute COVID-19 illness. Active surveillance will utilize self-report of PCCs from detailed surveys of persons ages 7 years and older with evidence of SARS-CoV-2 infection in the past 3 months. Respondents will complete follow-up surveys at 6-, 12- and 18-months post-infection. DISCUSSION: These data can help identify which groups are most affected by PCC, and what health differences among demographic groups exist, as well as indicate potential barriers to care. These additional levels of granularity can inform public health action and help direct needed clinical care for patients.This project was peer-reviewed and funding is through a Cooperative Agreement with the Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases (Abt Global NU581IP000001; Comagine Health NU581IP000002; Temple University NU581IP000003; Trustees of Indiana University NU581IP000004; University of Arizona NU581IP000005
Exploring the Association Between Patient-Centered Communication and Awareness of Human Papillomavirus Vaccine: A Cross-sectional Study
No full textResearch Appreciation Day Award Winner - School of Public Health, 2024 Research Award - 3rd PlacePurpose: Human papillomavirus (HPV) vaccination is effective in preventing anogenital and oropharyngeal cancers, including genital warts. The HPV vaccine is approved for individuals aged 9-45 years old and creates the opportunity for healthcare providers to educate parents, caregivers, and patients on the benefits of the vaccine. Effective provider-patient interactions promote collaboration, increase self-efficacy, and support decision-making. This study aimed to assess the association between patient-centered communication and patient awareness of the HPV vaccine. We also examined sociodemographic factors associated with HPV vaccine awareness.
Methods: The sample population included adults aged 18-45 (n=1384) from the 2022 Health Information National Trends Survey (Cycle 6). The outcome variable was HPV vaccine awareness (yes/no), assessed by whether the respondent has ever heard of the cervical cancer vaccine or HPV shot. The primary predictor variable was patient-centered communication, and this was operationalized using the 7-item Patient-Centered Communication scale (PCC scale). The items assessed respondents’ experiences during their healthcare visits, such as the chance to ask questions, attention to their feelings, involvement in decision-making, time availability, clarity of information presented, comprehension of information, and help with uncertainty. The scale response options ranged from 1=Always to 4=Never. The association between patient-centered communication and HPV vaccine awareness was examined using weighted multivariable logistic regression, while controlling for age, sex, race, education attainment, marital status, health insurance status, and number of healthcare visits in the past 12 months.
Results: The mean age of the sample population was 34.1 years (SD=7.2 years). Approximately 52.5% and 47.5% identified as women and men, respectively. Individuals identified as White non-Hispanic (56.2%), Black non-Hispanic (10.2%), Hispanic (19.6%), and Asian/Other non-Hispanic (14.0%). Approximately 40.4% of individuals had a college degree or higher, and 89.8% reported having health insurance coverage. Overall, 72.7% self-reported they had heard about the HPV vaccine. The PCC scale mean was 74.0 (range 0-100). Patient-centered communication was not statistically associated with HPV vaccine awareness. Compared to men, women had higher odds of HPV vaccine awareness (aOR=2.83; 95%CI=1.62-4.97). Individuals with some college (aOR=2.25; 95%CI=1.01-5.01) and college degree or higher (aOR=2.87; 95%CI=1.44-5.77) had higher odds of HPV vaccine awareness than those with less than a high school/12 years/high school diploma. Compared to individuals aged 18-26, individuals aged 27-45 had higher odds of HPV vaccine awareness (aOR=1.91; 95%CI=1.02-3.57). Black (aOR=0.24; 95%CI=0.12-0.49), Asian/Other (aOR=0.24; 95%CI=0.12-0.49), and Hispanic (aOR=0.36; 95%CI=0.21-0.59) individuals had lower odds of being aware of the HPV vaccine than whites.
Conclusions: The absence of statistically significant relationship between patient-centered communication and HPV vaccine awareness underscores the need to investigate other factors that influence patient knowledge and decision-making regarding the HPV vaccine. Provider recommendation is one of the known strategies to address misconceptions and increase uptake of the HPV vaccine, particularly among populations who are at increased risk for HPV. However, individuals with limited or no access to healthcare may seek health information from other readily available sources. Exploring racial/ethnic disparities in HPV vaccine awareness is imperative, including identifying effective, evidence-based dissemination strategies that meet the information needs of diverse populations
Retrospective chart review of children on Low-Dose Naltrexone
No full textPurpose
Low-dose naltrexone (LDN) is an opioid receptor antagonist that has shown beneficial effects for chronic pain management in adults. ‘Low dose’ refers to doses between 0.1 and 5 mg that have shown anti-inflammatory and antinociceptive effects (Parkitny & Younger, 2017). LDN targets toll-like receptor 4 (TLR4) on microglial cells, which cause nervous system inflammation through activating factors such as cytokines, interleukin (IL) 6, and tumor necrosis factor (TNF) (Younger et al., 2014). However, LDN usage remains unexplored in pediatric chronic pain. This is significant because between 15-35% of youth experience pain-related conditions such as abdominal pain and migraine, on top of other chronic pain conditions (Stancil et al., 2021; King et al., 2011). This study is the first to investigate the effects of LDN in a large cohort of children with chronic pain.
Methods
A retrospective chart review was conducted on a pediatric outpatient group at Cook Children’s Medical Center that received only LDN between January 2019 and June 2022. Functional disability inventory (FDI) and pain scores were analyzed at the initial and ‘best’ visit, i.e. the lowest FDI/pain score. The FDI is a 15-item questionnaire that measures limitations in children’s physical and psychosocial functioning. These questions include the patient’s ability to walk up the stairs, eat regular meals, and doing athletic activities. 284 total patients were prescribed LDN. Of these, 253 were excluded: 6 (2.3%) patients were prescribed LDN before March 1, 2018, 8 (3.1%) patients never started LDN, 86 (30.2%) patients had no follow-up data in the pain medicine clinic, and 153 (53.8%) patients were prescribed another medication in addition to LDN. In total, 31 patients were prescribed LDN and no other medications. Of those 31 patients, 25 had FDI scores and 23 had data for pain. Patients started LDN at an average age of 15.1 and ended LDN at an average age of 16.4. For FDI and pain scores, a Wilcoxon ranked sum test was performed since the data was ordinal and not normally distributed. IRB approval was obtained.
Results
Wilcoxon ranked sum test indicated FDI scores did significantly decrease from first (M=22.5) to best (M=16.4) (p<0.003). In contrast, the test did not reveal any significant differences between first (M=4.00) and best (M=3.52) pain scores (p<0.2).
Conclusion
The findings suggest that LDN may improve pain-related disability in pediatric patients, ultimately improving pain levels and psychosocial function. This also implies that LDN improves the daily functioning of children and allows them to complete routine tasks more efficiently. Results should be interpreted cautiously due to the retrospective study design and limited number of LDN-only cases available to review at this time. Additional prospective research should include whether LDN effects vary with age, or if certain diagnoses are more effectively treated with this medication
Association of Pediatric Head Trauma with Attention Deficit Hyperactivity Disorder (ADHD) among School-aged Children in the United States
No full textBackground
Pediatric concussion is an important issue in healthcare that has gained recognition in recent years. Concussion may lead to negative emotional and cognitive consequences. ADHD may be a potential neurobehavioral consequence of head trauma, with evidence suggesting an increased likelihood of ADHD in individuals who have experienced concussions or have a history of head trauma.
Objective
This study examined disparities in pediatric head trauma and the association of a history of pediatric head trauma with ADHD using nationally representative data from the United States.
Methods
We performed a cross-sectional study using the 2021 National Health Interview Survey (NHIS). The study was restricted to school-aged children (5-17 years) with no missing information on ADHD or head trauma. There were 5,960 participants representing ~52.11 million US children. Our key independent variable was concussion (Yes/No) with yes indicating a positive response to any question in the 2021 NHIS survey fitting the following descriptions: “ever lost consciousness”, “ever told had a concussion”, “ever dazed or memory gap”, and “ever headache, vomit, blurred vision, or mood change after blow to the head.” ADHD was derived from a question that asked about the diagnosis of ADHD by a health professional or doctor. We performed Rao-Scott Chi-square tests and logistic regression analyses to identify the association of concussion with ADHD while controlling for other explanatory variables (sex, race & ethnicity, age, poverty status, food security, housing security, problem paying medical bills, health insurance, region, metro, family structure, adult education level). All analyses were conducted with SAS 9.4 survey procedures.
Results
Among the sample, 8.1% had experienced head trauma, and 10.6% had been diagnosed with ADHD. A lower percentage of Non-Hispanic Blacks (NHB) experienced head trauma (5.5% vs. 9.6%) compared to Non-Hispanic Whites (NHW). A higher percentage of males (9.1% vs. 7.0%) had head trauma compared to females. The prevalence of head trauma was higher in minors 14-17 years (13.3% vs. 4.9%) compared to 5–10-year-old children. A higher percentage of those with head trauma (20.7% vs 9.8%) had ADHD compared to those without head trauma. After adjustment for other covariates, children with concussion were more likely to report ADHD (aOR = 1.81, 95% CI = 1.34, 2.45) compared to those without concussion.
Conclusion
NHWs, males, and minors aged between 14-17 years were more likely to report a history of head trauma. Head trauma was associated with ADHD even when adjusted for confounding variables. It has been speculated in the past that NHW predominance in head trauma may represent greater prevalence of reporting rather than an actual increase in head trauma in this group raising the question of whether lack of injury recognition in minority demographics represents a possible area of improvement for improved health outcomes. In addition, the positive correlation between ADHD and pediatric head trauma warrants further investigation to establish possible causal relationships
Epistatic impact of APOE and ACE2 genetic variants on SARS-CoV-2 and RAS dependent blood-brain barrier dysregulation.
No full textCoronavirus disease 2019 (COVID-19) is associated with respiratory and neurodegenerative symptoms, creating a need to understand the additional impact the pandemic might have on neurodegeneration and risk for neurodegenerative diseases, such as Alzheimer’s disease (AD) in aging populations post 2020. The blood-brain barrier (BBB) is an important interface that connects the periphery to the brain through the vasculature. When this protective barrier becomes dysregulated, the brain is vulnerable to infection, neuroinflammation, and cellular stress, which over time can lead to neurodegeneration and cognitive decline. The renin-angiotensin system (RAS) is an important regulator of vasculature via the activity of the hormone angiotensin II (Ang II). As a mediator of vasoconstrictive, oxidation, and inflammatory responses, its prolonged activity can be damaging and promote neurodegeneration at the BBB. Angiotensin-converting enzyme 2 (ACE2) is highly expressed in endothelial cells which cleaves Ang II into less harmful fragments to offset these potentially toxic effects. Genetic variants of ACE2 are increasingly considered risk factors for the development of vascular disorders (e.g. hypertension) due to their role in RAS-mediated dysregulation of body vasculature. Recent genetic studies have identified a relationship between genetic variants for ACE2, an obligate receptor for the severe acute respiratory syndrome coronavirus 2 (SCoV2), and increased risk and or/severity of COVID-19. Alzheimer’s disease (AD) is the greatest neurological risk among aging individuals and can be caused by both environmental & genetic risk factors. The strongest genetic risk factor for AD is variants in the apolipoprotein E gene (APOE), with the ɛ4 allele being associated with increased levels of amyloid β (Aβ), Tau proteins (p-Tau), neuroinflammation, and BBB permeability. A recent study by Wang et al also suggests a correlation between APOE ɛ4 and increased severity of COVID-19, suggesting some interplay between APOE and host factors related to SCoV2 infection. Furthermore, both ACE2 and APOE genetic variants disproportionately impact minority populations, highlighting a need to understand the health disparity of AD and COVID-19 risk across demographic groups. We hypothesize gene interactions (epistatic interactions) between genetic variants in ACE2 and APOE may exacerbate RAS-mediated BBB dysregulation, leading to increased AD phenotypes and SCoV2 neurological dysregulation. To address this hypothesis, we will create endothelial cells, astrocytes, and neurons containing APOE and ACE2 genetic variants of interest. These epistatic cells will be assessed for expression and functional changes related to BBB integrity. Using Ang II treatments and SCoV2 pseudo-virus models, we will assess the impact of COVID-19 and RAS on BBB integrity and functions. This study will help us understand the mechanisms and interplay of genetic risks for AD and COVID-19 related to RAS-mediated BBB dysregulation, potentially highlighting comorbidities among the aging population. By focusing on ACE2 variants disproportionately found in minority populations, we will provide knowledge surrounding two co-morbidities for neurodegeneration and elevate those at the highest risk for developing AD and/or COVID-19. Funding: This work is supported by the Neurobiology of Aging and Alzheimer’s Disease T32 Training Fellowship, and the IMSD Fellowship, Grant # 5 R25 GM125587-05 from the National Institutes of General Medical Sciences (NIGMS).Funding: This work is supported by the Neurobiology of Aging and Alzheimer’s Disease T32 Training Fellowship, and the IMSD Fellowship, Grant # 5 R25 GM125587-05 from the National Institutes of General Medical Sciences (NIGMS)
The Role of ECMO Cannulation on Pediatric Mortality
No full textPurpose:
Pediatric oncology, hemophagocytic histiocytosis (HLH), and bone marrow transplant (BMT) patients have variable degrees of underlying immune system suppression and/or dysregulation, putting them at high risk of developing serious illness and potentially requiring extracorporeal life support. Once supported by extracorporeal membrane oxygenation (ECMO), these patients are thought to have a higher mortality when compared to pediatric patients without these conditions. This study aims to describe specific approaches to ECMO support in this population, describing how these patients are cannulated, and how cannulae configuration potentially relates to outcomes.
Methods:
Retrospective data was collected from multiple institutions, identifying 176 pediatric patients with an oncologic, HLH, and/or BMT diagnosis who were supported by ECMO from 2010. This study evaluates pre-, on and post- ECMO characteristics including oncologic, HLH, and BMT diagnosis, status (active vs remission), reasons for ECMO, the type of ECMO, complications associated with ECMO support, and mortality.
Results:
Patients supported with veno-venous (VV) ECMO had the highest ECMO, ICU, and hospital survival compared to those supported with, or converted to, veno-arterial (VA) ECMO. Specifically, 67% of VV ECMO patients survived, while 53% of VA neck and 48% of VA femoral ECMO patients survived. Bleeding complications were high in all patients supported with ECMO. Intracranial hemorrhages occurred more frequently in patients with VA neck cannulation compared to femoral approaches, but even in patients on VV support without carotid cannulation, intra-cranial hemorrhage rates were high. Specifically, 27% of VA neck cannulated patients experienced a head bleed during ECMO, while 7% of VA femoral patients and 8% of VV ECMO patients did. Furthermore, 26% of VV ECMO patients required anticoagulation administration 48 hours prior to ECMO, while 94% of patients required anticoagulation during ECMO. 14% of VA neck cannulated patients and 10% of VA femoral cannulated patients required anticoagulation 48 hours prior to ECMO. However, 94% of VA neck cannulated patients and 86% of VA femoral cannulated patients required anticoagulation administration during ECMO. Lastly, femoral cannulation approaches resulted in limb ischemia with increased frequency.
Conclusions:
Pediatric patients requiring ECMO support during oncological processes require a variety of different cannulation strategies, each with their own associated risks. Overall patient morbidity including major bleeding events and ECMO complication rates are higher than can be expected compared to the average pediatric cohort