Now showing items 1-20 of 18798

    • Plasma neurofilament light as blood marker for poor brain white matter integrity among middle-aged urban adults.

      Beydoun, May A; Noren Hooten, Nicole; Weiss, Jordan; Maldonado, Ana I; Beydoun, Hind A; Katzel, Leslie I; Davatzikos, Christos; Gullapalli, Rao P; Seliger, Stephen L; Erus, Guray; et al. (2022-10-21)
      Plasma neurofilament light chain (NfL)'s link to dementia may be mediated through white matter integrity (WMI). In this study, we examined plasma NfL's relationships with diffusion tensor magnetic resonance imaging markers: global and cortical white matter fractional anisotropy (FA) and trace (TR). Plasma NfL measurements at 2 times (v1: 2004-2009 and v2: 2009-2013) and ancillary dMRI (vscan: 2011-2015) were considered (n = 163, mean time v1 to vscan = 5.4 years and v2 to vscan: 1.1 years). Multivariable-adjusted regression models, correcting for multiple-testing revealed that, overall, higher NfLv1 was associated with greater global TR (β ± SE: +0.0000560 ± 0.0000186, b = 0.27, p = 0.003, q = 0.012), left frontal WM TR (β ± SE: + 0.0000706 ± 0.0000201, b ± 0.30, p = 0.001, q = 0.0093) and right frontal WM TR (β ± SE: + 0.0000767 ± 0.000021, b ± 0.31, p < 0.001, q = 0.0093). These associations were mainly among males and White adults. Among African American adults only, NfLv2 was associated with greater left temporal lobe TR. "Tracking high" in NfL was associated with reduced left frontal FA (Model 2, body mass index-adjusted: β ± SE:-0.01084 ± 0.00408, p = 0.009). Plasma NfL is a promising biomarker predicting future brain white matter integrity (WMI) in middle-aged adults.
    • A Simple One-Parameter Percent Dissolved Versus Time Dissolution Equation that Accommodates Sink and Non-sink Conditions via Drug Solubility and Dissolution Volume.

      Polli, James E (2022-11-17)
      In vitro dissolution generally involves sink conditions, so dissolution equations generally do not need to accommodate non-sink conditions. Greater use of biorelevant media, which are typically less able to provide sink conditions than pharmaceutical surfactants, necessitates equations that accommodate non-sink conditions. One objective was to derive an integrated, one-parameter dissolution equation for percent dissolved versus time that accommodates non-sink effects via drug solubility and dissolution volume parameters, including incomplete solubility. A second objective was to characterize the novel equation by fitting it to biorelevant dissolution profiles of tablets of two poorly water-soluble drugs, as well as by conducting simulations of the effect of dose on dissolution profile. The Polli dissolution equation was derived, [Formula: see text], where M0 is the drug dose (mg), cs is drug solubility (mg/ml), V is dissolution volume (ml), and kd is dissolution rate coefficient (ml/mg per min). Maximum allowable percent dissolved was determined by drug solubility and not a fitted extent of dissolution parameter. The equation fit tablet profiles in the presence and absence of sink conditions, using a single fitted parameter, kd, and where solubility ranged over a 1000-fold range. kd was generally smaller when cs was larger. FeSSGF provided relatively small kd values, reflecting FeSSGF colloids are large and slowly diffusing. Simulations showed impact of non-sink conditions, as well as plausible kd values for various cs scenarios, in agreement with observed kd values. The equation has advantages over first-order and z-factor dissolution rate equations. An Excel file for regression is provided.
    • Micronuclei in Circulating Tumor Associated Macrophages Predicts Progression in Advanced Colorectal Cancer.

      Kasabwala, Dimpal M; Bergan, Raymond C; Gardner, Kirby P; Lapidus, Rena; Tsai, Susan; Aldakkak, Mohammed; Adams, Daniel L (2022-11-11)
      Micronuclei (MN) are fragments of damaged nucleic acids which budded from a cell's nuclei as a repair mechanism for chromosomal instabilities, which within circulating white blood cells (cWBCs) signifies increased cancer risk, and in tumor cells indicates aggressive subtypes. MN form overtime and with therapy induction, which requires sequential monitoring of rarer cell subpopulations. We evaluated the peripheral blood (7.5 mL) for MN in Circulating Stromal Cells (CStCs) in a prospective pilot study of advanced colorectal cancer patients (n = 25), identifying MN by DAPI+ structures (&lt;3 µm) within the cellular cytoplasm. MN+ was compared to genotoxic induction, progression free survival (PFS) or overall survival (OS) hazard ratios (HR) over three years. MN were identified in 44% (n = 11/25) of CStCs, but were not associated with genotoxic therapies (p = 0.110) nor stage (p = 0.137). However, presence of MN in CStCs was independently prognostic for PFS (HR = 17.2, 95% CI 3.6-80.9, p = 0.001) and OS (HR = 70.3, 95% CI 6.6-752.8, p = 0.002), indicating a non-interventional mechanism in their formation. Additionally, MN formation did not appear associated with chemotherapy induction, but was correlated with tumor response. MN formation in colorectal cancer is an underlying biological mechanism that appears independent of chemotherapeutic genotoxins, changes during treatment, and predicts for poor clinical outcomes.
    • Resveratrol in Liquor Exacerbates Alcoholic Liver Injury with a Reduced Therapeutic Effect in Mice: An Unsupervised Herbal Wine Habit Is Risky.

      Zhang, Songxia; Xu, Ying; Ye, Mengling; Ye, Wenli; Xiao, Jian; Zhou, Honghao; Zhang, Wei; Shu, Yan; Huang, Yun; Chen, Yao (2022-11-10)
      People in Eastern countries hold a tradition of soaking herbal medicine in wine; however, the efficacy and safety of herbal wine have not been rigorously assessed. By assessing the efficacy of resveratrol (RSV) in ethanol against alcoholic liver disease (ALD) in mice, we aimed to offer a perspective on the use of herbal wine. To simulate the behaviour of herbal wine users, RSV (15 mg/kg) soaked in ethanol (RSV-alcohol) was administrated via gavage to the mice, here with alcohol consumption-induced ALD. RSV soaked in water (RSV-water) was the treatment control. The efficacy and safety of RSV on ALD were evaluated. Compared with the RSV-water group, a higher rate of mortality was found in the RSV-alcohol group (50.0% vs. 20.0%), which also exhibited more severe liver injury. RSV significantly increased the exposure of alcohol by 126.0%, which was accompanied by a significant inhibition of the ethanol metabolic pathway. In contrast, alcohol consumption significantly reduced exposure to RSV by 95.0%. Alcohol consumption had little effect on the expression of drug-metabolizing enzymes in RSV; however, alcohol seemed to reduce the absorption of RSV. RSV in liquor exacerbates alcoholic liver injury and has a reduced therapeutic effect, suggesting that the habit of herbal wine use without supervision is risky.
    • Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip.

      Mahajan, Gautam; Doherty, Erin; To, Tania; Sutherland, Arlene; Grant, Jennifer; Junaid, Abidemi; Gulati, Aakanksha; LoGrande, Nina; Izadifar, Zohreh; Timilsina, Sanjay Sharma; et al. (2022-11-26)
      Background: A dominance of non-iners Lactobacillus species in the vaginal microbiome is optimal and strongly associated with gynecological and obstetric health, while the presence of diverse obligate or facultative anaerobic bacteria and a paucity in Lactobacillus species, similar to communities found in bacterial vaginosis (BV), is considered non-optimal and associated with adverse health outcomes. Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human model that faithfully reproduces the vaginal epithelial microenvironment for preclinical validation of potential therapeutics or testing hypotheses about vaginal epithelium-microbiome interactions. Results: Here, we describe an organ-on-a-chip (organ chip) microfluidic culture model of the human vaginal mucosa (vagina chip) that is lined by hormone-sensitive, primary vaginal epithelium interfaced with underlying stromal fibroblasts, which sustains a low physiological oxygen concentration in the epithelial lumen. We show that the Vagina Chip can be used to assess colonization by optimal L. crispatus consortia as well as non-optimal Gardnerella vaginalis-containing consortia, and to measure associated host innate immune responses. Co-culture and growth of the L. crispatus consortia on-chip was accompanied by maintenance of epithelial cell viability, accumulation of D- and L-lactic acid, maintenance of a physiologically relevant low pH, and down regulation of proinflammatory cytokines. In contrast, co-culture of G. vaginalis-containing consortia in the vagina chip resulted in epithelial cell injury, a rise in pH, and upregulation of proinflammatory cytokines. Conclusion: This study demonstrates the potential of applying human organ chip technology to create a preclinical model of the human vaginal mucosa that can be used to better understand interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products.
    • RIG-I and TLR-7/8 agonists as combination adjuvant shapes unique antibody and cellular vaccine responses to seasonal influenza vaccine.

      Jangra, Sonia; Laghlali, Gabriel; Choi, Angela; Rathnasinghe, Raveen; Chen, Yong; Yildiz, Soner; Coughlan, Lynda; García-Sastre, Adolfo; De Geest, Bruno G; Schotsaert, Michael (2022-11-08)
    • Global, regional and national estimates of influenza-attributable ischemic heart disease mortality.

      Chaves, Sandra S; Nealon, Joshua; Burkart, Katrin G; Modin, Daniel; Biering-Sørensen, Tor; Ortiz, Justin R; Vilchis-Tella, Victor M; Wallace, Lindsey E; Roth, Gregory; Mahe, Cedric; et al. (2022-11-18)
      Background: Influenza virus infection is associated with incident ischemic heart disease (IHD) events. Here, we estimate the global, regional, and national IHD mortality burden attributable to influenza. Methods: We used vital registration data from deaths in adults ≥50 years (13.2 million IHD deaths as underlying cause) to assess the relationship between influenza activity and IHD mortality in a non-linear meta-regression framework from 2010 to 2019. This derived relationship was then used to estimate the global influenza attributable IHD mortality. We estimated the population attributable fraction (PAF) of influenza for IHD deaths based on the relative risk associated with a given level of weekly influenza test positivity rate and multiplied PAFs by IHD mortality from the Global Burden of Disease study. Findings: Influenza activity was associated with increased risk of IHD mortality across all countries analyzed. The mean PAF of influenza for IHD mortality was 3.9% (95% uncertainty interval [UI] 2.5-5.3%), ranging from <1% to 10%, depending on country and year. Globally, 299,858 IHD deaths (95% UI 191,216-406,809) in adults ≥50 years could be attributed to influenza, with the highest rates per 100,000 population in the Central Europe, Eastern Europe and Central Asia Region (32.3; 95% UI 20.6-43.8), and in the North Africa and Middle East Region (26.7; 95% UI 17-36.2). Interpretation: Influenza may contribute substantially to the burden of IHD. Our results suggest that if there were no influenza, an average of 4% of IHD deaths globally would not occur.
    • Outcomes of Epilepsy Surgery for Patients with Epileptic Spasms: A Systematic Review and Meta Analysis

      Kolosky, Taylor; Goldstein Shipper, Andrea; Erdemir, Gozde (2022-12-03)
    • Virtual Reality: A Modern Option for Pain Relief for Surgical Procedures

      Bermudez, Bernard Jr.; Clark, Kelly; Akaolisa, Paul (2022-12-05)
    • Postdeployment Respiratory Health: The Roles of the Airborne Hazards and Open Burn Pit Registry and the Post-Deployment Cardiopulmonary Evaluation Network.

      Davis, Caroline W; Rabin, Alexander S; Jani, Nisha; Osterholzer, John J; Krefft, Silpa; Hines, Stella E; Arjomandi, Mehrdad; Robertson, Michelle W; Sotolongo, Anays M; Falvo, Michael J (2022-08-15)
      Background: Following deployment to the Southwest Asia theater of operations and Afghanistan, many service members and veterans report respiratory symptoms and concerns about their military and environmental exposures. The US Department of Veterans Affairs (VA) established the national Airborne Hazards and Open Burn Pit Registry (AHOBPR) in 2014 to help better understand long-term health conditions that may be related to these exposures. Observations: The AHOBPR provides an online questionnaire and optional health evaluation performed by a primary care or environmental health clinician. The clinical evaluation provides an opportunity for the service member or veteran to talk with a health care professional about their symptoms, exposures, and potential treatment. Data derived from questionnaire responses and health evaluations facilitate medical surveillance and research. The VA also established a network of specialists, referred to as the Post-Deployment Cardiopulmonary Evaluation Network (PDCEN). The PDCEN identifies veterans within the AHOBPR who self-report certain conditions or have unexplained dyspnea and conducts comprehensive diagnostic evaluations. Primary objectives of PDCEN evaluations are to define respiratory and related conditions that are present, determine whether conditions are related to deployment, and work with the veteran's clinician to identify treatments and/or follow-up care to improve their health. We utilize a case example to illustrate the role of the primary care practitioner in connecting veterans to PDCEN clinical evaluations. Conclusions: AHOBPR clinical evaluations represent an initial step to better understand postdeployment health conditions. The PDCEN clinical evaluation extends the AHOBPR evaluation by providing specialty care for certain veterans requiring more comprehensive evaluation while systematically collecting and analyzing clinical data to advance the field.
    • Establishing an in vitro model of TANC2-associated disease

      McNair, Ruchael; Nusraty, Sabrina; Iffland, Philip, II, 1986- (2022-12-02)
    • Patients value their own pain over braking safety when deciding when to return to driving: a discrete choice experiment on lower extremity injuries.

      DeLeon, Genaro A; Rolle, Nicholas P; Burke, Cynthia E; McKegg, Phillip C; Hannan, Zachary D; Ghulam, Qasim M; Gupta, Jayesh; Bangura, Abdulai; O'Connor, Katherine C; Slobogean, Gerard P; et al. (2022-07-07)
      Objective: To quantify patient preferences towards time to return to driving relative to compromised reaction time and potential complication risks. Design: Cross-sectional discrete choice experiment. Setting: Academic trauma center. Patients: Ninety-six adult patients with an operative lower extremity fracture from December 2019 through December 2020. Intervention: None. Main outcome measurement: Patient completed a discrete choice experiment survey consisting of 12 hypothetical return to driving scenarios with varied attributes: time to return to driving (range: 1 to 6 months), risk of implant failure (range: 1% to 12%), pain upon driving return (range: none to severe), and driving safety measured by braking distance (range: 0 to 40 feet at 60 mph). The relative importance of each attribute is reported on a scale of 0% to 100%. Results: Patients most valued a reduced pain level when resuming driving (62%), followed by the risk of implant failure (17%), time to return to driving (13%), and braking safety (8%). Patients were indifferent to returning to driving at 1 month (median utility: 28, interquartile range [IQR] -31 to 80) or 2 months (median utility: 59, IQR: 41 to 91) postinjury. Conclusion: Patients with lower extremity injuries demonstrated a willingness to forego earlier return to driving if it might mean a decrease in their pain level. Patients are least concerned about their driving safety, instead placing higher value on their own pain level and chance of implant failure. The findings of this study are the first to rigorously quantify patient preferences toward a return to driving and heterogeneity in patient preferences.
    • Integrative analysis deciphers the heterogeneity of cancer-associated fibroblast and implications on clinical outcomes in ovarian cancers.

      Zhao, Yan; Mei, Song; Huang, Yixuan; Chen, Junru; Zhang, Xinlei; Zhang, Peng (2022-11-14)
      Accumulating evidence has recognized that cancer-associated fibroblasts (CAFs) are major players in the desmoplastic stroma of ovarian cancer, modulating tumor progression and therapeutic response. However, it is unclear regarding the signatures of CAFs could be utilized to predict the clinical outcomes of ovarian cancer patients. To fill in this gap, we explored the intratumoral compartment of ovarian cancer by analyzing the single-cell RNA-sequencing (scRNA-seq) datasets of ovarian carcinoma samples, and identified two distinct CAFs (tumor-promoting CAF_c1 subtype and myofibroblasts-like CAF_c2 subtype). The clinical significance of CAF subtypes was further validated in The Cancer Genomics Atlas (TCGA) database and other independent immunotherapy response datasets, and the results revealed that the patients with a higher expression of CAF_c1 signatures had a worse prognosis and showed a tendency of resistance to immunotherapy. This work uncovered the signatures of the CAF_c1 subtype that could serve as a novel prognostic indicator and predictive marker for immunotherapy.
    • Academic leadership in physician assistant/associate medical education: a cross-sectional analysis of the association with doctoral degree, gender, and minority status.

      Kibe, Lucy W; Kayingo, Gerald; Schrode, Katrina M; Klein, Alicia (2022-11-23)
      Background: There is a critical need for a diverse pool of academic leaders to increase the number and diversity of the medical workforce. Physician Assistant/Associate (PA) is a growing medical profession. Although the master's degree is the terminal degree for PAs, a growing number of PAs obtain a variety of doctoral degrees. However, there is no standardized training for academic PA leaders. The purpose of this study was to identify factors associated with PA academic leadership. Specifically, this study explored the following factors: doctoral degree credentials, gender and underrepresented minority status. Methods: Using the 2019 Physician Assistant Education Association Faculty and Directors survey, we assessed the relationship between academic leadership groups [Program Director (PD), Academic Director (AD), and Clinical Director (CD)] doctoral degree, gender, and underrepresented minority in medicine (URIM) status. Multivariable logistic regression models were used to determine the predictors of being in a leadership role. Results with p < 0.05 were considered statistically significant. Results: Of the 956 participants, 71% were female, 4% Hispanic, 86% White, 4% Black, 2% Asian, and 1% Native Hawaiian/Pacific Islander/American Indian/Alaska Native. Overall, 9% were URIM. Mean age was 45.6 (SD = 10.2) years. Average time in PA education was 2.9 years (SD = 1.4). Approximately 50% (n = 472) had a leadership role (PD-24%, AD-10%, CD-16%). Of all leaders, 68% were female, 9% were URIM, and 19% had a doctoral degree. Having a doctoral degree increased the odds of being a PD [AOR 2.38, CI [1.57-3.59], p = < 0.0001, AD and CD = non-significant]. More time in PA education increased the odds of being a PD [AOR 1.10, CI [1.07-1.12, p = < 0.0001] and AD [AOR 1.06, CI [1.03-1.09], p = < 0.0001], but not a CD. Gender and URIM status were not significantly associated with leadership roles. URIMs had doctorate degrees at higher rates than non-URIMs. Conclusion: PA academic leaders differ by doctoral degree attainment but not by gender and URIM status. URIM faculty are grossly underrepresented in the PA professorate, but disproportionately have doctoral degrees. Academic training opportunities for all PA academic leaders and strategies to increase URIM faculty are needed.
    • Multiplier Method for Predicting the Sitting Height Growth at Maturity: A Database Analysis.

      Jauregui, Julio J; Hlukha, Larysa P; McClure, Philip K; Paley, Dror; Shualy, Mordchai B; Goldberg, Maya B; Herzenberg, John E (2022-11-17)
      This study aims to develop multipliers for the spine and sitting height to predict sitting height at maturity. With the aid of longitudinal and cross-sectional clinical databases, we divided the total sitting height, cervical, thoracic, and lumbar lengths at skeletal maturity by these same four factors at each age for each percentile given. A series of comparisons were then carried out between the multipliers as well as the percentiles and the varied racial and ethnic groups within them. Regarding sitting height, there was little variability and correlated with the multipliers calculated for the thoracic and lumbar spine. The multiplier method has demonstrated accuracy that is not influenced by generation, percentile, race, and ethnicity. This multiplier can be used to anticipate mature sitting height, the heights of the thoracic, cervical, and lumbar spine, as well as the lack of spinal growth after spinal fusion surgery in skeletally immature individuals.
    • Immune-Mediated Pathogenesis in Dengue Virus Infection.

      Khanam, Arshi; Gutiérrez-Barbosa, Hector; Lyke, Kirsten E; Chua, Joel V (2022-11-21)
      Dengue virus (DENV) infection is one of the major public health concerns around the globe, especially in the tropical regions of the world that contribute to 75% percent of dengue cases. While the majority of DENV infections are mild or asymptomatic, approximately 5% of the cases develop a severe form of the disease that is mainly attributed to sequential infection with different DENV serotypes. The severity of dengue depends on many immunopathogenic mechanisms involving both viral and host factors. Emerging evidence implicates an impaired immune response as contributing to disease progression and severity by restricting viral clearance and inducing severe inflammation, subsequently leading to dengue hemorrhagic fever and dengue shock syndrome. Moreover, the ability of DENV to infect a wide variety of immune cells, including monocytes, macrophages, dendritic cells, mast cells, and T and B cells, further dysregulates the antiviral functions of these cells, resulting in viral dissemination. Although several risk factors associated with disease progression have been proposed, gaps persist in the understanding of the disease pathogenesis and further investigations are warranted. In this review, we discuss known mechanisms of DENV-mediated immunopathogenesis and its association with disease progression and severity.