• Racial differences in the effect of granulocyte macrophage colony-stimulating factor on improved walking distance in peripheral artery disease: The PROPEL randomized clinical trial

      McDermott, M.M.; Polonsky, T.S.; Guralnik, J.M. (American Heart Association Inc., 2019)
      Background The effects of race on response to medical therapy in people with peripheral artery disease (PAD) are unknown. Methods and Results In the PROPEL (Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD) Trial, PAD participants were randomized to 1 of 4 groups for 6 months: supervised treadmill exercise+granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) (Group 1), exercise+placebo (Group 2), attention control+GM‐CSF (Group 3), or attention control+placebo (Group 4). Change in 6‐minute walk distance was measured at 12‐ and 26‐week follow‐up. In these exploratory analyses, groups receiving GM‐CSF (Groups 1 and 3), placebo (Groups 2 and 4), exercise (Groups 1 and 2), and attention control (Groups 2 and 4) were combined, maximizing statistical power for studying the effects of race on response to interventions. Of 210 PAD participants, 141 (67%) were black and 64 (30%) were white. Among whites, GM‐CSF improved 6‐minute walk distance by +22.0 m (95% CI: −4.5, +48.5, P=0.103) at 12 weeks and +44.4 m (95% CI: +6.9, +82.0, P=0.020) at 26 weeks, compared with placebo. Among black participants, there was no effect of GM‐CSF on 6‐minute walk distance at 12‐week (P=0.26) or 26‐week (−5.0 m [−27.5, +17.5, P=0.66]) follow‐up, compared with placebo. There was an interaction of race on the effect of GM‐CSF on 6‐minute walk change at 26‐week follow‐up (P=0.018). Exercise improved 6‐minute walk distance in black (P=0.006) and white (P=0.034) participants without interaction. Conclusions GM‐CSF improved 6‐minute walk distance in whites with PAD but had no effect in black participants. Further study is needed to confirm racial differences in GM‐CSF efficacy in PAD. Copyright 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
    • Assessment of Machine Learning vs Standard Prediction Rules for Predicting Hospital Readmissions

      Morgan, D.J.; Bame, B.; Zimand, P. (American Medical Association, 2019)
      Importance: Hospital readmissions are associated with patient harm and expense. Ways to prevent hospital readmissions have focused on identifying patients at greatest risk using prediction scores. Objective: To identify the type of score that best predicts hospital readmissions. Design, Setting, and Participants: This prognostic study included 14 062 consecutive adult hospital patients with 16 649 discharges from a tertiary care center, suburban community hospital, and urban critical access hospital in Maryland from September 1, 2016, through December 31, 2016. Patients not included as eligible discharges by the Centers for Medicare & Medicaid Services or the Chesapeake Regional Information System for Our Patients were excluded. A machine learning rank score, the Baltimore score (B score) developed using a machine learning technique, for each individual hospital using data from the 2 years before September 1, 2016, was compared with standard readmission risk assessment scores to predict 30-day unplanned readmissions. Main Outcomes and Measures: The 30-day readmission rate evaluated using various readmission scores: B score, HOSPITAL score, modified LACE score, and Maxim/RightCare score. Results: Of the 10 732 patients (5605 [52.2%] male; mean [SD] age, 54.56 [22.42] years) deemed to be eligible for the study, 1422 were readmitted. The area under the receiver operating characteristic curve (AUROC) for individual rules was 0.63 (95% CI, 0.61-0.65) for the HOSPITAL score, which was significantly lower than the 0.66 for modified LACE score (95% CI, 0.64-0.68; P < .001). The B score machine learning score was significantly better than all other scores; 48 hours after admission, the AUROC of the B score was 0.72 (95% CI, 0.70-0.73), which increased to 0.78 (95% CI, 0.77-0.79) at discharge (all P < .001). At the hospital using Maxim/RightCare score, the AUROC was 0.63 (95% CI, 0.59-0.69) for HOSPITAL, 0.64 (95% CI, 0.61-0.68) for Maxim/RightCare, and 0.66 (95% CI, 0.62-0.69) for modified LACE score. The B score was 0.72 (95% CI, 0.69-0.75) 48 hours after admission and 0.81 (95% CI, 0.79-0.84) at discharge. In directly comparing the B score with the sensitivity at cutoff values for modified LACE, HOSPITAL, and Maxim/RightCare scores, the B score was able to identify the same number of readmitted patients while flagging 25.5% to 54.9% fewer patients. Conclusions and Relevance: Among 3 hospitals in different settings, an automated machine learning score better predicted readmissions than commonly used readmission scores. More efficiently targeting patients at higher risk of readmission may be the first step toward potentially preventing readmissions.
    • Typhoid Vaccine Acceleration Consortium Malawi: A Phase III, Randomized, Double-blind, Controlled Trial of the Clinical Efficacy of Typhoid Conjugate Vaccine Among Children in Blantyre, Malawi

      Meiring, J.E.; Laurens, M.B.; Patel, P. (Oxford University Press, 2019)
      BACKGROUND: Typhoid fever is an acute infection characterized by prolonged fever following the ingestion and subsequent invasion of Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen. The incidence of typhoid fever has been most reported in children 5-15 years of age, but is increasingly recognized in children younger than 5 years old. There has been a recent expansion of multidrug-resistant typhoid fever globally. Prior typhoid vaccines were not suitable for use in the youngest children in countries with a high burden of disease. This study aims to determine the efficacy of a typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization, by testing it in children 9 months through 12 years of age in Blantyre, Malawi. METHODS: In this Phase III, individually randomized, controlled, double-blind trial of the clinical efficacy of TCV, 28 000 children 9 months through 12 years of age will be enrolled and randomized in a 1:1 ratio to receive either Vi-TCV or a meningococcal serogroup A conjugate vaccine. A subset of 600 of these children will be further enrolled in an immunogenicity and reactogenicity sub-study to evaluate the safety profile and immune response elicited by Vi-TCV. Recruiting began in February 2018. RESULTS: All children will be under passive surveillance for at least 2 years to determine the primary outcome, which is blood culture-confirmed S. Typhi illness. Children enrolled in the immunogenicity and reactogenicity sub-study will have blood drawn before vaccination and at 2 timepoints after vaccination to measure their immune response to vaccination. They will also be followed actively for adverse events and serious adverse events. CONCLUSIONS: The introduction of a single-dose, efficacious typhoid vaccine into countries with high burden of disease or significant antimicrobial resistance could have a dramatic impact, protecting children from infection and reducing antimicrobial usage and associated health inequity in the world's poorest places. This trial, the first of a TCV in Africa, seeks to demonstrate the impact and programmatic use of TCVs within an endemic setting. CLINICAL TRIALS REGISTRATION: NCT03299426. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.
    • Effects of severe hypoglycemia on cardiovascular outcomes and death in the Veterans Affairs Diabetes Trial

      Davis, S.N.; Duckworth, W.; Emanuele, N. (American Diabetes Association Inc., 2019)
      OBJECTIVE To determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS This post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA 1c 9.4 ± 2.0%) of 11.5 6 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA 1c <7.0%) versus standard (HbA 1c <8.5%) glucose control. RESULTS The rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P <0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012). CONCLUSIONS Severe hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia. © 2018 by the American Diabetes Association.
    • Donor blood remains a source of heavy metal exposure

      White, K.M.R.; Anderson, Berry, A.L.; White, S.F. (Nature Publishing Group, 2019)
    • Etripamil: Self-management of supraventricular tachycardia is not far away?

      Faisaluddin, M.; Ashish, K.; Hajra, A. (Elsevier Ireland Ltd, 2019)
    • Using 340B drug discounts to provide a financially sustainable medication discharge service

      Wu, T.; Williams, C.; Vranek, K. (Elsevier Inc., 2019)
      The 340B Drug Pricing Program was intended to stretch federal resources by providing significant discounts to covered entities providing care to underserved populations. Program implementation and evidence of expanding services to higher income patients has brought more scrutiny and calls for elimination of the program. While additional review and reform may be warranted, profitability from 340B discounts enables covered entities to provide additional services that may not be feasible in absence of the program. This case report demonstrates one institution's use of 340B discounts to financially justify providing bedside medication delivery services for patients at the time of discharge from an inpatient admission. A simple financial model was developed using hospital data and inputs from available literature to estimate gross profit and earnings before interest, taxes, depreciation, and amortization (EBITDA) with and without 340B discounts. Without the 340B drug price discounts, the service would operate at a financial loss, and further investigation must be done to determine whether other clinical or economic benefits would warrant discharge medication delivery at the institution. © 2018 The Authors
    • The Gene Ontology Resource: 20 years and still GOing strong

      Carbon, S.; Douglass, E.; Dunn, N. (Oxford University Press, 2019)
      The Gene Ontology resource (GO; http://geneontology.org) provides structured, computable knowledge regarding the functions of genes and gene products. Founded in 1998, GO has become widely adopted in the life sciences, and its contents are under continual improvement, both in quantity and in quality. Here, we report the major developments of the GO resource during the past two years. Each monthly release of the GO resource is now packaged and given a unique identifier (DOI), enabling GO-based analyses on a specific release to be reproduced in the future. The molecular function ontology has been refactored to better represent the overall activities of gene products, with a focus on transcription regulator activities. Quality assurance efforts have been ramped up to address potentially out-of-date or inaccurate annotations. New evidence codes for high-Throughput experiments now enable users to filter out annotations obtained from these sources. GO-CAM, a new framework for representing gene function that is more expressive than standard GO annotations, has been released, and users can now explore the growing repository of these models. We also provide the 'GO ribbon' widget for visualizing GO annotations to a gene; the widget can be easily embedded in any web page. © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
    • Toxoplasma gondii IgG associations with sleepwake problems, sleep duration and timing

      Corona, C.C.; Zhang, M.; Wadhawan, A. (De Gruyter, 2019)
      Background: Evidence links Toxoplasma gondii (T. gondii), a neurotropic parasite, with schizophrenia, mood disorders and suicidal behavior, all of which are associated and exacerbated by disrupted sleep. Moreover, low-grade immune activation and dopaminergic overstimulation, which are consequences of T. gondii infection, could alter sleep patterns and duration. Methods: Sleep data on 833 Amish participants [mean age (SD) = 44.28 (16.99) years; 59.06% women] were obtained via self-reported questionnaires that assessed sleep problems, duration and timing. T. gondii IgG was measured with ELISA. Data were analyzed using multivariable logistic regressions and linear mixed models, with adjustment for age, sex and family structure. Results: T. gondii seropositives reported less sleep problems (p < 0.005) and less daytime problems due to poor sleep (p < 0.005). Higher T. gondii titers were associated with longer sleep duration (p < 0.05), earlier bedtime (p < 0.005) and earlier mid-sleep time (p < 0.05). Conclusions: It seems unlikely that sleep mediates the previously reported associations between T. gondii and mental illness. Future longitudinal studies with objective measures are necessary to replicate our findings. Copyright 2019 Celine C. Corona, et al.
    • Bazedoxifene as a novel GP130 inhibitor for Colon Cancer therapy

      Wei, J.; Ma, L.; Lai, Y.-H. (BioMed Central Ltd., 2019)
      Background: Interleukin-11 (IL-11), a dominant IL-6 family cytokine, is involved in tumorigenesis, tumor progression and differentiation in colon cancer cells. IL-11 signaling has been recently identified as a potential therapeutic target in colon cancer. Bazedoxifene, a third- generation selective estrogen modulator approved by the Food and Drug Administration (FDA), is a novel inhibitor of IL-11/GP130 signaling discovered by docking modeling. Methods: In this study, the inhibition efficacy of bazedoxifene in colon cancer cells and its potential mechanism were investigated in vitro and in vivo by using MTT cell viability assay, BrdU cell proliferation assay, colony formation assay, wound-healing/cell migration assay, immunofluorescence, western blot assay and the mouse xenograft tumor model. Results: Bazedoxifene inhibits phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and its nuclear translocation induced by IL-11 in colon cancer cells. It also inhibits p-STAT3 induced by IL-6 and IL-11 but not by OSM or STAT1 phosphorylation induced by INF-γ in human colon cancer cells. In addition, bazedoxifene can significantly inhibit phosphorylation of AKT and STAT3 downstream targets. Furthermore, bazedoxifene alone or together with oxaliplatin can significantly induce apoptosis, inhibit cell viability, cell colony formation and cell migration in colon cancer cells. Knock-down of IL-11R can reduce the sensitivity of colon cancer cells to bazedoxifene. IL-11 can reduce the efficacy of oxaliplatin-mediated inhibition of cell viability. Consistent with in vitro findings, bazedoxifene alone also attenuated HCT-15 xenograft tumor burden and reduced p-STAT3, p-AKT and p-ERK in vivo. Its combination with oxaliplatin attenuated DLD-1 xenograft tumor burden and reduced p-STAT3 in vivo. Conclusions: Taken together, these results support bazedoxifene as a novel and effective therapeutic agent targeting IL-11/GP130 signaling for human colorectal cancer therapy. © 2019 The Author(s).
    • Prescription opioid and benzodiazepine misuse is associated with suicidal ideation in older adults

      Schepis, T.S.; Simoni-Wastila, L.; McCabe, S.E. (John Wiley and Sons Ltd, 2019)
      Objectives: Suicide in older adults is a major public health issue. Past research across the US adult population has linked prescription medication misuse with suicidal ideation. No work has evaluated associations between prescription opioid or benzodiazepine misuse and suicidal ideation in older adults, and this work aimed to address that gap. Methods/design: Data were from adults 50 years and older participating in the 2015 to 2016 National Survey on Drug Use and Health (n = 17,608). Design-based logistic regression evaluated links between any past-year prescription opioid or benzodiazepine use without misuse or prescription misuse and past-year suicidal ideation, after controlling for sociodemographic, physical health, mental health, and substance use correlates associated with suicidal ideation. Results: After controlling for all correlates, past-year use without misuse of prescription opioids or benzodiazepines was not associated with past-year suicidal ideation in older adults. In contrast, past-year opioid misuse (AOR = 1.84, 95% CI = 1.07-3.19) and benzodiazepine misuse (AOR = 2.00, 95% CI = 1.01-3.94) were significantly associated with past-year suicidal ideation, even after controlling for all covariates. While 2.2% of US older adults not engaged in either opioid or benzodiazepine misuse reported past-year suicidal ideation, 25.4% of those who misused both medication classes endorsed such suicidality (AOR = 4.73, 95% CI = 2.07-10.79). Conclusions: Both past-year prescription opioid and benzodiazepine misuse are associated with past-year suicidal ideation in US older adults. Clinicians encountering older adult patients at-risk for or engaged in prescription medication misuse also should screen for suicidality. © 2018 John Wiley & Sons, Ltd.
    • Evaluation of a blended-learning training concept to train oncology physicians to advise their patients about complementary and integrative medicine (KOKON-KTO): Study protocol for a prospective, multi-center, cluster-randomized trial

      Helmer, S.M.; Rogge, A.A.; Fischer, F. (BioMed Central Ltd., 2019)
      Background: Many cancer patients are interested in complementary and integrative medicine during and after regular cancer treatment. Given the high number of users it is important that physicians and patients engage in a dialog about useful complementary and integrative medicine therapies during cancer treatment. In a prospective, multi-center, cluster-randomized evaluation study we will develop, implement and evaluate a training program for oncology physicians advising their patients on complementary and integrative medicine. The main objective of the study is to evaluate whether training physicians in a blended-learning approach (e-learning + skills-training workshop) in providing advice to their cancer patients on complementary and integrative medicine, in addition to handing out an information leaflet about reputable websites, has different effects on the outcomes of patients, physicians, and their interaction level, compared to only giving out the information leaflet. Methods/design: Forty-eight oncology physicians will be included into a cluster-randomized trial to either participate or not in the blended-learning training. Physicians will then advise 10 cancer patients each, resulting in 480 patients participating in the trial. The blended learning consists of nine units of up to 45 min of e-learning and 18 units of up to 45 min of on-site skills-training workshop focusing. Outcomes will be measured on the physician, patient, and physician-patient-interaction level. Discussion: A blended-learning program for oncology physicians to advise their cancer patients in a systematic way and a reasonable time frame on complementary and integrative medicine will be evaluated in depth in a large cluster-randomized trial. Trial registration: German Clinical Trials Register, ID: DRKS00012704. Registered on 28 August 2017. © 2019 The Author(s).
    • Clinical implications of asymptomatic plasmodium falciparum infections in Malawi

      Buchwald, A.G.; Sixpence, A.; Chimenya, M. (Oxford University Press, 2019)
      Background. Asymptomatic Plasmodium falciparum infections are common in Malawi; however, the implications of these infections for the burden of malaria illness are unknown. Whether asymptomatic infections eventually progress to malaria illness, persist without causing symptoms, or clear spontaneously remains undetermined. We identified asymptomatic infections and evaluated the associations between persistent asymptomatic infections and malaria illness. Methods. Children and adults (N = 120) who presented at a health facility with uncomplicated malaria were followed monthly for 2 years. During follow-up visits, participants with malaria symptoms were tested and, if positive, treated. Samples from all visits were tested for parasites using both microscopy and polymerase chain reaction, and all malaria infections underwent genotyping. Cox frailty models were used to estimate the temporal association between asymptomatic infections and malaria illness episodes. Mixed models were used to estimate the odds of clinical symptoms associated with new versus persistent infections. Results. Participants had a median follow-up time of 720 days. Asymptomatic infections were detected during 23% of visits. Persistent asymptomatic infections were associated with decreased risk of malaria illness in all ages (hazard ratio 0.50, P < .001). When asymptomatic infections preceded malaria illness, newly-acquired infections were detected at 92% of subsequent clinical episodes, independent of presence of persistent infections. Malaria illness among children was more likely due to newly-acquired infections (odds ratio, 1.4; 95% confidence interval, 1.3-1.5) than to persistent infections. Conclusions. Asymptomatic P. falciparum infections are associated with decreased incidence of malaria illness, but do not protect against disease when new infection occurs. Copyright 2018 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.
    • Correlates of reported modern contraceptive use among postpartum HIV-positive women in rural Nigeria: An analysis from the MoMent prospective cohort study

      Chinaeke, E.E.; Fan-Osuala, C.; Bathnna, M. (BioMed Central Ltd., 2019)
      Background: Nigeria has an annual population of ~ 200,000 women who are both pregnant and HIV-positive. High unmet need for family planning in this population could lead to unintended pregnancies, along with the increased risk of mother-to-child transmission of HIV (MTCT). To identify modifiable barriers and facilitators in effective family planning, we examined correlates of modern contraceptive use among HIV-positive women enrolled in the MoMent prevention of MTCT (PMTCT) implementation research study in rural North-Central Nigeria. Methods: In this prospective cohort study, HIV-positive pregnant women were enrolled at 20 Primary Healthcare Centers and followed up to 12 months postpartum. Baseline socio-demographic, clinical and obstetric data were collected at enrollment. Participants were to receive routine family planning counselling from healthcare workers during postnatal visits. Analysis utilized baseline data linked to available family planning information collected from each woman at the first postpartum visit. Multivariate logistic regression was performed to determine factors associated with modern contraceptive use. Results: Out of 497 women enrolled, family planning data was available for 399 (80.3%) women, of whom 349 (87.5%) received family planning counselling, and 321 (80.5%) were 30 years old or less. Two-thirds (268, 67.2%) of the cohort analyzed had 1-2 children at baseline; 24.8% (n = 99) had 3-4 children, and 8.0% (n = 32) had > 4 children. Approximately half (199, 49.9%) of the women reported no modern contraceptive use in the postpartum period. Male condoms (116, 29.1%) were the most reported method of contraception; other methods reported included oral hormones (71, 17.8%) and intrauterine devices (13, 3.2%). Only disclosure of HIV status to male partner or relative (aOR = 2.0, 95% CI: 1.2-3.3; p = 0.01) and receipt of family planning counselling (aOR = 2.3, 95% CI: 1.1-4.8; p = 0.03) were positively associated with reported modern contraceptive use. Age, marital or educational status, religious affiliation, employment status, gravidity and parity were non-correlates. Conclusions: Family planning counselling and disclosure of HIV status are modifiable positive predictors of contraceptive use among our cohort of postpartum HIV-positive women in rural Nigeria. Rates of unintended pregnancy and concomitant risk of MTCT could be significantly reduced through strategies that facilitate these correlates. Clinical trials registration: Clinicaltrials.gov registration number: NCT 01936753; registered September 3, 2013. © 2019 The Author(s).
    • Short-time antibacterial effects of dimethylaminododecyl methacrylate on oral multispecies biofilm in vitro

      Zhou, Y.; Wang, S.; Zhou, X. (Hindawi Limited, 2019)
      Quaternary ammonium compounds constitute a large group of antibacterial chemicals with a potential for inhibiting dental plaque. The aims of this study were to evaluate short-time antibacterial and regulating effects of dimethylaminododecyl methacrylate (DMADDM) on multispecies biofilm viability, reformation, and bacterial composition in vitro. DMADDM, chlorhexidine (CHX), and sodium fluoride (NaF) were chosen in the present study. Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii were used to form multispecies biofilm. Cytotoxicity assay was used to determine the optimal tested concentration. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and resazurin test of biofilm were conducted to study the biomass changes and metabolic changes of controlled multispecies biofilm. Scanning electron microscopy (SEM) was used to observe biofilm images. TaqMan real-time polymerase chain reaction was performed to evaluate the proportion change in multispecies biofilm of different groups. Cytotoxicity assay showed that there existed a certain concentration application range for DMADDM, CHX, and NaF. MTT assay and resazurin test results showed that DMADDM and CHX groups decreased multispecies biofilm growth and metabolic activity (p < 0.05), no matter after 1 min or 5 min direct contact killing or after 24 h regrowth. The proportion of S. mutans decreased steadily in DMADDM and CHX groups after 1 min and 5 min direct contact killing and 24 h regrowth, compared to control groups. A novel DMADDM-containing solution was developed, achieving effective short-time antibacterial effects and regulation ability of biofilm formation. Copyright 2019 Yujie Zhou et al.
    • Iron accentuated reactive oxygen species release by NADPH oxidase in activated microglia contributes to oxidative stress in vitro 11 Medical and Health Sciences 1109 Neurosciences

      Yauger, Y.J.; Bermudez, S.; Moritz, K.E. (BioMed Central Ltd., 2019)
      Background: Excessive iron contributes to oxidative stress after central nervous system injury. NADPH oxidase (NOX) enzymes are upregulated in microglia after pro-inflammatory activation and contribute to oxidative stress. The relationship between iron, microglia, NOX, and oxidative stress is currently unclear. Methods: We evaluated the effects of iron on lipopolysaccharide (LPS)-activated microglia and its secondary effect within neuronal co-cultures. Further, NOX2 and four specific inhibitors were tested to evaluate the relationship with the reactive oxygen species (ROS)-producing enzymes. Results: An iron dose-dependent increase in ROS production among microglia treated with LPS was identified. Interestingly, despite this increase in ROS, inflammatory polarization alterations were not detected among the microglia after exposure to iron and LPS. Co-culture experimentation between primary neurons and exposed microglia (iron and LPS) significantly reduced neuronal cell number at 24 h, suggesting a profound neurotoxic effect despite the lack of a change in polarization phenotype. NOX2 and NOX4 inhibition significantly reduced ROS production among microglia exposed to iron and LPS and reduced neuronal damage and death in response to microglial co-culture. Conclusions: In conclusion, iron significantly increased ROS production and neurotoxicity without exacerbating LP-activated microglia phenotype in vitro, suggesting that iron contributes to microglia-related oxidative stress, and this may be a viable therapeutic target for injury or neurodegeneration. Further, this study highlights both NOX2 and NOX4 as potential therapeutic targets in the treatment of iron-induced microglia-related inflammation and neurotoxicity. Copyright 2019 The Author(s).
    • BMI-related cortical morphometry changes are associated with altered white matter structure

      Medic, N.; Kochunov, P.; Ziauddeen, H. (Nature Publishing Group, 2019)
      Background: While gross measures of brain structure have shown alterations with increasing body mass index (BMI), the extent and nature of such changes has varied substantially across studies. Here, we sought to determine whether small-scale morphometric measures might prove more sensitive and reliable than larger scale measures and whether they might offer a valuable opportunity to link cortical changes to underlying white matter changes. To examine this, we explored the association of BMI with millimetre-scale Gaussian curvature, in addition to standard measures of morphometry such as cortical thickness, surface area and mean curvature. We also assessed the volume and integrity of the white matter, using white matter signal intensity and fractional anisotropy (FA). We hypothesised that BMI would be linked to small-scale changes in Gaussian curvature and that this phenomenon would be mediated by changes in the integrity of the underlying white matter. Methods: The association of global measures of T1-weighted cortical morphometry with BMI was examined using linear regression and mediation analyses in two independent groups of healthy young to middle aged human subjects (n 1 = 52, n 2 = 202). In a third dataset of (n 3 = 897), which included diffusion tensor images, we sought to replicate the significant associations established in the first two datasets, and examine the potential mechanistic link between BMI-associated cortical changes and global FA. Results: Gaussian curvature of the white matter surface showed a significant, positive association with BMI across all three independent datasets. This effect was mediated by a negative association between the integrity of the white matter and BMI. Conclusions: Increasing BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults. Our results are consistent with a model whereby BMI-linked cortical changes are mediated by the effects of BMI on white matter microstructure. © 2018, Springer Nature Limited.
    • Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network

      Levy, K.D.; Blake, K.; Fletcher-Hoppe, C. (Nature Publishing Group, 2019)
      Purpose: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. Methods: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. Results: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. Conclusion: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs. Copyright 2018, The Author(s).
    • Assessing the Impact of a Vi-polysaccharide Conjugate Vaccine in Preventing Typhoid Infections Among Nepalese Children: A Protocol for a Phase III, Randomized Control Trial

      Theiss-Nyland, K.; Shakya, M.; Colin-Jones, R. (Oxford Academic, 2019)
      BACKGROUND: Enteric fever is estimated to affect 11-20 million people worldwide each year. Morbidity and mortality from enteric fever primarily occur in lower-income countries, with children under 5 years of age experiencing a significant portion of the burden. Over the last few decades, the control of enteric fever has focused primarily on improved water and sanitation, with the available vaccines unsuitable for children and primarily used by travelers. A new typhoid conjugate vaccine (Vi-TCV), prequalified by the World Health Organization (WHO) and highly immunogenic in children under 5, has the potential to reduce the typhoid burden in endemic countries. METHODS: This study is a double-blinded, randomized, controlled trial with a 2-year follow-up to assess the protective impact of the Vi-TCV vaccine, compared with a control vaccine, in children from 9 months to 16 years of age. The primary outcome of interest is the reduction in the number of culture-confirmed typhoid cases attributable to Vi-TCV. Approximately 20 000 children living in the Lalitpur district, within the Kathmandu valley, will be enrolled in the study and followed to measure both safety and efficacy data, which will include adverse events, hospitalizations, antibiotic use, and fever frequency. RESULTS: Both the intervention and control vaccines are WHO prequalified vaccines, which provide a health benefit to all participants. Children have been chosen to participate because they bear a substantial burden of both typhoid morbidity and mortality in this population. The results of this study will be disseminated through a series of published articles. The findings will also be made available to the participants and the broader community, as well as local stakeholders, within Nepal. CONCLUSIONS: This is the first large-scale, individually randomized, controlled trial of Vi-TCV in children in an endemic setting, and will provide new data on Vi-TCV field efficacy. With Vi-TCV introduction being considered in high-burden countries, this study will support important policy decisions. CLINICAL TRIALS REGISTRATION: The trial is registered on the ISRCTN registry (for details, see https://doi.org/10.1186/ISRCTN43385161; registry number: ISRCTN 43385161). Copyright The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.
    • Neuroimaging evolution of ischemia in men and women: an observational study

      Dula, A.N.; Luby, M.; King, B.T. (Wiley-Blackwell, 2019)
      Objective: We present an exploratory study for identification of sex differences in imaging biomarkers that could further refine selection of patients for acute reperfusion therapy and trials based on sex and imaging targets. Methods: The Lesion Evolution in Stroke and Ischemia On Neuroimaging (LESION) study included consecutive acute stroke patients who underwent MRI within 24-h of time from last known well and prior to therapy. Those demonstrating a potential therapeutic target on imaging were identified by presence of: (1) arterial occlusion on angiography, (2) focal ischemic region on perfusion maps, or (3) a mismatch of perfusion versus diffusion imaging lesion size. The prevalence of imaging targets within clinically relevant time intervals was calculated for each patient and examined. The relationship of time from stroke onset to probability of detection of imaging targets was evaluated. Results: Of 7007 patients screened, of which 86.7% were scanned with MRI, 1092 patients (477/615 men/women) were included in LESION. The probability of imaging target detection was significantly different between men and women, with women more likely to present with all assessed imaging targets, odds ratios between 1.36 and 1.59, P<0.02, adjusted for NIHSS, age, and time from last known well to MRI scan. This trend held for the entire 24-h studied. Interpretation: Women present more often with treatable ischemic stroke than men. The greater probability of potentially viable and/or treatable imaging targets in women at all time points suggests that tissue injury is slower to evolve in women. Copyright 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.