Design and application of a multi-modal process tomography system

This paper presents a design and application study of an integrated multi-modal system designed to support a range of common modalities: electrical resistance, electrical capacitance and ultrasonic tomography. Such a system is designed for use with complex processes that exhibit behaviour changes over time and space, and thus demand equally diverse sensing modalities. A multi-modal process tomography system able to exploit multiple sensor modes must permit the integration of their data, probably centred upon a composite process model. The paper presents an overview of this approach followed by an overview of the systems engineering and integrated design constraints. These include a range of hardware oriented challenges: the complexity and specificity of the front end electronics for each modality; the need for front end data pre-processing and packing; the need to integrate the data to facilitate data fusion; and finally the features to enable successful fusion and interpretation. A range of software aspects are also reviewed: the need to support differing front-end sensors for each modality in a generic fashion; the need to communicate with front end data pre-processing and packing systems; the need to integrate the data to allow data fusion; and finally to enable successful interpretation. The review of the system concepts is illustrated with an application to the study of a complex multi-component process

The Erpenbeck high frequency instability theorem for ZND detonations

The rigorous study of spectral stability for strong detonations was begun by J.J. Erpenbeck in [Er1]. Working with the Zeldovitch-von Neumann-D\"oring (ZND) model, which assumes a finite reaction rate but ignores effects like viscosity corresponding to second order derivatives, he used a normal mode analysis to define a stability function V(\tau,\eps) whose zeros in $\Re \tau>0$ correspond to multidimensional perturbations of a steady detonation profile that grow exponentially in time. Later in a remarkable paper [Er3] he provided strong evidence, by a combination of formal and rigorous arguments, that for certain classes of steady ZND profiles, unstable zeros of $V$ exist for perturbations of sufficiently large transverse wavenumber \eps, even when the von Neumann shock, regarded as a gas dynamical shock, is uniformly stable in the sense defined (nearly twenty years later) by Majda. In spite of a great deal of later numerical work devoted to computing the zeros of V(\tau,\eps), the paper \cite{Er3} remains the only work we know of that presents a detailed and convincing theoretical argument for detecting them. The analysis in [Er3] points the way toward, but does not constitute, a mathematical proof that such unstable zeros exist. In this paper we identify the mathematical issues left unresolved in [Er3] and provide proofs, together with certain simplifications and extensions, of the main conclusions about stability and instability of detonations contained in that paper. The main mathematical problem, and our principal focus here, is to determine the precise asymptotic behavior as \eps\to \infty of solutions to a linear system of ODEs in $x$, depending on \eps and a complex frequency $\tau$ as parameters, with turning points $x_*$ on the half-line $[0,\infty)$

Resistance in Enterobacterales Is Higher among People Living with Human Immunodeficiency Virus

Background: Multidrug-resistant Enterobacterales (MDR-E) are important pathogens. People living with human immunodeficiency virus (HIV; PLWH) may be at greater risk for MDR-E infection given relatively high antibiotic exposure and burden of comorbidities. Methods: We analyzed data from 36 521 patients in a healthcare system in North Carolina who had a clinical culture with growth of an Enterobacterales species from 2000 to 2018; 440 were PLWH. We used generalized linear models to estimate prevalence ratios and differences, contrasting PLWH and people not living with HIV (PNLWH) for resistance to individual antibiotic classes, as well as MDR-E. We assessed trends in prevalence over time by calculating the 5-year moving average and fitting restricted cubic spline models. Results: The overall prevalence of MDR-E was higher among PLWH (21.5%; 95% confidence interval [CI], 18.2%-25.1%) vs PNLWH (16.5%; 95% CI, 16.2%-16.9%), with an adjusted prevalence ratio of 1.38 (95% CI, 1.14-1.65). PLWH had higher rates of antimicrobial resistance than PNLWH for all antibiotic classes analyzed, including penicillins, penicillin/beta lactamase inhibitor combinations, and sulfonamides. MDR-E prevalence was 3 to 10 percentage points higher among PLWH than PNLWH throughout the study period based on the 5-year moving average. Conclusions: In a large clinical study population in the southeastern United States from 2000 to 2018, the prevalence of antibacterial resistance among Enterobacterales was consistently higher among PLWH than PNLWH. These data highlight the importance of identifying and mitigating the factors that contribute to antimicrobial resistance in PLWH, given the potential clinical consequences of these resistant pathogens

Predicting Risk of Multidrug-Resistant Enterobacterales Infections Among People With HIV

Background: Medically vulnerable individuals are at increased risk of acquiring multidrug-resistant Enterobacterales (MDR-E) infections. People with HIV (PWH) experience a greater burden of comorbidities and may be more susceptible to MDR-E due to HIV-specific factors. Methods: We performed an observational study of PWH participating in an HIV clinical cohort and engaged in care at a tertiary care center in the Southeastern United States from 2000 to 2018. We evaluated demographic and clinical predictors of MDR-E by estimating prevalence ratios (PRs) and employing machine learning classification algorithms. In addition, we created a predictive model to estimate risk of MDR-E among PWH using a machine learning approach. Results: Among 4734 study participants, MDR-E was isolated from 1.6% (95% CI, 1.2%-2.1%). In unadjusted analyses, MDR-E was strongly associated with nadir CD4 cell count ≤200 cells/mm3 (PR, 4.0; 95% CI, 2.3-7.4), history of an AIDS-defining clinical condition (PR, 3.7; 95% CI, 2.3-6.2), and hospital admission in the prior 12 months (PR, 5.0; 95% CI, 3.2-7.9). With all variables included in machine learning algorithms, the most important clinical predictors of MDR-E were hospitalization, history of renal disease, history of an AIDS-defining clinical condition, CD4 cell count nadir ≤200 cells/mm3, and current CD4 cell count 201-500 cells/mm3. Female gender was the most important demographic predictor. Conclusions: PWH are at risk for MDR-E infection due to HIV-specific factors, in addition to established risk factors. Early HIV diagnosis, linkage to care, and antiretroviral therapy to prevent immunosuppression, comorbidities, and coinfections protect against antimicrobial-resistant bacterial infections

Relationship of Racial Residential Segregation to Newly Diagnosed Cases of HIV among Black Heterosexuals in US Metropolitan Areas, 2008–2015

Social science and public health literature has framed residential segregation as a potent structural determinant of the higher HIV burden among black heterosexuals, but empirical evidence has been limited. The purpose of this study is to test, for the first time, the association between racial segregation and newly diagnosed heterosexually acquired HIV cases among black adults and adolescents in 95 large US metropolitan statistical areas (MSAs) in 2008–2015. We operationalized racial segregation (the main exposure) using Massey and Denton’s isolation index for black residents; the outcome was the rate of newly diagnosed HIV cases per 10,000 black adult heterosexuals. We tested the relationship of segregation to this outcome using multilevel multivariate models of longitudinal (2008–2015) MSA-level data, controlling for potential confounders and time. All covariates were lagged by 1 year and centered on baseline values. We preliminarily explored mediation of the focal relationship by inequalities in education, employment, and poverty rates. Segregation was positively associated with the outcome: a one standard deviation decrease in baseline isolation was associated with a 16.2% reduction in the rate of new HIV diagnoses; one standard deviation reduction in isolation over time was associated with 4.6% decrease in the outcome. Exploratory mediation analyses suggest that black/white socioeconomic inequality may mediate the relationship between segregation and HIV. Our study suggests that residential segregation may be a distal determinant of HIV among black heterosexuals. The findings further emphasize the need to address segregation as part of a comprehensive strategy to reduce racial inequities in HIV

Evidence for HIV transmission across key populations: a longitudinal analysis of HIV and AIDS rates among Black people who inject drugs and Black heterosexuals in 84 large U.S. metropolitan areas, 2008–2016

Purpose: To assess cross-population linkages in HIV/AIDS epidemics, we tested the hypothesis that the number of newly diagnosed AIDS cases among Black people who inject drugs (PWID) was positively related to the natural log of the rate of newly diagnosed HIV infections among Black non-PWID heterosexuals in 84 large U.S. metropolitan statistical areas (MSAs) in 2008–2016. Methods: We estimated a multilevel model centering the time-varying continuous exposures at baseline between the independent (Black PWID AIDS rates) and dependent (HIV diagnoses rate among Black heterosexuals) variables. Results: At MSA level, baseline (standardized β = 0.12) Black PWID AIDS rates and change in these rates over time (standardized β = 0.11) were positively associated with the log of new HIV diagnoses rates among Black heterosexuals. Thus, MSAs with Black PWID AIDS rates that were 1 standard deviation= higher at baseline also had rates of newly diagnosed HIV infections among Black non-PWID heterosexuals that were 10.3% higher. A 1 standard deviation increase in independent variable over time corresponded to a 7.8% increase in dependent variable. Conclusions: Black PWID AIDS rates may predict HIV rates among non-PWID Black heterosexuals. Effective HIV programming may be predicated, in part, on addressing intertwining of HIV epidemics across populations

Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies.

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved

Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension

Objectives To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Methods Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Results Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Conclusions Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function. Trial registration number NCT02526160