Unfavorable social determinants of health and mortality risk by cardiovascular disease status: Findings from a National Study of United States Adults.

BACKGROUND: The association between cumulative burden of unfavorable social determinants of health (SDoH) and all-cause mortality has not been assessed by atherosclerotic cardiovascular disease (ASCVD) status on a population level in the United States. METHODS: We assessed the association between cumulative social disadvantage and all-cause mortality by ASCVD status in the National Health Interview Survey, linked to the National Death Index. RESULTS: In models adjusted for established clinical risk factors, individuals experiencing the highest level of social disadvantage (SDoH-Q4) had over 1.5 (aHR = 1.55; 95%CI = 1.22, 1.96) and 2-fold (aHR = 2.21; 95% CI = 1.91, 2.56) fold increased risk of mortality relative to those with the most favorable social profile (SDoH-Q1), respectively for adults with and without ASCVD; those experiencing co-occurring ASCVD and high social disadvantage had up to four-fold higher risk of mortality (aHR = 3.81; 95%CI = 3.36, 4.32). CONCLUSIONS: These findings emphasize the importance of a healthcare model that prioritizes efforts to identify and address key social and environmental barriers to health and wellbeing, particularly in individuals experiencing the double jeopardy of clinical and social risk.

Development and Application of a Multidimensional Database for the Detection of Quaternary Ammonium Compounds and Their Phase I Hepatic Metabolites in Humans.

The COVID-19 pandemic has led to significantly increased human exposure to the widely used disinfectants quaternary ammonium compounds (QACs). Xenobiotic metabolism serves a critical role in the clearance of environmental molecules, yet limited data are available on the routes of QAC metabolism or metabolite levels in humans. To address this gap and to advance QAC biomonitoring capabilities, we analyzed 19 commonly used QACs and their phase I metabolites by liquid chromatography-ion mobility-tandem mass spectrometry (LC-IM-MS/MS). In vitro generation of QAC metabolites by human liver microsomes produced a series of oxidized metabolites, with metabolism generally occurring on the alkyl chain group, as supported by MS/MS fragmentation. Discernible trends were observed in the gas-phase IM behavior of QAC metabolites, which, despite their increased mass, displayed smaller collision cross-section (CCS) values than those of their respective parent compounds. We then constructed a multidimensional reference SQLite database consisting of m/z, CCS, retention time (rt), and MS/MS spectra for 19 parent QACs and 81 QAC metabolites. Using this database, we confidently identified 13 parent QACs and 35 metabolites in de-identified human fecal samples. This is the first study to integrate in vitro metabolite biosynthesis with LC-IM-MS/MS for the simultaneous monitoring of parent QACs and their metabolites in humans.

Association of cardiovascular risk profile with premature all-cause and cardiovascular mortality in US adults: findings from a national study.

OBJECTIVE: To assess the association between cardiovascular risk factor (CRF) profile and premature all-cause and cardiovascular disease (CVD) mortality among US adults (age < 65). METHODS: This study used data from the National Health Interview Survey from 2006 to 2014, linked to the National Death Index for non-elderly adults aged < 65 years. A composite CRF score (range = 0-6) was calculated, based on the presence or absence of six established cardiovascular risk factors: hypertension, diabetes, hypercholesterolemia, smoking, obesity, and insufficient physical activity. CRF profile was defined as "Poor" (≥ 3 risk factors), "Average" (1-2), or "Optimal" (0 risk factors). Age-adjusted mortality rates (AAMR) were reported across CRF profile categories, separately for all-cause and CVD mortality. Cox proportional hazard models were used to evaluate the association between CRF profile and all-cause and CVD mortality. RESULTS: Among 195,901 non-elderly individuals (mean age: 40.4 ± 13.0, 50% females and 70% Non-Hispanic (NH) White adults), 24.8% had optimal, 58.9% average, and 16.2% poor CRF profiles, respectively. Participants with poor CRF profile were more likely to be NH Black, have lower educational attainment and lower income compared to those with optimal CRF profile. All-cause and CVD mortality rates were three to four fold higher in individuals with poor CRF profile, compared to their optimal profile counterparts. Adults with poor CRF profile experienced 3.5-fold (aHR: 3.48 [95% CI: 2.96, 4.10]) and 5-fold (aHR: 4.76 [3.44, 6.60]) higher risk of all-cause and CVD mortality, respectively, compared to those with optimal profile. These results were consistent across age, sex, and race/ethnicity subgroups. CONCLUSIONS: In this population-based study, non-elderly adults with poor CRF profile had a three to five-fold higher risk of all-cause and CVD mortality, compared to those with optimal CRF profile. Targeted prevention efforts to achieve optimal cardiovascular risk profile are imperative to reduce the persistent burden of premature all-cause and CVD mortality in the US.

Proton versus photon adjuvant radiotherapy: a multicenter comparative evaluation of recurrence following spinal chordoma resection.

OBJECTIVE: Chordomas are rare tumors of the skull base and spine believed to arise from the vestiges of the embryonic notochord. These tumors are locally aggressive and frequently recur following resection and adjuvant radiotherapy. Proton therapy has been introduced as a tissue-sparing option because of the higher level of precision that proton-beam techniques offer compared with traditional photon radiotherapy. This study aimed to compare recurrence in patients with chordomas receiving proton versus photon radiotherapy following resection by applying tree-based machine learning models. METHODS: The clinical records of all patients treated with resection followed by adjuvant proton or photon radiotherapy for chordoma at Mayo Clinic were reviewed. Patient demographics, type of surgery and radiotherapy, tumor recurrence, and other variables were extracted. Decision tree classifiers were trained and tested to predict long-term recurrence based on unseen data using an 80/20 split. RESULTS: Fifty-three patients with a mean ± SD age of 55.2 ± 13.4 years receiving surgery and adjuvant proton or photon therapy to treat chordoma were identified; most patients were male. Gross-total resection was achieved in 54.7% of cases. Proton therapy was the most common adjuvant radiotherapy (84.9%), followed by conventional or external-beam radiation therapy (9.4%) and stereotactic radiosurgery (5.7%). Patients receiving proton therapy exhibited a 40% likelihood of having recurrence, significantly lower than the 88% likelihood observed in those treated with nonproton therapy. This was confirmed on logistic regression analysis adjusted for extent of tumor resection and tumor location, which revealed that proton adjuvant radiotherapy was associated with a decreased risk of recurrence (OR 0.1, 95% CI 0.01-0.71; p = 0.047) compared with photon therapy. The decision tree algorithm predicted recurrence with an accuracy of 90% (95% CI 55.5%-99.8%), with the lowest risk of recurrence observed in patients receiving gross-total resection with adjuvant proton therapy (23%). CONCLUSIONS: Following resection, adjuvant proton therapy was associated with a lower risk of chordoma recurrence compared with photon therapy. The described machine learning models were able to predict tumor progression based on the extent of tumor resection and adjuvant radiotherapy modality used.

Cardiovascular disease in Filipino American men and women: A 2023 update.

With more than 4.2 million people, Filipino Americans are the third largest Asian group in the US and the largest Southeast Asian group in the country. Despite relatively favorable average socioeconomic indicators compared to the general US population, Filipino Americans face a significant burden of traditional cardiovascular risk factors, particularly among men. Moreover, Filipino Americans have high rates of cardiovascular death, often occurring at a younger age compared to other minority groups and Non-Hispanic White adults. In view of these trends, in 2010 the American Heart Association designated Filipino Americans as a high cardiovascular risk group. Despite this, in 2023, Filipino Americans remain underrepresented in landmark cardiovascular cohort studies and are often over looked as a group at increased cardiovascular risk. In this updated narrative review, we summarize the current state of knowledge about the burden of cardiovascular risk factors and diseases experienced by the Filipino American population. Our aim is to inform enhanced clinical, population, and policy-level prevention interventions and boost research in this space.

Defining Vascular Deserts to Describe Access to Care and Identify Sites for Targeted Limb Preservation Outreach.

BACKGROUND: Access to care plays a critical role in limb salvage in chronic limb-threatening ischemia (CLTI). A "medical desert" describes a community lacking access to medical necessities, resulting in increased morbidity and mortality. We sought to describe vascular deserts, which we defined as regions with decreased access to specialty care. METHODS: All California providers performing vascular surgery procedures were identified through online provider and health care facility searches. Facility participation in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) lower extremity bypass (LEB) and peripheral vascular intervention (PVI) modules was also determined. Addresses were geocoded with a 30-mile surrounding buffer using ArcGIS (Geographic information systems), creating maps based on care type, including all providers performing vascular procedures, board-certified vascular surgeons, and facilities participating in VQI modules. Public census data overlayed on the maps demonstrated population composition in desert versus nondesert regions. Subsequently, data from the Healthy Places Index (HPI) was overlayed, providing data regarding 25 social factors, comprising an overall HPI score and percent, with lower scores corresponding to poorer health and outcomes. RESULTS: Maps depicting care regions demonstrated decreased provider coverage with increasing specialty care, with the VQI provider map showing the most prominent "desert" regions. When comparing nondesert versus desert regions by care type, demographics including race, the percentage of the population 200% below the poverty line, and the rate of uninsured residents were described. Social determinants of health were then described for desert and nondesert regions by care type, including the HPI percentage and specific domain factors. The percentage of uninsured residents was significant only in the desert and nondesert areas served by board-certified vascular surgeons (19.6 vs. 16.8%, P < 0.001). The mean HPI percentile was significantly lower in board-certified provider and VQI facility deserts than nondeserts (50.48% vs. 40.65%, P < 0.001 and 52.68% vs. 43.12%, P < 0.001, respectively). The economic and education factor percentiles were significantly lower in all desert populations, while the housing, social, and pollution factors were significantly higher in nondesert regions. Health care access, transportation, and neighborhood factor percentiles were significantly lower in board-certified and VQI facility deserts than in the nondesert areas. CONCLUSIONS: Access to vascular care plays a significant role in limb salvage. Through mapping vascular deserts, patient demographics, and social factors in desert regions are better understood, and areas that would benefit most from targeted outreach and limb preservation programs for CLTI are identified.

A Snapshot on Oral and Maxillofacial Surgery Resident Scholarly Activity: Can We Do Better?

BACKGROUND: The Commission on Dental Accreditation (CODA) requires oral and maxillofacial surgery (OMS) residents to engage in scholarly activity. Currently, it is unknown how this mandate translates into research output. PURPOSE: The purpose of this study was to quantify the research output of OMS residents. In addition, we sought to identify characteristics associated with resident productivity. STUDY DESIGN: This was a cross-sectional study of all OMS residents during the 2021-2022 academic year. Attempts were made to obtain resident rosters from every CODA-accredited OMS program. Resident names were searched in PubMed (https://pubmed.ncbi.nlm.nih.gov/) to identify peer-reviewed publications. Postgraduate year (PGY), program name, and total publication count during residency were recorded for each resident. Academic status and fellowship affiliation of the residency program were also included. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: The primary predictor was PGY level of each resident. MAIN OUTCOME VARIABLE: The main outcome variable was the publication count of each OMS resident during the 2021-2022 academic year. COVARIATES: The covariates were the academic status and the fellowship affiliation of the residency program. A program was determined academic if they were associated with a dental or medical school. A program was determined fellowship associated if they had any CODA approved fellowship. ANALYSES: Simple bivariate comparisons were performed using Wilcoxon signed-rank tests. RESULTS: Complete resident rosters were identified for 87 residency programs. One thousand one hundred thirty two residents were queried and a total of 548 peer-reviewed publications were identified. There was a mean of 6.30 publications per program and 0.43 publications per resident. More than half of all residents had no identifiable publication. PGY5 residents averaged the most publications per resident (1.45) followed by PGY6 (1.04) and PGY4 (0.63). Academic programs had significantly more publications per resident than nonacademic programs (median of 3.00 vs 0.00, P = .02). Programs with a fellowship association also had more publications per resident (median of 5.00 vs 2.00, P < .01). CONCLUSION: Current CODA research requirements do not translate into resident publications. Publication counts appeared to slightly increase with PGY level; however, OMS resident productivity still lags far behind that of other surgical subspecialties.

Opportunities for using in silico-based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors.

Therapeutic drug monitoring (TDM) involves frequent measurements of drug concentrations to ensure levels remain within a therapeutic window, and it is especially useful for drugs with narrow therapeutic indices or extensive interindividual pharmacokinetic variability. This technique has never been applied to immuno-oncology drugs, but, given recent examinations of clinical data (both exposure and response) on a number of these drugs, further investigations into TDM may be justified to reduce costs as well as potentially reducing the severity and/or duration of immune-related adverse events. Specifically, all but one of the approved PD-1 and PD-L1 inhibitors (pembrolizumab, nivolumab, cemiplimab-rwlc, atezolizumab, avelumab, durvalumab) have been shown to exhibit a plateaued exposure-response (E-R) curve at doses evaluated extensively to date, as well as time-dependent changes in drug exposure. Furthermore, responders have a greater decrease in drug clearance over time and would, therefore, have supratherapeutic serum concentrations. With frequent trough measurements, it is possible to use pharmacokinetic modelling and simulation to estimate drug clearance via Bayesian methods. Based on patient-specific estimates for clearance, optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels, especially as the clearance of the drug decreases over time. This review will comprehensively discuss each of the FDA approved PD-1, PD-L1/2 and CTLA-4 inhibitors regarding their indications and current recommended dosing, with evidence supporting the investigation of these types of TDM strategies.

Role of resting state MRI temporal latency in refractory pediatric extratemporal epilepsy lateralization.

BACKGROUND: Pediatric epilepsy affects 0.5-1% of children, with 10-30% of these children refractory to medical anticonvulsant therapy and potentially requiring surgical intervention. Analysis of resting state functional MRI (rsMRI) signal temporal differences (latency) has been proposed to study the pathological cognitive processes. PURPOSE/HYPOTHESIS: To quantitatively and qualitatively analyze the correlation of rsMRI signal latency to pediatric refractory extratemporal epilepsy seizure foci lateralization. STUDY TYPE: Retrospective review. POPULATION: With Institutional Review Board approval, rsMRI and anatomical MRI scans were obtained from 38 registered pediatric epilepsy surgery patients from Washington University and 259 healthy control patients from the ADHD-200 dataset. FIELD STRENGTH/SEQUENCE: 3 T echo planar imaging (EPI) blood oxygenation level-dependent (BOLD) sequence. ASSESSMENT: The images were transformed to pediatric atlases in Talairach space. Preoperative voxelwise latency maps were generated with parabolic interpolation of the rsMRI signal lateness or earliness when compared with the global mean signal (GMS) using cross-covariance analysis. STATISTICAL TESTS: Latency z-score maps were created for each epilepsy patient by voxelwise calculation using healthy control mean and standard deviation maps. Voxelwise hypothesis testing was performed via multiple comparisons corrected (false discovery and familywise error rate) and uncorrected methods to determine significantly late and early voxels. Significantly late and/or early voxels were counted for the right and left hemisphere separately. The hemisphere with the greater proportion of significantly late and/or early voxels was hypothesized to contain the seizure focus. Preoperative rsMRI latency analysis hypotheses were compared with postoperative seizure foci lateralization determined by resection images. RESULTS: Preoperative rsMRI latency analysis correctly identified seizure foci lateralization of 64-85% of postoperative epilepsy resections with the proposed methods. RsMRI latency lateralization analysis was 77-100% sensitive and 58-79% specific. In some patients, qualitative analysis yielded preoperative rsMRI latency patterns specific to procedure performed. DATA CONCLUSION: Preoperative rsMRI signal latency of pediatric epilepsy patients was correlated with seizure foci lateralization. J. Magn. Reson. Imaging 2019;49:1347-1355.

The unseen patient: competing priorities between patients and providers when cannabis is used in pregnancy, a qualitative study.

Objectives: This study aimed to explore competing priorities when cannabis is used during pregnancy from the perspective of providers and Black and Latina people. Maternal cannabis use is increasingly common, but patients and providers alike struggle to navigate it. Methods: This pilot used qualitative, constructivist ground theory methods to conduct semi-structured, remote interviews between 16 November 2021, and 7 February 2022 with 7 Black and Latina people who used cannabis during pregnancy, and 10 providers between 15 March 2022, and 6 April 2022, all of who were in Southern California, U.S. Results: We identified three main findings: (1) Providers reported barriers to caregiving and relationship building with patients due to maternal cannabis use stigma, (2) Providers prioritized the fetus despite patients' current health system challenges that drove cannabis use, and (3) Both patients and providers engaged in personal research beyond the healthcare system to better understand maternal cannabis use. Discussion: Our findings indicate that challenges exist between people who use cannabis during pregnancy and providers. Both groups need accurate, sociocultural sensitive information about maternal cannabis use via a harm reduction lens.

Analysis of demographics and the impact of adjuvant radiotherapy on a nationwide cohort of patients with high-grade spinal meningiomas.

Background: Although typically benign, 5% of spinal meningiomas (SMs) present with higher-grade features (World Health Organization grades 2 and 3). High-grade SMs are poorly studied and the role of adjuvant radiotherapy in their management remains controversial. We hence aimed to study the demographic characteristics of this rare tumor and investigate the outcomes associated with the use of surgery with adjuvant therapy in contrast to surgery alone. Methods: The National Cancer Database was queried for patients with SMs from 2004 to 2017. Basic statistics were used to identify differences between low- and high-grade tumors in terms of baseline characteristics. Surgery with and without adjuvant radiotherapy were compared after (1:1) propensity-score matching. Kaplan-Meier survival analysis was conducted to study overall survival. All analyses were performed on R. Results: A total of 13 184 patients diagnosed with SMs were included, of whom only 5% (n = 669) had high-grade SMs. Patients with high-grade SMs presented at a younger median age (57 years [IQR: 44-68] versus 65 years [54-75]; P < .001) and were more commonly males (33% vs 20%; P < .001). After propensity-score matching, survival analysis revealed similar overall survival outcomes in patients with high-grade SM undergoing both surgery and radiotherapy as compared to those only receiving surgery (P = .19). Conclusions: This study reveals major demographic differences between high- and low-grade SMs. There were no benefits associated with the use of adjuvant radiotherapy. However, due to confounding, overall survival outcomes between patients receiving surgery alone and those receiving surgery with adjuvant radiotherapy are not causally interpretable.

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature.

PURPOSE: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. EXPERIMENTAL DESIGN: Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. RESULTS: We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide. CONCLUSIONS: In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

Are We the Problem? A Call to Action for Addressing Institutional Challenges to Engaging Community Partners in Research.

Community-engaged research (CEnR) is a potent tool for addressing health inequities and fostering equitable relationships among communities, researchers, and institutions. CEnR involves collaboration throughout the research process, demonstrating improvements in study recruitment and retention, intervention efficacy, program sustainability, capacity building among partners, and enhanced cultural relevance. Despite the increasing demand for CEnR, institutional policies, particularly human participation protection training (HPP), lag behind, creating institutional barriers to community partnerships. Here, we highlight challenges encountered in our ongoing study, Fostering Opportunities in Research through Messaging and Education (FOR ME), focused on promoting shared decision-making around clinical trial participation among Black women diagnosed with breast cancer. Grounded in CEnR methods, FOR ME has a partnership with a community-based organization (CBO) that addresses the needs of Black women with breast cancer. Our CBO partner attempted to obtain HPP training, which was administratively burdensome and time-consuming. As CEnR becomes more prevalent, academic and research institutions, along with researchers, are faced with a call to action to become more responsive to community partner needs. Accordingly, we present a guide to HPP training for community partners, addressing institutional barriers to community partner participation in research. This guide outlines multiple HPP training pathways for community partners, aiming to minimize institutional barriers and enhance their engagement in research with academic partners.

Pharmacist-led review of empagliflozin and ertugliflozin following formulary update.

OBJECTIVES: To evaluate the appropriateness of the medication management for anyone who might have been affected by the Horizon New Jersey Health Medicaid Health Maintenance Organization (HNJH Medicaid HMO) formulary update from empagliflozin to ertugliflozin and to then optimize drug selection and monitoring. STUDY DESIGN: This is a single-center, 2-phase, pilot project led by 2 pharmacy students and the lead clinical pharmacist at a federally qualified health center in Trenton, New Jersey. METHODS: The primary outcome of the study is the number and percentage of patients whose prescription was changed inappropriately from empagliflozin to ertugliflozin. Secondary outcomes include the number and percentage of patients whose prescription was changed inappropriately because of failure to consider cardiovascular history and/or missed renal function checks and whether pharmacists were able to optimize therapy. Data were generated from electronic health record reports and analyzed in Microsoft Excel. RESULTS: A total of 126 unique patients were identified as receiving empagliflozin and/or ertugliflozin and 16 patients were switched from empagliflozin to ertugliflozin, all of whom had HNJH Medicaid HMO. Thirteen of the 16 (81.3%) patients were managed inappropriately based on their history of cardiovascular disease or inappropriate renal monitoring. Pharmacists recommended 22 interventions for patients who received empagliflozin and/or ertugliflozin, and all recommendations were accepted by providers. CONCLUSIONS: Following the HNJH Medicaid HMO's coverage update from empagliflozin to ertugliflozin, some patients received inappropriate therapy and providers accepted clinical pharmacists' recommendations to optimize therapy.

Race and Ethnicity Reporting and Enrollment Disparities in Clinical Trials Leading to FDA Approvals for Breast Cancer Between 2010 and 2020.

BACKGROUND: We determined the race and ethnicity demographics and reporting trends of clinical trials leading to Food and Drug Administration (FDA) approvals for breast cancer. METHODS: We collected enrollment and reporting data from clinical trials leading to FDA novel and new use approvals for breast cancer from 2010 to 2020 from Drugs@FDA, ClinicalTrials.gov, and associated journal manuscripts. Enrollment demographics were compared to the US cancer population estimates obtained using National Cancer Institute-Surveillance, Epidemiology, and End Results and 2010 US Census databases. RESULTS: Seventeen drugs received approval based on 18 clinical trials with a total enrollment of 12,334. For approvals from 2010 to 2015 and from 2016 to 2020, there was no significant difference in race (80% vs. 91.6%, P = .34) or ethnicity reporting (20% vs. 33.3%, P = .5) on ClinicalTrials.Gov, manuscripts, and FDA labels. For trials that reported race and ethnicity, White, Asian, Black, and Hispanic patients represented 73.8%, 16.4%, 3.7%, and 10.4% of trial participants. Relative to their US cancer incidence, Black (31% of expected) patients were underrepresented compared with White (90% of expected), Hispanic (115%), and Asian (327% of expected) patients. CONCLUSION: We observed no significant difference in race and ethnicity reporting in pivotal clinical trials leading to FDA approval for breast cancer from 2010 to 2020. Black patients were underrepresented in these pivotal trials relative to White, Hispanic, and Asian patients. Ethnicity reporting remained low throughout the study period. Innovative approaches are needed to ensure equitable benefit of novel therapeutics.

Volumetric Compression Shifts Rho GTPase Balance and Induces Mechanobiological Cell State Transition.

During development and disease progression, cells are subject to osmotic and mechanical stresses that modulate cell volume, which fundamentally influences cell homeostasis and has been linked to a variety of cellular functions. It is not well understood how the mechanobiological state of cells is programmed by the interplay of intracellular organization and complex extracellular mechanics when stimulated by cell volume modulation. Here, by controlling cell volume via osmotic pressure, we evaluate physical phenotypes (including cell shape, morphodynamics, traction force, and extracellular matrix (ECM) remodeling) and molecular signaling (YAP), and we uncover fundamental transitions in active biophysical states. We demonstrate that volumetric compression shifts the ratiometric balance of Rho GTPase activities, thereby altering mechanosensing and cytoskeletal organization in a reversible manner. Specifically, volumetric compression controls cell spreading, adhesion formation, and YAP nuclear translocation, while maintaining cell contractile activity. Furthermore, we show that on physiologically relevant fibrillar collagen I matrices, which are highly non-elastic, cells exhibit additional modes of cell volume-dependent mechanosensing that are not observable on elastic substrates. Notably, volumetric compression regulates the dynamics of cell-ECM interactions and irreversible ECM remodeling via Rac-directed protrusion dynamics, at both the single-cell level and the multicellular level. Our findings support that cell volume is a master biophysical regulator and reveal its roles in cell mechanical state transition, cell-ECM interactions, and biophysical tissue programming.

Association of Income Status with Stroke in Non-Elderly Adults in the United States, 2012-2018.

Stroke is becoming increasingly prevalent among the non-elderly adults (<65 years of age) in the United States. Using the National Health Interview Survey database from 2012 to 2018, we examined the association of traditional risk factors, sociodemographic, cardiovascular risk factor (CRF) profile, family income, and educational attainment in young (18-44 years) and middle-aged (45-64 years) adults. CRF profiles were defined by the number of traditional risk factors with "Poor" (≥4 risk factors), "Average," or "Optimal" (0-1). The study included 168,862 non-elderly adults (55% in young adults). Overall prevalence of stroke was 1.83% among the non-elderly (0.64% and 3.31% in young- and middle-aged adults, respectively). Adults with low family income, lesser education, and who were Non-Hispanic Blacks were more likely to have stroke. Those with poor CRF profiles exhibited a 3-4 times higher odds of stroke compared to those with optimal CRF profiles. Lower income status coupled with a poor CRF profile augmented the prevalence of stroke in non-elderly adults. This national survey of non-elderly US adults showed a correlation between lower income and education, both factors of SES, and stroke. When viewed together, there was an increasing stroke burden in the non-elderly with worsening CRF profile, income status, and educational attainment.

Self-assembly of mesoscale collagen architectures and applications in 3D cell migration.

3D in vitro tumor models have recently been investigated as they can recapitulate key features in the tumor microenvironment. Reconstruction of a biomimetic scaffold is critical in these models. However, most current methods focus on modulating local properties, e.g. micro- and nano-scaled topographies, without capturing the global millimeter or intermediate mesoscale features. Here we introduced a method for modulating the collagen I-based extracellular matrix structure by disruption of fibrillogenesis and the gelation process through mechanical agitation. With this method, we generated collagen scaffolds that are thickened and wavy at a larger scale while featuring global softness. Thickened collagen patches were interconnected with loose collagen networks, highly resembling collagen architecture in the tumor stroma. This thickened collagen network promoted tumor cell dissemination. In addition, this novel modified scaffold triggered differences in morphology and migratory behaviors of tumor cells. Altogether, our method for altered collagen architecture paves new ways for studying in detail cell behavior in physiologically relevant biological processes. STATEMENT OF SIGNIFICANCE: Tumor progression usually involves chronic tissue damage and repair processes. Hallmarks of tumors are highly overlapped with those of wound healing. To mimic the tumor milieu, collagen-based scaffolds are widely used. These scaffolds focus on modulating microscale topographies and mechanics, lacking global architecture similarity compared with in vivo architecture. Here we introduced one type of thick collagen bundles that mimics ECM architecture in human skin scars. These thickened collagen bundles are long and wavy while featuring global softness. This collagen architecture imposes fewer steric restraints and promotes tumor cell dissemination. Our findings demonstrate a distinct picture of cell behaviors and intercellular interactions, highlighting the importance of collagen architecture and spatial heterogeneity of the tumor microenvironment.