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Exploring the Association between Reproductive Health and Cognitive Function in Hispanic and Non-Hispanic Women: Insights from a HABS-HD Study
No full textPurpose: Alzheimer’s disease (AD), a progressive neurodegenerative disease with nearly two-thirds of dementia cases found in women, leads to memory loss, cognitive deficits, and behavioral changes, significantly impacting daily life. Given the disproportionate effect of AD on women, it is crucial to understand the risk factors, including reproductive health variables, that may contribute to the development of dementia and AD. Such understanding can provide valuable insights for dementia prevention and the development of personalized, gender-specific medicine. This study aimed to examine the association between reproductive health variables such as bilateral oophorectomy and pregnancy complications and cognitive performance in Hispanic and non-Hispanic women. Method: Self-reported data from 309 cognitively normal women (165 non-Hispanic white and 144 Hispanic) enrolled in the Health and Aging Brain Study: Health Disparities (HABS-HD) project, an epidemiological study of aging in community-based participants, were analyzed. Reproductive health variables examined included bilateral oophorectomy, pregnancy complications, number of pregnancies, and number of children. The cognitive assessment comprised neuropsychological test scores in five domains: memory (logical memory I & II), executive functioning (digit symbol substitution), attention (digit span), language (F-A-S), and global cognition (mini‐mental state examination). Linear regression statistical analyses were conducted, with ethnicity serving as a stratification variable. Results: Linear regression analyses revealed significant associations between reproductive health variables and cognitive domains, with distinct patterns observed among ethnic groups. Bilateral oophorectomy was linked to decreased immediate memory in Hispanic women (B=.176, SE=1.691, t=2.211, p=.029) and lower language performance in non-Hispanic white women (B=-.228, SE=1.980, t=-2.682, p=.008). Pregnancy complications were associated with poorer attention scores in Hispanic women (B=.163; SE=.000, T=2.203, p=.029). However, the number of children and pregnancies were not associated with cognitive performance. Conclusion: This study suggests that reproductive health variables, such as bilateral oophorectomy and pregnancy complications, were differentially associated with cognitive assessment performance among Hispanic and non-Hispanic women. A surgical history of bilateral oophorectomy may be associated with a decline in cognitive performance in both Hispanic and non-Hispanic women. Limitations, including sample size constraints and reliance on self-reported medical history, are acknowledged. Nonetheless, this study underscores the need for continued investigation into the intersection of reproductive health and cognitive function to inform targeted interventions and personalized healthcare approaches for dementia prevention across diverse communities
Spontaneous and evoked angiotensin II sniffer cell activity in the lamina terminalis in vitro
Get PDFAngiotensin II (ANG II) has been shown to have central nervous system effects. Although tissue renin-angiotensin systems (RAS) have been demonstrated in multiple tissues, the existence of a brain RAS is still a matter of debate. These studies test for angiotensin release from brain slices prepared from adult male Sprague-Dawley rats and male and female renin knock-out rats using Chinese hamster ovary cells modified to express both the angiotensin II type 1 receptor and a fluorescent calcium indicator. Sniffer cells were placed on the slices and calcium transients were measured from those located on or adjacent to the median preoptic nucleus with and without stimulation of the subfornical organ. Bath application of tetrodotoxin (1 microM) significantly attenuated spontaneous events while abolishing evoked sniffer cell activity. Bath application of dl-AP4 (10 microM, glutamatergic antagonist) did not affect either spontaneous or evoked release. Incubating the slices with fluorocitrate to inactive astrocytes did not influence sniffer cell activity in the MnPO. Pharmacological experiments indicate that ANG II release is largely both renin (aliskiren 10 microM) and ACE-1 (captopril 100 microM) dependent. However, experiments with brain slices prepared from male and female Renin knock-out rats suggest that alternative synthetic pathways may exist. Finally, these studies demonstrate that increases in ANG II release are observed following 7 days of chronic intermittent hypoxia. These studies suggest the existence of a tissue-specific RAS in the brain that involves canonical and alternative ANG II synthetic pathways and is upregulated in an animal model of sleep apnea.NEW & NOTEWORTHY These studies used Chinese hamster ovary cells that were cloned to express an angiotensin receptor (At1ra) and a calcium indicator (R-GECO) to detect the release of angiotensin from brain slices containing the lamina terminalis of rats. Some of the experiments use tissue from renin knockout rats. The results support the existence of an angiotensin system in the brain that may involve alternative synthetic pathways and is upregulated by intermittent hypoxia.This work was supported by National Institutes of Health Grants P01 HL088052 and R01 HL155977 (to G.E.F. and J.T.C.)
Three Pediatric cases of Bow hunter's Syndrome
No full textBackground: Bow hunter’s syndrome is a rare condition in which the vertebral artery is compressed during head rotation, potentially leading to recurrent vessel injury, dissection, and stroke. If gone unrecognized and left untreated, this syndrome can result in recurrent strokes. This case series describes three pediatric males diagnosed with bow hunter’s syndrome subsequently treated with cervical spinal fusion.
Case information: Three previously healthy male patients (median age: 8) with posterior circulation strokes were treated at a single institution. Demographics, stroke score, and treatments are summarized in Table 1. Two patients experienced recurrent strokes while the third underwent endovascular thrombectomy for an acute basilar artery occlusion. Acute medical treatment otherwise included anticoagulation and neck stabilization with cervical collar due to clinical suspicion of bow hunter's syndrome. The diagnosis was subsequently confirmed via dynamic conventional angiography performed with neck rotation. All three patients received an occiput to C3 vertebra fusion. Follow up imaging performed 3 months post fusion showed no evidence of additional strokes.
Conclusions: Bow hunter’s syndrome is a rare cause of posterior circulation strokes amongst children and should be included in the differential diagnosis of likely patients given the high likelihood of stroke recurrence. The diagnostic gold standard is dynamic conventional angiography to confirm vertebral artery compression. Cervical spine stabilization to limit neck rotation and anticoagulation may help reduce the risk of stroke recurrence until neurosurgical intervention can be pursued. Further studies are necessary to follow the long term outcomes of patients treated with cervical spinal fusion and develop a standard of care for bow hunter’s syndrome
Leveraging Graph Attention Mechanisms to Create an Explainable Multi-Function Machine Learning Model
No full textPurpose:
Identifying target-specific ligands is a difficult task, especially in cases where receptors display high structural similarity. Such is the case for metabotropic glutamate receptor subtype 2 (mGlu2) and metabotropic glutamate receptor subtype 3 (mGlu3), which are prime targets for various neurological treatments. However, signal transduction through these two receptors often yields opposing physiological function and differentially affect pathologies.
Methods:
Understanding the need to differentiate ligands based on their binding to mGlu2 and mGlu3, we employed a machine learning (ML) approach. The ML model performed three distinct tasks and leveraged transfer learning to inform each subsequent task. Task 1: Simple Classification was performed, as the ML model predicted if the ligands displayed selectivity for the mGlu2 or mGlu3 class. Task 2: Regression was performed, as the ML model estimated the IC50 values of individual input ligands. The classification weights from Task 1 were broadcasted into the attention layers of the ML model for Task 2, serving as a starting point. Task 3: Classification was performed, as the ML model sought to determine if a ligand displayed low or high potency for the target class. Classification weights and regression weights from previous tasks were broadcasted into the model.
Results:
The model yielded greater than 99% accuracy in the selectivity classification task, while also delivering satisfactory performance when predicting potency (72.80% error). The model yielded 83% accuracy in correctly identifying high potency mGlu2 ligands, as high potency mGlu2 compounds. Meanwhile, the algorithm displayed 75% accuracy in correctly identifying high potency mGlu3 ligands, as high potency mGlu3 compounds.
Conclusions:
This approach allows for prediction of multiple target properties using a single model. With access to other high-quality datasets, this model has the potential to apply to other ligand classes of interest, posing great potential for drug repurposing studies.This work is partially supported by a grant (#RP210046) from the Cancer Prevention and Research Institute of Texas (CPRIT)
Proof-of-concept studies with a computationally designed M(pro) inhibitor as a synergistic combination regimen alternative to Paxlovid
No full textAs the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M(pro)) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 muM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M(pro). In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.Funding of this work was provided by NIH GM032136 to W.L.J., NIH R24OD026440 to P.K., Yale CoReCT pilot funding for COVID to W.L.J. and K.S.A., NIH/NIAID 1U19AI171443 (K.S.A., Developmental Project), and T32 GM148333 to C.P. This research used resources AMX (Highly Automated Macromolecular Crystallography) and FMX (Frontier Microfocusing Macromolecular Crystallography) of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE- SC0012704. The Center for BioMolecular Structure is primarily supported by the NIH, National Institute of General Medical Sciences (NIGMS) through a Center Core P30 Grant (P30GM133893), and by the DOE Office of Biological and Environmental Research (KP1605010). This work is also based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH (P30 GM124165). The Eiger 16M detector on 24- ID- E is funded by an NIH- ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE- AC02- 06CH11357
Lifestyle Medicine Health Education and Intervention Program "Family Central"
No full textPurpose: Since the declaration of the obesity epidemic, children have been bearing the consequences of this public health crisis. Obesity is associated with adverse health outcomes, including type 2 diabetes, hypertension, cardiovascular disease, and cancer. Minority children and those of low socioeconomic status face higher rates of obesity. Children of obese parents are more likely to become overweight or obese themselves. Given this background, our goal was to determine the most effective ways to initiate and maintain healthful lifestyle behaviors that could prevent and reverse chronic diseases among socioeconomically disadvantaged families. The overall objective of this study was to measure the efficacy of text message platforms as an e-health intervention in delivering personalized health education content to parents of overweight/obese children by observing changes in their knowledge and attitudes of healthful lifestyle choices and the overall resultant health outcomes in their children. Methods: We customized an e-health intervention using the Mosio text message platform to address the six tenets of lifestyle medicine: nutrition, physical activity, stress management, sleep, tobacco cessation, and social connection. 19 adult caregivers of overweight/obese children from the UNTHSC Pediatric Mobile Clinic were enrolled. Caregivers were randomly assorted to an intervention group, who received 2+ educational briefs via the text message platform, Mosio, and a control group, who were referred to the patient portal for education, which is standard of care. Goal-setting behavior was examined by asking participants to set a weekly lifestyle goal and rate their confidence and motivation to achieve these goals on a scale of 1 to 10. Results: Results of this study were limited by low sample size and the effects of the COVID-19 pandemic on enrollment and retention. No statistically significant results were calculated between the intervention and control groups. Qualitative analysis yielded positive responses on an individual basis. Thematic analysis revealed the most significant utilization of SMART goal setting in the domains of physical activity, social connection, and stress management. Feedback from participants demonstrated that text message interventions helped them stay consistent with routine, avoid falling into bad habits, and create healthy habits for their family. Conclusions: While there were no statistically significant findings of this study, positive qualitative data suggests that the innovative Mosio interactive platform may serve as an ideal tool for inducing attitudinal, knowledge, and behavioral stage changes and, ultimately, acquisition of healthful lifestyle behaviors that combat chronic disease
ADHD Management in Adolescents and its Impact to Lower Incidence of Risky Sexual Behavior
No full textBackground: Attention-deficit/hyperactivity disorder (ADHD) is a neurological condition that is recognized by an ongoing pattern of inattention with or without hyperactivity and impulsivity that interferes with functioning or development. In 2020, it was reported that ADHD affects 9.6% of children ages 6-11 and 13.6% of adolescents ages 12-17. Therapies that include medications and/or interventions can aid in reducing symptoms and improving functioning. ADHD can be associated with sexual health outcomes such as higher rates of sexually transmitted infections and elevated rates of risky sexual behavior, like condomless sex. Adolescents with ADHD have an earlier age of intercourse, more lifetime sexual partners, higher rates of pregnancy, and higher rates of lifetime STIs. However, few studies have investigated sexual health promotion for those diagnosed with ADHD.
Purpose: The purpose of the present study is to explore current literature examining the relationship between ADHD and risky sexual behavior among adolescents.
Methods: A literature review process was conducted using PubMed and Google Scholar. The reference list of the relevant articles was screened for titles and abstracts containing the keywords: Attention-deficit hyperactivity disorder, ADHD, risky sexual behaviors, STI, Sexually Transmitted Infections, Syphilis, Chlamydia, human papillomavirus, herpes, sexually transmitted diseases. The retrospective search was limited to articles in English, from 2010 or later, and included the keywords listed above in the title or abstract. Articles reviewed included qualitative and quantitative studies and systematic reviews.
Results: In current literature, the incidence of risky sexual behavior has been shown to decrease with either stimulant medication therapy or behavioral therapy for comorbid psychiatric disorders like substance abuse. There are varying conclusions in published literature giving attributes of lowering risky sexual behavior through drug intervention and others to behavioral therapy. These different conclusions of effective therapy come from our limited current understanding of ADHD and the vast array of patient circumstances, such as the varying severity of ADHD, other psychiatric symptoms, and other behavioral influences in the patient's life. Through these studies, we can conclude that patient-centered approaches are pivotal in addressing risky sexual behaviors.
Conclusion: These results indicate that ADHD symptoms can be managed with stimulant medication; however, psychiatric therapy shows a promising effect on decreasing risky sexual behavior among adolescents with ADHD, especially for those presenting with psychiatric comorbidities. To decrease risky sexual behavior and its consequences, medication alone may not be effective for most adolescent patients with ADHD, and early intervention for adolescents with ADHD is essential. By translating these findings into clinical care, we can move toward reducing the negative sexual health outcomes experienced by adolescents with ADHD
Examination of Pregaming: Associations with Drinking Cognitions, Alcohol Use, and Negative Consequences at the Daily-Level among Adolescents and Young Adults
No full textResearch Appreciation Day Award Winner - School of Public Health, 2024 Research Award - 2nd PlacePurpose: While research indicates that adolescents and young adults pregame (i.e., drink before going to an event or gathering), it is unclear how daily-level cognitions relate to pregaming behavior and how pregaming relates to alcohol consumption and consequences. We examined (1) occasion-level associations between drinking cognitions (i.e., willingness, attitudes, injunctive norms) and pregaming among adolescents and young adults, and (2) occasion-level associations between pregaming with quantity of alcohol consumed and negative consequences. We also explored potential moderating effects of age on the above associations as well as the moderating effects of the number of drinks on the association between pregaming and the number of negative consequences on drinking days. Methods: Participants from Texas (age 15-25) were enrolled in a longitudinal ecological momentary assessment (EMA) study employing a 3-week EMA burst format (8 surveys weekly, up to 2 times per day). These bursts were scheduled quarterly over a span of 12 months. Participants who reported any drinking days were included in the present analyses. The final analytic sample included 490 individuals ages 15-25 (53.6% Female, 45.2% White Non-Hispanic, Mean Age = 21.2 SD = 2.7). Data were analyzed with mixed effects multilevel models. Results: Multilevel models revealed that occasion-level drinking cognitions (i.e., occasions with higher willingness to drink and more positive attitudes toward pregaming than one’s usual) were associated with greater likelihood of pregaming (Willingness: odds ratio (OR=1.80) = X, p < 0.0001; attitudes: OR = 1.54, p = 0.0009), whereas injunctive norms were not significantly associated. Compared to drinking days when people did not pregame, pregaming days were associated with consuming more drinks (rate ratio (RR) = 1.79, p < 0.0001). For consequences, the positive association between alcohol use and number of consequences was reduced on pregaming days (p of the interaction term between number of drinks and pregame = 0.04). Age was not a significant moderator in any models tested. Conclusion: This study contributes to the literature by examining occasion-level associations between drinking cognitions with pregaming and the role of pregaming in experiencing negative consequences. These findings can be used to inform individual-level intervention approaches by incorporating risk information about willingness and attitudes and their association with pregaming
Relationship Between Pain and Total Healthcare Expenditure in Elderly Osteoarthritis Patients: An Interpretable Machine Learning (ML) Investigation with eXtreme Gradient Boosting
No full textObjective:
Osteoarthritis (OA), a painful degenerative joint condition, affects over 32.5 million adults in the United States and one-fourth experience severe joint pain. In 2019, adults with OA had $45.4 billion more annual expenditures relative to those without OA. Although statistical methods have been utilized in studying the additional costs associated with pain among adults with OA, there is still a notable gap in understanding the relationship through the lens of ML methods. The objective of this study is to determine pain as a leading predictor of economic burden among older adults (age > 65 years) with OA using ML methods.
Methods:
We used data on older adults (age > 65 years) with OA (N = 1,640) from the 2021 Medical Expenditure Panel Survey (MEPS), a nationally representative survey of households in the US. Log-transformed total healthcare expenditures, which included payments by the insurers and the patients, represented the economic burden. We employed eXtreme Gradient Boosting (XGBoost) regression to determine key predictors. Global and local interpretations of associations were performed using a SHapley Additive exPlanation (SHAP), including a Partial Dependence Plot (PDP) for pain. Our predictive model utilized 24 features including biological (sex, age), race and ethnicity, clinical (pain, polypharmacy, physical and mental health status, and chronic conditions), and Social Determinants of Health (SDOH) such as marital status, education, poverty status, census region, insurance coverage, and prescription drug coverage. Chronic conditions included anxiety, depression, thyroid disease, diabetes, hypertension, coronary artery disease, cancer, hyperlipidemia, asthma, and chronic obstructive pulmonary disease. Pain interfering with regular work over the past four weeks was assessed using the Veterans Rand 12-item Health survey (VR-12), employing a Likert scale ranging from 0 (none) to 4 (extreme) to represent pain level.
Missing values for pain level were imputed using K-Nearest Neighbors (KNN) Imputation. The model building included 70% training and 30% testing split of the data and 3-fold cross-validations using Python 3.10.12. Model performance was evaluated with R-square, mean absolute error, and Root Mean Square Error (RMSE) using the test dataset.
Results:
Approximately, one in 4 adults with OA reported moderate to extreme pain. The top 3 predictors of healthcare expenditures were: polypharmacy, physical health, and pain level. Higher pain levels and polypharmacy were associated with higher total expenditures. Excellent physical health was associated with lower total healthcare expenditures. Additionally, the SHAP PDP suggested a linear relationship between pain levels and total expenditures. Model performance was modest with a mean absolute error (1.086), RMSE (1.736), and R-square (0.452) for total expenditures.
Conclusion:
Higher pain levels predicted higher economic burden in older adults with OA. Effective management of pain may be a pathway to reduce the economic burden of OA. As polypharmacy was a leading predictor of healthcare expenditures, this model underscores the importance of reducing polypharmacy use in older adults with medication utilization review and management
Type II Diabetes Mellitus and COVID-19: A Case Series Exploring Insulin Management in Patients from Two Family Medicine Clinics
No full textPurpose:
About 37 million Americans have diabetes and out of this population, over 90% of them have type 2 diabetes. An estimated $200 billion per year is spent on managing this disease.
There is limited data on factors that could explain whether diabetic patients experienced better HgbA1C control during the COVID-19 pandemic. The relationship between diabetes medications (DM) and diabetes outcomes during the COVID era is not well-characterized. In this case series, we aimed to evaluate type II diabetes outcomes pre-COVID-19 vs. COVID-19 era.
Methods:
This case series was conducted in two family medicine clinics that included patients with type II diabetes. The following data from all patients at least 18 years or older on 3/1/2019 were extracted: hemoglobin A1c, medication prescriptions (insulin use patterns, non-insulin prescription patterns oral diabetes medications), and number of prescriptions discontinued. We followed a guidance statement from the American College of Physicians in terms of how outpatient diabetes is managed and used A1c of less than 8% as the threshold to assess the clinical outcomes for this outpatient population. A1c values were compared between two cohorts, a pre-COVID-19 cohort (March 1, 2019-March 13, 2020) and a COVID-19 era cohort (March 14, 2020-March 31, 2021). An analysis was performed on all patients whose A1c control status was changed, defined as the last A1c in each of the two study periods changed either from > 8% to =< 8% (got better), or from =< 8% to > 8% (got worse). For each of the patients with A1c control status change, we identified patterns of diabetic medication prescriptions during the COVID-19 era: (1) insulin and other DM medications, (2) no insulin but other DM medication, or (3) insulin-only prescriptions.
Results:
Eighty-one patients fulfilled the study criteria. Fifty-three patients got better, and 28 patients got worse. Of the 52 cases, 28 got better due to insulin use. Eighteen of these patients discontinued their insulin at some point during the study period. Of the 28 patients that got worse. Out of the 26 cases, 10 of them got worse while on insulin. Nine out of 10 of these patients discontinued their insulin at some point during the study period. Only 1 patient was on their insulin medication throughout the entire study. Out of the 28 cases with some form of diabetes management therapy, 16 of them were on non-insulin medications. Thirteen out of 16 of these patients discontinued at least one of their medications at some point during the study period. 23 out of 26 patients discontinued at least one prescription.
Conclusion:
This case series demonstrates how two family medicine clinics treated diabetic patients during a pandemic. The majority were using insulin throughout COVID-19 era and did experience changes to their medication profile with other DM medications. A1c levels did change significantly from pre-COVID-19 to COVID-19 era, while prescriptions for diabetic treatment were reduced. This study identified the importance of keeping insulin and other DM medication prescriptions through a pandemic and how COVID-19 impacted Hemoglobin A1C and overall diabetes care.University of Texas Arlington and the North Texas Regional Institutional Review Boards, [2019-163]