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Item Analysis of apoB Concentrations Across Early Adulthood and Predictors for Rates of Change Using CARDIA Study Data(Journal of Lipid Research, 2022-12) Wilkins, John T.; Ning, Hongyan; Sniderman, Allan; Stone, Neil; Otvos, James; Jacobs, David R.; Shah, Ravi; Murthy, Venkatesh L.; Rana, Jamal; Allen, Norrina; Lloyd-Jones, Donald M.The cumulative exposure to apolipoprotein B (apoB)-containing lipoproteins in the blood during early adult life is a central determinant of atherosclerotic cardiovascular disease risk. To date, the patterns and rates of change in apoB through early adult life have not been described. Here, we used NMR to measure apoB concentrations in up to 3055 Coronary Artery Risk Development in Young Adults (CARDIA) Study participants who attended the years 2 (Y2), 7 (Y7), 15 (Y15), 20 (Y20), and 30 (Y30) exams. We examined individual-level spaghetti plots of apoB change, and we calculated average annualized rate of apoB concentration change during follow-up. We used multivariable linear regression models to assess the associations between CARDIA participant characteristics and annualized rates of apoB change. Male sex, higher measures of adiposity, lower HDL-C, lower Healthy Eating Index, and higher blood pressures were observed more commonly in individuals with higher apoB level at Y2 and Y20. Inter- and intra-individual variation in apoB concentration over time was substantial-while the mean (SD) rate of change was 0.52 (1.0) mg/dl/year, the range of annualized rates of change was -6.26 to +9.21 mg/dl/year. At baseline, lower first apoB measurement, female sex, White race, lower BMI, and current tobacco use were associated with apoB increase. We conclude that the significant variance in apoB level over time and the modest association between baseline measures and rates of apoB change suggest that the ability to predict an individual's future apoB serum concentrations, and thus their cumulative apoB exposure, after a one-time assessment in young adulthood is low.Item The nutraceutical electrophile scavenger 2-hydroxybenzylamine (2-HOBA) attenuates gastric cancer development caused by Helicobacter pylori(Biomedicine & Pharmacotherapy, 2022-12-06) Gobert, Alain P.; Asim, Mohammad; Smith, Thaddeus M.; Williams, Kamery J.; Barry, Daniel P.; Allaman, Margaret M.; McNamara, Kara M.; V. Hawkins, Caroline; Delgado, Alberto G.; Piazuelo, M. Blanca; Rathmacher, John A.; Wilson, Keith T.Stomach cancer is a leading cause of cancer death. Helicobacter pylori is a bacterial gastric pathogen that is the primary risk factor for carcinogenesis, associated with its induction of inflammation and DNA damage. Dicar-bonyl electrophiles are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. 2-hydroxybenzylamine (2-HOBA) is a natural compound derived from buckwheat seeds and acts as a potent scavenger of reactive aldehydes. Our goal was to investigate the effect of 2-HOBA on the pathogenesis of H. pylori infection. We used transgenic FVB/N insulin-gastrin (INS -GAS) mice as a model of gastric cancer. First, we found that 2-HOBA is bioavailable in the gastric tissues of these mice after supplementation in the drinking water. Moreover, 2-HOBA reduced the development of gastritis in H. pylori-infected INS-GAS mice without affecting the bacterial colonization level in the stomach. Further, we show that the development of gastric dysplasia and carcinoma was significantly reduced by 2-HOBA. Concom-itantly, DNA damage were also inhibited by 2-HOBA treatment in H. pylori-infected mice. In parallel, DNA damage was inhibited by 2-HOBA in H. pylori-infected gastric epithelial cells in vitro. In conclusion, 2-HOBA, which has been shown to be safe in human clinical trials, represents a promising nutritional compound for the chemoprevention of the more severe effects of H. pylori infection. KeywordsItem Association of Psychosocial Factors on COVID-19 Testing among YWCA Service Recipients(International Journal of Environmental Research and Public Health, 2023-01-11) Blasingame, Miaya; Mallett, Veronica; Cook, Mekeila; Im, Wansoo; Wilus, Derek; Kimbrough, Robin; Ikwuezunma, Gini; Orok, Ekemini; Reed, Breia; Akanbi, Victoria; Amoo-Asante, AurdieThe purpose of this study was to examine how psychosocial factors affect receipt of COVID-19 testing among Black and Hispanic women. In this cross-sectional study of Black and Hispanic women who received services from the YWCAs in Atlanta, El Paso, Nashville, and Tucson between 2019 and 2021 (n = 662), we used Patient-Reported Outcomes Measurement Information Systems (PROMIS) item bank 1.0 short forms to examine the impact of psychosocial factors (i.e., depression, anxiety, social isolation, instrumental support, emotional support, and companionship) on COVID-19 testing. Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals for receipt of a COVID-19 test associated with psychosocial factors while adjusting for confounders. There was little effect of moderate/severe depressions or anxiety on receipt of COVID-19 testing. Black (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.26-1.29) and Hispanic (OR 0.61, 95% CI 0.38-0.96) women with high levels of emotional support were less likely to receive the COVID-19 test. While high levels of instrumental support was associated with less likely receipt of the COVID-19 test among Black women (OR 0.75, 95% CI 0.34-1.66), it was associated with more likely receipt among Hispanic women (OR 1.19, 95% CI 0.74-1.92). Our findings suggest that certain psychosocial factors influence one's decision to get a COVID-19 test which can be useful in encouraging preventive healthcare such as screening and vaccination.Item Service delivery challenges in HIV care during the first year of the COVID-19 pandemic: results from a site assessment survey across the global IeDEA consortium(Journal Of The International Aids Society, 2022-12-11) Duda, Stephany N.IntroductionInterruptions in treatment pose risks for people with HIV (PWH) and threaten progress in ending the HIV epidemic; however, the COVID-19 pandemic's impact on HIV service delivery across diverse settings is not broadly documented. MethodsFrom September 2020 to March 2021, the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium surveyed 238 HIV care sites across seven geographic regions to document constraints in HIV service delivery during the first year of the pandemic and strategies for ensuring care continuity for PWH. Descriptive statistics were stratified by national HIV prevalence (<1%, 1-4.9% and >= 5%) and country income levels. ResultsQuestions about pandemic-related consequences for HIV care were completed by 225 (95%) sites in 42 countries with low (n = 82), medium (n = 86) and high (n = 57) HIV prevalence, including low- (n = 57), lower-middle (n = 79), upper-middle (n = 39) and high- (n = 50) income countries. Most sites reported being subject to pandemic-related restrictions on travel, service provision or other operations (75%), and experiencing negative impacts (76%) on clinic operations, including decreased hours/days, reduced provider availability, clinic reconfiguration for COVID-19 services, record-keeping interruptions and suspension of partner support. Almost all sites in low-prevalence and high-income countries reported increased use of telemedicine (85% and 100%, respectively), compared with less than half of sites in high-prevalence and lower-income settings. Few sites in high-prevalence settings (2%) reported suspending antiretroviral therapy (ART) clinic services, and many reported adopting mitigation strategies to support adherence, including multi-month dispensing of ART (95%) and designating community ART pick-up points (44%). While few sites (5%) reported stockouts of first-line ART regimens, 10-11% reported stockouts of second- and third-line regimens, respectively, primarily in high-prevalence and lower-income settings. Interruptions in HIV viral load (VL) testing included suspension of testing (22%), longer turnaround times (41%) and supply/reagent stockouts (22%), but did not differ across settings. ConclusionsWhile many sites in high HIV prevalence settings and lower-income countries reported introducing or expanding measures to support treatment adherence and continuity of care, the COVID-19 pandemic resulted in disruptions to VL testing and ART supply chains that may negatively affect the quality of HIV care in these settings.Item Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma A Phase 3 Prospective Externally Controlled Cohort Trial(JAMA Oncology, 2022-11-17) Thompson, Reid C.IMPORTANCE Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. OBJECTIVE To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax L) to standard of care (SOC) extends survival among patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. INTERVENTIONS The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. MAIN OUTCOMES AND MEASURES The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. RESULTS A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). CONCLUSIONS AND RELEVANCE In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.Item Occupational demands associated with rotator cuff disease surgery in the UK Biobank(Scand J Work Environ Health, 2022-10) Yanik, Elizabeth L.; Keener, Jay; Stevens, Martin J.; Walker-Bone, Karen E.; Dale, Ann Marie; Ma, Yinjiao; Colditz, Graham A.; Wright, Rick W.; Saccone, Nancy L.; Jain, Nitin B.; Evanoff, Bradley A.Objectives Physically-demanding occupations may increase rotator cuff disease (RCD) risk and need for sur- gery. We linked a job-exposure matrix (JEM) to the UK Biobank cohort study to measure physical occupational exposures and estimate associations with RCD surgery.Methods Jobs and UK Standard Occupational Classification (SOC) codes were recorded during the UK Biobank verbal interview. Lifetime job histories were captured through a web-based survey. UK SOC codes were linked to a JEM based on the US O*NET database. O*NET-based scores [static strength, dynamic strength, general physical activities, handling/moving objects (range=1-7), time spent using hands, whole body vibration, and cramped/awkward positions (range=1-5)] were assigned to jobs. RCD surgeries were identified through linked national hospital inpatient records. Multivariable Cox regression was used to calculate hazard ratios (HR) as estimates of associations with RCD surgery. Among those with lifetime job histories, associations were estimated for duration of time with greatest exposure (top quartile of exposure).Results Of 277 808 people reporting jobs, 1997 (0.7%) had an inpatient RCD surgery. After adjusting for age, sex, race, education, area deprivation, and body mass index, all O*NET variables considered were associated with RCD surgery (HR per point increase range=1.10-1.45, all P<0.005). A total of 100 929 people reported life- time job histories, in which greater exposures were significantly associated with RCD surgery after >10 years of work (eg, HR for 11-20 versus 0 years with static strength score >= 4 = 2.06, 95% confidence interval 1.39-3.04).Conclusion Workplace physical demands are an important risk factor for RCD surgery, particularly for workers with more than a decade of exposure.Item Reforming Reimbursement for the US Food and Drug Administration's Accelerated Approval Program to Support State Medicaid Programs(Jama Health Forum, 2022-11-18) Sachs, Rachel E.; Donohue, Julie M.; Dusetzina, Stacie B.IMPORTANCE The US Food and Drug Administration (FDA) has an accelerated approval program that has become the subject of scholarly attention and criticism, not only for the FDA's oversight of the program but also for its implications for payers. OBSERVATIONS State Medicaid programs' legal obligations to provide reimbursement for accelerated approval products have created fiscal challenges for Medicaid that have been exacerbated by industry's changing use of the accelerated approval program over time. Although strategies for accelerated approval reforms have been proposed, most focus on reforming the FDA's accelerated approval pathway and product regulation without taking into account the implications of this pathway for state Medicaid programs. There is a need for policy reforms that balance the goal of speeding approval of important medicines with states' real concerns regarding spending on medications with little evidence of clinical benefits. Areas of potential reform include formulary exclusion, Medicaid rebates, value-based pricing, and consolidated purchasing or carve outs. CONCLUSIONS AND RELEVANCE Policy makers may wish to consider options for reforming reimbursement for accelerated approval products in addition to reforms to the FDA's operation of the pathway. Policy reform proposals can provide a range of options to evaluate trade-offs of access and pricingItem Post-COVID-19 human memory impairment: A PRISMA-based systematic review of evidence from brain imaging studies(Frontiers In Aging Neuroscience, 2022-12-09) Shan, Dan; Li, Shaoyang; Xu, Ruichen; Nie, Glen; Xie, Yangyiran; Han, Junchu; Gao, Xiaoyi; Zheng, Yuandian; Xu, Zhen; Dai, ZhihaoMany people with coronavirus disease 2019 (COVID-19) report varying degrees of memory impairment. Neuroimaging techniques such as MRI and PET have been utilized to shed light on how COVID-19 affects brain function in humans, including memory dysfunction. In this PRISMA-based systematic review, we compared and summarized the current literature looking at the relationship between COVID-19-induced neuropathological changes by neuroimaging scans and memory symptoms experienced by patients who recovered from COVID-19. Overall, this review suggests a correlational trend between structural abnormalities (e.g., cortical atrophy and white matter hyperintensities) or functional abnormalities (e.g., hypometabolism) in a wide range of brain regions (particularly in the frontal, parietal and temporal regions) and memory impairments in COVID-19 survivors, although a causal relationship between them remains elusive in the absence of sufficient caution. Further longitudinal investigations, particularly controlled studies combined with correlational analyses, are needed to provide additional evidence.Item Mean Coronary Cross-Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV(Journal Of The American Heart Association, 2022-12-06) Werede, Ayoda T. T.; Terry, James G. G; Nair, Sangeeta; Temu, Tecla M. M.; Shepherd, Bryan E. E.; Bailin, Samuel S. S.; Mashayekhi, Mona; Gabriel, Curtis L. L.; Lima, Morgan; Woodward, Beverly Owen; Hannah, LaToya; Mallal, Simon A. A.; Beckman, Joshua A. A.; Li, Jonathan Z. Z.; Fajnzylber, Jesse; Harrison, David G. G.; Carr, John Jeffrey; Koethe, John R. R.; Wanjalla, Celestine N. N.BackgroundPersons with HIV have a higher prevalence of coronary artery disease compared with their HIV-negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross-sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. Methods and ResultsWe assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV-related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (rho=0.91, P<0.0001). Higher mean corCSA was present in those with coronary artery calcium (P=0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (rho=0.35, P=0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4(+) T-cell count (rho=-0.2, P=0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from rho=0.19, P=0.08 to rho=0.3, P=0.01). CorCSA was also inversely correlated with plasma IL-10 (rho=-0.25, P=0.03) but had no relationship with IL-6 (rho=0.11, P=0.4) or IL-1 beta (rho=0.08, P=0.5). ConclusionsPositive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T-cell count, lower circulating IL-10, and possibly a longer antiretroviral therapy duration in persons with HIV. RegistrationClinicaltrials.gov; Unique identifier: NCT04451980.Item Essentialism and Enhancing Healthcare Experiences: The Strategic Pursuit of "Less"(Journal of Patient Experience, 2019-06) Cooley, LauraItem The impact of data quality and source data verification on epidemiologic inference: a practical application using HIV observational data(BMC Public Health, 2019-12-30) Giganti, Mark J.; Shepherd, Bryan E.; Caro-Vega, Yanink; Luz, Paula M.; Rebeiro, Peter F.; Maia, Marcelle; Julmiste, Gaetane; Cortes, Claudia; McGowan, Catherine C.; Duda, Stephany N.Background: Data audits are often evaluated soon after completion, even though the identification of systematic issues may lead to additional data quality improvements in the future. In this study, we assess the impact of the entire data audit process on subsequent statistical analyses. Methods: We conducted on-site audits of datasets from nine international HIV care sites. Error rates were quantified for key demographic and clinical variables among a subset of records randomly selected for auditing. Based on audit results, some sites were tasked with targeted validation of high-error-rate variables resulting in a post-audit dataset. We estimated the times from antiretroviral therapy initiation until death and first AIDS-defining event using the pre-audit data, the audit data, and the post-audit data. Results: The overall discrepancy rate between pre-audit and audit data (n = 250) across all audited variables was 17.1%. The estimated probability of mortality and an AIDS-defining event over time was higher in the audited data relative to the pre-audit data. Among patients represented in both the post-audit and pre-audit cohorts (n = 18, 999), AIDS and mortality estimates also were higher in the post-audit data. Conclusion: Though some changes may have occurred independently, our findings suggest that improved data quality following the audit may impact epidemiological inferences.Item Cost-Effectiveness of Multigene Pharmacogenetic Testing in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention(Value in Health, 2020-01) Dong, Olivia M.; Wheeler, Stephanie B.; Cruden, Gracelyn; Lee, Craig R.; Voora, Deepak; Dusetzina, Stacie B.; Wiltshire, TimObjective: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with singlegene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective. Methods: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained. Results: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%). Conclusions: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.Item Identification of drug-specific public TCR driving severe cutaneous adverse reactions(Nature Communications, 2019-08-08) Phillips, Elizabeth Jane; Mallal, Simon AlexanderDrug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public alpha beta TCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype- specificity and an bias for HLA-B*15:02. This public alpha beta TCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public alpha beta TCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.Item Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations(Biophysical Journal, 2019-08) Wilson, Blake A.; Ramanathan, Arvind; Lopez, Carlos F.Cardiolipin is an anionic lipid found in the mitochondrial membranes of eukaryotes ranging from unicellular microorganisms to metazoans. This unique lipid contributes to various mitochondrial functions, including metabolism, mitochondrial membrane fusion and/or fission dynamics, and apoptosis. However, differences in cardiolipin content between the two mitochondrial membranes, as well as dynamic fluctuations in cardiolipin content in response to stimuli and cellular signaling events, raise questions about how cardiolipin concentration affects mitochondrial membrane structure and dynamics. Although cardiolipin's structural and dynamic roles have been extensively studied in binary mixtures with other phospholipids, the biophysical properties of cardiolipin in higher number lipid mixtures are still not well resolved. Here, we used molecular dynamics simulations to investigate the cardiolipin-dependent properties of ternary lipid bilayer systems that mimic the major components of mitochondrial membranes. We found that changes to cardiolipin concentration only resulted in minor changes to bilayer structural features but that the lipid diffusion was significantly affected by those alterations. We also found that cardiolipin position along the bilayer surfaces correlated to negative curvature deflections, consistent with the induction of negative curvature stress in the membrane monolayers. This work contributes to a foundational understanding of the role of cardiolipin in altering the properties in ternary lipid mixtures composed of the major mitochondrial phospholipids, providing much-needed insights to help understand how cardiolipin concentration modulates the biophysical properties of mitochondrial membranes.Item Multiplexed Adaptive RT-PCR Based on L-DNA Hybridization Monitoring for the Detection of Zika, Dengue, and Chikungunya RNA(Scientific Reports, 2019-08-06) Euliano, Erin M.; Hardcastle, Austin N.; Victoriano, Christie M.; Gabella, William E.; Haselton, Frederick R.; Adams, Nicholas M.Reverse transcription polymerase chain reaction (RT-PCR) is the gold standard for the molecular diagnosis of many infectious diseases, including RNA viruses, but is generally limited to settings with access to trained personnel and laboratory resources. We have previously reported a fundamentally simpler thermal cycling platform called Adaptive PCR, which dynamically controls thermal cycling conditions during each cycle by optically monitoring the annealing and melting of mirror-image L-DNA surrogates of the PCR primers and targets. In this report, we integrate optically-controlled reverse transcription and single-channel monitoring of L-DNAs to develop a multiplexed Adaptive RT-PCR instrument and assay for the detection of Zika, dengue, and chikungunya virus RNA with high target specific and low limits of detection. The assay is demonstrated to detect as low as 5 copies/reaction of Zika or chikungunya RNA and 50 copies/reaction of dengue RNA. The multiplexed Adaptive RT-PCR instrument is robust and has many of the features required to implement diagnostic assays for RNA viruses in settings that lack traditional laboratory resources.Item Methylmercury exposure, genetic variation in metabolic enzymes, and the risk of glioma(Scientific Reports, 2019-07-26) Creed, Jordan H.; Peeri, Noah C.; Anic, Gabriella M.; Thompson, Reid C.; Olson, Jeffrey J.; LaRocca, Renato, V.; Chowdhary, Sajeel A.; Brockman, John D.; Gerke, Travis A.; Nabors, Louis B.; Egan, Kathleen M.Methylmercury (MeHg) is an environmental neurotoxin with human exposure mainly from dietary intake of contaminated fish. Exposure to MeHg has been implicated in neurological damage, but research on its role in cancers, specifically glioma, is limited. In a glioma case-control study, we examined associations between toenail mercury (Hg) and glioma risk. We also examined genetic polymorphisms in 13 genes related to MeHg metabolism for association with glioma risk; genetic associations were also studied in the UK Biobank cohort. Median toenail Hg in cases and controls, respectively, was 0.066 mu g/g and 0.069 mu g/g (interquartile range (IQR): 0.032-0.161 and 0.031-0.150 mu g/g). Toenail Hg was not found to be significantly associated with glioma risk (Odds Ratio: 1.02; 95% Confidence Interval: 0.91, 1.14; p = 0.70 in analysis for ordinal trend with increasing quartile of toenail MeHg). No genetic variant was statistically significant in both of the studies; one variant, rs11859163 (MMP2) had a combined p-value of 0.02 though it was no longer significant after adjustment for multiple testing (Bonferroni corrected p = 1). This study does not support the hypothesis that exposure to MeHg plays a role in the development of glioma at levels of exposure found in this study population.Item A human memory circuit derived from brain lesions causing amnesia(NATURE COMMUNICATIONS, 2019-08-02) Ferguson, Michael A.; Lim, Chun; Cooke, Danielle; Darby, R. Ryan; Wu, Ona; Rost, Natalia S.; Corbetta, Maurizio; Grafman, Jordan; Fox, Michael D.Human memory is thought to depend on a circuit of connected brain regions, but this hypothesis has not been directly tested. We derive a human memory circuit using 53 case reports of strokes causing amnesia and a map of the human connectome (n = 1000). This circuit is reproducible across discovery (n = 27) and replication (n = 26) cohorts and specific to lesions causing amnesia. Its hub is at the junction of the presubiculum and retrosplenial cortex. Connectivity with this single location defines a human brain circuit that incorporates > 95% of lesions causing amnesia. Lesion intersection with this circuit predicts memory scores in two independent datasets (N1 = 97, N2 = 176). This network aligns with neuroimaging correlates of episodic memory, abnormalities in Alzheimer's disease, and brain stimulation sites reported to enhance memory in humans.Item Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response(Nature Communications, 2019-07-22) Antunes, Krist Helen; Fachi, Jose Luis; de Paula, Rosemeire; da Silva, Emanuelle; Pral, Lais Passariello; dos Santos, Adara Aurea; Dias, Greicy Brisa Malaquias; Vargas, Jose Eduardo; Puga, Renato; Mayer, Fabiana QuoosSevere respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-beta (IFN-beta) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-beta response. The effect of acetate on RSV infection was abolished in Gpr43(-/-) mice. Our findings reveal antiviral effects of acetate involving IFN-beta in lung epithelial cells and engagement of GPR43 and IFNAR.Item Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis(International Journal of Molecular Sciences, 2019-06-01) Linton, MacRae F.; Moslehi, Javid J.; Babaev, Vladimir R.The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in Akt isoforms or modulation of the Akt activity levels in macrophages significantly affect their polarization phenotype and consequently atherosclerosis in mice. Moreover, the activity levels of Akt signaling determine the viability of monocytes/macrophages and their resistance to pro-apoptotic stimuli in atherosclerotic lesions. Therefore, elimination of pro-apoptotic factors as well as factors that antagonize or suppress Akt signaling in macrophages increases cell viability, protecting them from apoptosis, and this markedly accelerates atherosclerosis in mice. In contrast, inhibition of Akt signaling by the ablation of Rictor in myeloid cells, which disrupts mTORC2 assembly, significantly decreases the viability and proliferation of blood monocytes and macrophages with the suppression of atherosclerosis. In addition, monocytes and macrophages exhibit a threshold effect for Akt protein levels in their ability to survive. Ablation of two Akt isoforms, preserving only a single Akt isoform in myeloid cells, markedly compromises monocyte and macrophage viability, inducing monocytopenia and diminishing early atherosclerosis. These recent advances in our understanding of Akt signaling in macrophages in atherosclerosis may have significant relevance in the burgeoning field of cardio-oncology, where PI3K/Akt inhibitors being tested in cancer patients can have significant cardiovascular and metabolic ramifications.Item Salidroside inhibits the proliferation and migration of gastric carcinoma cells and tumor growth via the activation of ERS-dependent autophagy and apoptosis(RSC Advances, 2019-08-18) Yan, Wei; Li, Kai; Buhe, Amin; Li, Tianxiong; Tian, Peirong; Hong, JunThe endoplasmic reticulum stress (ERS)-induced autophagy and apoptosis are favorable for the suppression of many cancer types. Salidroside (Salid) has been proven to be capable of inducing the apoptosis of many cancer cells. However, the underlying mechanisms and whether Salid can activate the autophagic system have still not been explained thoroughly. Herein, the inhibition effect of Salid on the growth and progress of gastric cancer and the underlying mechanisms were investigated. With the SGC-7901 cells acting as the cancer model cells, we ascertained that Salid exerted a superior antagonism effect on the growth and migration of gastric cancer cells in a dose-dependent manner. Additionally, Salid exhibited strong capacity to induce cell apoptosis by the down-regulation of proliferation-related genes (Ki67 and PCNA), increase in the pro-apoptotic protein C-caspase-3, and changing the levels of other related genes. A mechanism study revealed that the levels of the ERS-related genes, such as CHOP, C-caspase-12, GADD34, and BiP, in the SGC-7901 cells dramatically changed post-treatment by Salid, indicating the involvement of ERS in Salid-inducing cell apoptosis. In addition, the increased LC3(+) autophagic vacuoles, enhanced conversion of LC3-I to LC3-II, and inhibition of the PI3K/Akt/mTOR pathway further confirmed the activation of autophagy induced by Salid. Importantly, the effect of Salid in regulating the levels of autophagy-related proteins or the signaling pathway could be markedly depressed by co-incubating with Wortmannin (Wort), an autophagy inhibitor. The final evaluation of the tumor therapy efficacy exhibited satisfactory cancer growth inhibition by Salid with negligible toxicity to normal tissues. In summary, the present work provides a comprehensive effective evaluation of Salid for treating gastric cancer. The detailed investigation of the underlying mechanisms may offer a rational reference for the future applications of Salid in clinic.