Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have ...indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.
Soil and bedrock weathering and phosphate (P) fertilizers may both contribute to the uranium (U) load of rivers in agricultural regions, but controls over their relative influence are not well known. ...This study investigates the U sources to rivers in Ohio, United States, part of the Eastern Corn Belt in the Mississippi River watershed. We present a regional picture of seasonal U sources to rivers based on four analyses: 1) a spatial analysis of legacy soil and water data, 2) new measurements of U and carbonate weathering products from rivers at 50 locations across the state collected seasonally over two years, 3) a weekly time series with additional 234U/238U (n = 5) and 87Sr/86Sr (n = 5) measurements from an agricultural river, and 4) a mass-balance approach to U addition to the landscape based on reported P fertilizer use. Uranium concentrations in surface waters collected statewide ranged 0.1–21 nM (n = 132), with significantly higher concentrations in the glaciated agricultural portion of the state (mean = 7.3 nM; n = 105) than the non-glaciated portion (mean = 2.0 nM; n = 24). Concentrations in the glaciated region were highest during the spring and summer and decreased during baseflow. In the time-series, concentrations were ~7 nM during baseflow and ~14 nM during intermediate seasonal discharge conditions, indicating a second more surficial endmember source of U in addition to bedrock weathering that is well correlated with other carbonate weathering products. Systematic increases in 87Sr/86Sr and decreases in 234U/238U with increasing discharge confirm a changing source of carbonate and U weathering and a third surficial endmember during high discharge events. Our mass balance approach and geochemical analysis suggest that elevated U concentrations are the result of carbonate weathering deep in the soil column during elevated seasonal flow. Further work on U dynamics in agricultural rivers is required to understand mechanism controlling seasonal changes in U concentrations and 234U/238U in downstream rivers and U flux.
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•Glacial history, lithology, and P fertilizers can control U load in agricultural rivers.•Relative U inputs from weathering and fertilizer sources are not well known.•Seasonal elevated riverine U is associated with activation of glacial till flow paths.•U and Sr isotopes point to multiple carbonate sources of U with changing discharge.
The growing demand for plasma protein products has caused concern in many countries who largely rely on importing plasma products produced from plasma collected in the United States and Europe. ...Optimizing recruitment and retention of a diversity of plasma donors is therefore important for supporting national donation systems that can reliably meet the most critical needs of health services. This series of three systematic reviews aims to synthesize the known barriers and enablers to source plasma donation from the qualitative and survey-based literature and identify which strategies that have shown to be effective in promoting increased intention to, and actual donation of, source plasma.
Primary studies involving source or convalescent plasma donation via plasmapheresis will be included. The search strategy will capture all potentially relevant studies to each of the three reviews, creating a database of plasma donation literature. Study designs will be subsequently identified in the screening process to facilitate analysis according to the unique inclusion criteria of each review (i.e., qualitative, survey, and experimental designs). The search will be conducted in the electronic databases SCOPUS, MEDLINE, EMBASE, PsycINFO, and CINAHL without date or language restrictions. Studies will be screened, and data will be extracted, in duplicate by two independent reviewers with disagreements resolved through consensus. Reviews 1 and 2 will draw on the Theoretical Domains Framework and Intersectionality, while Review 3 will be informed by Behaviour Change Intervention Ontologies. Directed content analysis and framework analysis (Review 1), and descriptive and inferential syntheses (Reviews 2 and 3), will be used, including meta-analyses if appropriate.
This series of related reviews will serve to provide a foundation of what is known from the published literature about barriers and enablers to, and strategies for promoting, plasma donation worldwide.
80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative ...outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality.
This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494.
Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications.
Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications.
National Institute for Health Research Global Health Research Unit.
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•Dehydration conditions yielding highly reactive MgO for energy storage were found.•Controlling dehydration avoids the need for chemical modification by doping.•Controlled dehydration ...prevents premature material fatigue.•Impurities in MgO from natural magnesite significantly affect rehydration performance.
Systematic variation of the dehydration temperature and time enables the preparation of highly reactive magnesium oxide for thermochemical energy storage purposes. The reactivity of the MgO, resulting from varying dehydration conditions has been studied by a comparative approach, including reactive surface area, particle morphology and reactivity towards rehydration. For the rehydration an in-situ powder X-Ray diffraction setup is used, allowing for continuous monitoring of Mg(OH)2 formation. The outcome of this investigation was subsequently applied to MgO from natural magnesites to assess the impact of impurities in the material on rehydration reactivity.
Mutations that result in the loss of the protein dysferlin result in defective muscle membrane repair and cause either a form of limb girdle muscular dystrophy (type 2B) or Miyoshi myopathy. Most ...patients are compound heterozygotes, often carrying one allele with a nonsense mutation. Using dysferlin-deficient mouse and human myocytes, we demonstrated that membrane blebbing in skeletal muscle myotubes in response to hypotonic shock requires dysferlin. Based on this, we developed an in vitro assay to assess rescue of dysferlin function in skeletal muscle myotubes. This blebbing assay may be useful for drug discovery/validation for dysferlin deficiency. With this assay, we demonstrate that the nonsense suppression drug, ataluren (PTC124), is able to induce read-through of the premature stop codon in a patient with a R1905X mutation in dysferlin and produce sufficient functional dysferlin (approximately 15% of normal levels) to rescue myotube membrane blebbing. Thus ataluren is a potential therapeutic for dysferlin-deficient patients harboring nonsense mutations.
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•Transition metal salts react reversibly and highly exothermic with ammonia.•Highest storage densities are 8.75 GJ m−3 for NiCl2 and 6.38 GJ m−3 for CuSO4.•Ammonia uptake and release ...is fully reversible.•Transition metal sulphates feature perfect cycle stability.•Operational temperature window for energy storage ranges between 25 and 350 °C.
Materials with high volumetric energy storage capacities are targeted for high-performance thermochemical energy storage systems. The reaction of transition metal salts with ammonia, forming reversibly the corresponding ammonia-coordination compounds, is still an under-investigated area for energy storage purposes, although, from a theoretical perspective this should be a good fit for application in medium-temperature storage solutions between 25 °C and 350 °C.
In the present study, the potential of reversible ammoniation of a series of transition metal chlorides and sulphates with gaseous ammonia for suitability as thermochemical energy storage system was investigated. Among the investigated metal chlorides and sulphates, candidates combining high energy storage densities and cycle stabilities were found. For metal chlorides, during the charging / discharging cycles in the presence of ammonia slow degradation and evaporation of the materials was observed. This issue was circumvented by reducing the operating temperature and cycling between different degrees of ammoniation, e.g. in the case of NiCl2 by cycling between Ni(NH3)2Cl2 and Ni(NH3)6Cl2. In contrast, sulphates are perfectly stable under all investigated conditions. The combination of CuSO4 and NH3 provided the most promising result directing towards applicability, as the high energy storage density of 6.38 GJ m−3 is combined with full reversibility of the storage reaction and no material degradation over cycling. The results of this comparative systematic material evaluation encourage for a future consideration of the so far underrepresented transition metal ammoniates as versatile thermochemical energy storage materials.
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•Isothermal PbO/PbCO3·2PbO energy storage system based on CO2 pressure cycling.•MnO and PbO carbonate below 50 bar of CO2 pressure between 25 and 500 °C.•Moisture is crucial for ...carbonation of the metal oxides.•Chemical history and origin govern performance of thermochemical storage materials.
Metal carbonates are attractive materials for combining carbon capture and thermochemical energy storage. Carbonate materials feature high decomposition and formation temperatures and may be considered in applications in combination with concentrating solar power. In the present study in-situ P-XRD carbonation (1–8 bar CO2) and reactor-based experiments (1–55 bar CO2) are combined focusing on the effect of elevated CO2 pressures on carbonation of metal oxides. Carbonation of MnO and PbO at CO2 pressures between 8 and 50 bar in the presence of moisture resulted in reaction with CO2, forming the corresponding carbonates at notably lower temperatures than under dry CO2 atmosphere of 1 bar. This enables the application of metal oxide/metal carbonate reaction couples for energy storage at temperatures between 25 and 500 °C. Based on the reversible carbonation/decarbonation of PbO under varying CO2 pressures, an isothermal storage cycle between PbO/PbCO3·2PbO, triggered by changing the CO2 pressure between 2 and 8 bar, was developed.
Abstract
Background
In adults, anti–tumor necrosis factor-α (TNF-α) therapy is associated with progression of latent tuberculosis (TB) infection (LTBI) to TB disease, but pediatric data are limited.
...Methods
Retrospective multicenter study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti–TNF-α therapy.
Results
Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified: Crohn’s disease (n = 8; 42%) and juvenile idiopathic arthritis (n = 6; 32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-γ release assay) was performed in 15 patients before commencing anti–TNF-α therapy but only identified 1 LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti–TNF-α therapy and TB diagnosis was 13.1 (IQR, 7.1–20.3) months. All cases presented with severe disease, predominantly miliary TB (n = 14; 78%). One case was diagnosed postmortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR, 46–66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae.
Conclusions
LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti–TNF-α therapy are prone to severe TB disease and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low-TB-prevalence settings.
Children and adolescents on tumor necrosis factor-ɑ inhibitors are prone to severe tuberculosis disease, especially miliary tuberculosis, resulting in significant morbidity. False-negative immunodiagnostic tests are common and a low threshold to initiate targeted investigations is recommended.
Purpose
– The purpose of this paper is to examine challenges and potential of big data in heterogeneous business networks and relate these to an implemented logistics solution.
...Design/methodology/approach
– The paper establishes an overview of challenges and opportunities of current significance in the area of big data, specifically in the context of transparency and processes in heterogeneous enterprise networks. Within this context, the paper presents how existing components and purpose-driven research were combined for a solution implemented in a nationwide network for less-than-truckload consignments.
Findings
– Aside from providing an extended overview of today’s big data situation, the findings have shown that technical means and methods available today can comprise a feasible process transparency solution in a large heterogeneous network where legacy practices, reporting lags and incomplete data exist, yet processes are sensitive to inadequate policy changes.
Practical implications
– The means introduced in the paper were found to be of utility value in improving process efficiency, transparency and planning in logistics networks. The particular system design choices in the presented solution allow an incremental introduction or evolution of resource handling practices, incorporating existing fragmentary, unstructured or tacit knowledge of experienced personnel into the theoretically founded overall concept.
Originality/value
– The paper extends previous high-level view on the potential of big data, and presents new applied research and development results in a logistics application.
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