Imaging-SIMS (Secondary Ion Mass Spectroscopy) Studies of Advanced Materials

This article describes the application of scanning ion microprobe (SIM) microanalysis for the characterization of advanced engineered materials. In conjunction with secondary ion mass spectrometry (SIMS), scanning ion microprobes can image elemental distributions over surfaces with high lateral resolution (50-100 nm). With this technique, most elements, including isotopes, can be detected with good sensitivity. The principles and instrumentation associated with the SIM/SIMS technique are briefly described and ongoing developments are outlined. The analytical capabilities of the technique are illustrated by case studies of aluminum-lithium alloys, zinc oxide varistors, aluminum matrix composites, and photographic materials

Ion Microscopy: A New Approach for Subcellular Localization of Labelled Molecules

Secondary ion mass spectroscopy (SIMS) was used to obtain images representing the intracellular distribution of molecules labelled with carbon 14. Deoxyadenosine labelled with carbon 14 was added to a cultured human fibroblast cell medium, and the intracellular distribution of this molecule was studied using three different SIMS instruments: the CAMECA IMS 3F and SMI 300 ion microscopes and the UC-HRL scanning ion microprobe. Carbon 14 distribution images obtained by this method show that deoxyadenosine U-C14 is present in the cytoplasm as well as the nucleus, with a higher concentration in\u27 the nucleoli. Our study clearly demonstrates that ion microscopy is well suited for carbon 14 detection and localization at the subcellular level, permitting a wide variety of microanalytical tracer experiments

Eliciting experts’ tacit models for the interpretation of soil information, an example from the evaluation of potential benefits from conservation agriculture

© 2020 The Authors We examined a procedure to elicit the tacit models underlying expert opinions on environmental factors that affect the absolute yield benefits expected from the adoption of conservation agriculture (CA) practices in southern Africa. The procedure is based on expert evaluation of the expected improvement in crop yield on adoption of CA in a particular scenario or ‘state’, a state being a specified set of soil conditions captured by a standard soil profile description from a specified agroecological zone (AEZ) of Zambia. Mixed groups of scientists including soil scientists, agronomists, agricultural economists and other environmental scientists, facilitated by experienced senior researchers, were presented with multiple subsets each of three states, and asked to rank the states in each subset with respect to expected yield improvement under CA. The groups of scientists could be divided into two sets. Each set comprised two groups, and the agreement on ranking between groups within each set was larger than would be expected if the ranking were done at random. For both sets of groups the ranking could be modelled with respect to properties of the soil, and the contrast between AEZ. The models revealed two contrasting groups of conceptual assumptions. One group broadly expected larger absolute yield improvements from conservation agriculture in settings where water is most likely to be limiting and the carbon status of the soil is poor. By contrast, the other group expected larger improvements where water was less likely to be limiting. These contrasting views are relevant to current discussions as to whether conservation agriculture, which is promoted as a ‘climate smart’ strategy for cropping, is sufficiently attractive for smallholder producers in conditions where crop production is already challenging, and whether the potential benefits in areas where water availability is not of itself a common limitation should be considered. The elicited models could be translated directly into competing hypotheses to be tested, perhaps in on-farm trials of conservation agriculture practices over contrasting soils in the different AEZ. The method, based on modelling the ranking process, could be of more general interest for the elicitation of expert opinion about complex soil, crop and environmental systems

Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial

BACKGROUND: Dolutegravir (DTG), combined with a backbone of two NRTIs, is currently the preferred first-line treatment for HIV in childhood. CHAPAS4 is an ongoing randomized controlled trial (#ISRCTN22964075) investigating second-line treatment options for children with HIV. We did a nested PK substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food, as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4-trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets (DT) and children ≥20 kg took 50 mg film-coated tablets (FCT). Steady-state 24 h DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 h after observed DTG intake with food. Reference adult PK data and paediatric data from the ODYSSEY-trial was used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: 39 children on DTG were included in this PK substudy. The Geometric Mean (GM), (CV%) AUC0-24h was 57.1 h*mg/L (38.4%) which was approximately 8% below the average AUC0-24h in children in the ODYSSEY-trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%) which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY-trial and adult references

Inadequate lopinavir concentrations with modified 8-hourly lopinavir/ritonavir 4:1 dosing during rifampicin-based tuberculosis treatment in children living with HIV

BACKGROUND: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. METHODS: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. RESULTS: Of 20 children enrolled; 15, 1-7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve 0-24 55.32 mg/h/L [0.30-398.7 mg/h/L]; C max 3.04 mg/L [0.03-18.6 mg/L]; C 8hr 0.90 mg/L [0.01-13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve 24 121.63 mg/h/L [2.56-487.3 mg/h/L]; C max 9.45 mg/L [0.39-26.4 mg/L]; C 12hr 3.03 mg/L [0.01-17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. CONCLUSIONS: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation

Prevalence and risk factors for Betaherpesvirus DNAemia in children >3 weeks and <2 years of age admitted to a large referral hospital in sub-Saharan Africa

Background. Betaherpesviruses are established causes of morbidity and mortality in immunosuppressed patient groups but have been little studied in sub-Saharan Africa, the epicenter of the human immunodeficiency virus (HIV) pandemic. In this region, primary infections with human cytomegalovirus (HCMV) and human herpesvirus type 6 (HHV-6) type 6 are endemic in infancy, but the clinical impact of these infections among pediatric inpatient groups is poorly characterized and assumptive, based largely on data from Western populations. Methods. We used TaqMan polymerase chain reaction to screen sera from a group of 303 pediatric inpatients aged between 3 weeks and 2 years, at the University Teaching Hospital in Lusaka, Zambia. We report the prevalence of DNAemia and viral loads within this patient group, and evaluate possible clinical associations/risk factors for betaherpesvirus infections in these hospitalized children. Results. We detected betaherpesvirus DNAemia in 59.1% (179/303) of children. HCMV was the most prevalent (41.3%), followed by HHV-6B (20.5%), HHV-7 (20.1%), and HHV-6A (0.3%). HIV infection (odds ratio OR], 2.31; 95% confidence interval CI], 1.37-3.90; P = .002), being underweight (OR, 1.82; 95% CI, 1.06-3.12; P = .03), and an admission diagnosis of suspected meningitis (OR, 5.72; 95% CI, 1.07-30.5; P = .041) were independently associated with an increased odds of HCMV DNAemia. Conversely, HHV-6B and HHV-7 DNAemia were not associated with HIV, underweight, or admission diagnosis. Median HCMV viral load was moderately but significantly higher in HIV-infected children. Conclusions. Highly prevalent HCMV DNAemia was independently associated with HIV infection and being underweight across all age groups, and was also associated with meningitis, with previously underappreciated implications for the health and development of African children

First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial

BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075

Clinical standards for drug-susceptible TB in children and adolescents

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents. METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document. RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent. CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.National Institutes of HealthRevisión por pare

Impact of systematic early tuberculosis detection using Xpert MTB/RIF Ultra in children with severe pneumonia in high tuberculosis burden countries (TB-Speed pneumonia): a stepped wedge cluster randomized trial

Background In high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples. Methods TB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks post-discharge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial. Discussion In addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children, the strength of such pragmatic research is that it provides some evidence regarding the feasibility of the intervention as part of routine care. Should this intervention be successful, safe and well tolerated, it could be systematically implemented at district hospital level where children with severe pneumonia are referred. Trial registration ClinicalTrials.gov, NCT03831906. Registered 6 February 2019