Rational use of antibiotics by community health workers and caregivers for children with suspected pneumonia in Zambia: A cross-sectional mixed methods study

Background: Antibiotic resistance is an issue of growing global concern. One key strategy to minimise further development of resistance is the rational use of antibiotics, by providers and patients alike. Through integrated community case management (iCCM), children diagnosed with suspected pneumonia are treated with antibiotics; one component of an essential package to reduce child mortality and increase access to health care for remote populations. Through the use of clinical algorithms, supportive supervision and training, iCCM also offers the opportunity to improve the rational use of antibiotics and limit the spread of resistance in resource-poor contexts. This study provides evidence on antibiotic use by community health workers (CHWs) and caregivers to inform iCCM programmes, safeguarding current treatments whilst maximising access to care. Methods: 1497 CHW consultations were directly observed by non-clinical researchers, with measurement of respiratory rate by CHWs recorded by video. Videos were used to conduct a retrospective reference standard assessment of respiratory rate by experts. Fifty-five caregivers whose children were prescribed a 5-day course of antibiotics for suspected pneumonia were followed up on day six to assess adherence through structured interviews and pill counts. Six focus group discussions and nine in depth interviews were conducted with CHWs and caregivers to supplement quantitative findings. Results: The findings indicate that CHWs adhered to treatment guidelines for 92 % of children seen, prescribing treatment corresponding to their assessment. However, only 65 % of antibiotics prescribed were given for children with experts' confirmed fast breathing pneumonia. Qualitative data indicates that CHWs have a good understanding of pneumonia diagnosis, and although caregivers sometimes applied pressure to receive drugs, CHWs stated that treatment decisions were not influenced. 46 % of caregivers were fully adherent and gave their child the full 5-day course of dispersible amoxicillin. If caregivers who gave treatment for 3 to 5 days were considered, adherence increased to 76 %. Conclusions: CHWs are capable of prescribing treatment corresponding to their assessment of respiratory rate. However, rational use of antibiotics could be strengthened through improved respiratory rate assessment, and better diagnostic tools. Furthermore, a shorter course of dispersible amoxicillin could potentially improve caregiver adherence, reducing risk of resistance and cost

Potential enhancement of post-stroke angiogenic response by targeting the oligomeric aggregation of p53 protein

Tumor suppressor gene p53 and its aggregate have been found to be involved in many angiogenesis-related pathways. We explored the possible p53 aggregation formation mechanisms commonly occur after ischemic stroke, such as hypoxia and the presence of reactive oxygen species (ROS). The angiogenic pathways involving p53 mainly occur in nucleus or cytoplasm, with one exception that occurs in mitochondria. Considering the high mitochondrial density in brain and endothelial cells, we proposed that the cyclophilin D (CypD)-dependent vascular endothelial cell (VECs) necrosis pathway occurring in the mitochondria is one of the major factors that affects angiogenesis. Hence, targeting p53 aggregation, a key intermediate in the pathway, could be an alternative therapeutic target for post-stroke management

Regulation of fibroblast Fas expression by soluble and mechanical pro-fibrotic stimuli

Abstract Background Fibroblast apoptosis is a critical component of normal repair and the acquisition of an apoptosis-resistant phenotype contributes to the pathogenesis of fibrotic repair. Fibroblasts from fibrotic lungs of humans and mice demonstrate resistance to apoptosis induced by Fas-ligand and prior studies have shown that susceptibility to apoptosis is enhanced when Fas (CD95) expression is increased in these cells. Moreover, prior work shows that Fas expression in fibrotic lung fibroblasts is reduced by epigenetic silencing of the Fas promoter. However, the mechanisms by which microenvironmental stimuli such as TGF-β1 and substrate stiffness affect fibroblast Fas expression are not well understood. Methods Primary normal human lung fibroblasts (IMR-90) were cultured on tissue culture plastic or on polyacrylamide hydrogels with Young’s moduli to recapitulate the compliance of normal (400 Pa) or fibrotic (6400 Pa) lung tissue and treated with or without TGF-β1 (10 ng/mL) in the presence or absence of protein kinase inhibitors and/or inflammatory cytokines. Expression of Fas was assessed by quantitative real time RT-PCR, ELISA and Western blotting. Soluble Fas (sFas) was measured in conditioned media by ELISA. Apoptosis was assessed using the Cell Death Detection Kit and by Western blotting for cleaved PARP. Results Fas expression and susceptibility to apoptosis was diminished in fibroblasts cultured on 6400 Pa substrates compared to 400 Pa substrates. TGF-β1 reduced Fas mRNA and protein in a time- and dose-dependent manner dependent on focal adhesion kinase (FAK). Surprisingly, TGF-β1 did not significantly alter cell-surface Fas expression, but did stimulate secretion of sFas. Finally, enhanced Fas expression and increased susceptibility to apoptosis was induced by combined treatment with TNF-α/IFN-γ and was not inhibited by TGF-β1. Conclusions Soluble and matrix-mediated pro-fibrotic stimuli promote fibroblast resistance to apoptosis by decreasing Fas transcription while stimulating soluble Fas secretion. These findings suggest that distinct mechanisms regulating Fas expression in fibroblasts may serve different functions in the complex temporal and spatial evolution of normal and fibrotic wound-repair responses.https://deepblue.lib.umich.edu/bitstream/2027.42/143539/1/12931_2018_Article_801.pd

ATLAS Run 1 searches for direct pair production of third-generation squarks at the Large Hadron Collider

This paper reviews and extends searches for the direct pair production of the scalar supersymmetric partners of the top and bottom quarks in proton-proton collisions collected by the ATLAS collaboration during the LHC Run 1. Most of the analyses use 20 fb$^{-1}$ of collisions at a centre-of-mass energy of $\sqrt{s}$ = 8 TeV, although in some case an additional 4.7 fb$^{-1}$ of collision data at $\sqrt{s}$ = 7 TeV are used. New analyses are introduced to improve the sensitivity to specific regions of the model parameter space. Since no evidence of third-generation squarks is found, exclusion limits are derived by combining several analyses and are presented in both a simplified model framework, assuming simple decay chains, as well as within the context of more elaborate phenomenological supersymmetric models

Pathogen infection and selection on fertilization success in Cucumis sativus

We investigated whether resistant pollen genotypes can be selected for when the maternal plants are infected and whether infection can result to changes in the pistil nutrient level influencing reproductive outcome. Both resistance and susceptibility come with costs that may affect pre- and post-fertilization reproductive functions. We performed the study by crossing zucchini yellow mosaic virus resistant and susceptible pollen (from a hybrid donor) to infected and healthy maternal plants. We also analysed the pistil nutrient content in both treatments and found an increase of the susceptible and not resistant genotypes when maternal plants were infected. The level of nutrients K, P and S was higher in the pistils of the infected maternal plants than the healthy ones. Pistil nutrient level did not affect pollen tube growth rates, as indicated by seed siring patterns along the fruit. We propose that the effect on the siring ability of pollen carrying the susceptible and resistant alleles occurred at the post-fertilization stage, possibly as an indirect result of different growth rates of the two embryo genotypes under elevated nutrient conditions. We discuss our results with respect to possibilities of differential selection, costs and reproductive implications

Pathogen infection and selection on fertilization success in Cucumis sativus

We investigated whether resistant pollen genotypes can be selected for when the maternal plants are infected and whether infection can result to changes in the pistil nutrient level influencing reproductive outcome. Both resistance and susceptibility come with costs that may affect pre- and post-fertilization reproductive functions. We performed the study by crossing zucchini yellow mosaic virus resistant and susceptible pollen (from a hybrid donor) to infected and healthy maternal plants. We also analysed the pistil nutrient content in both treatments and found an increase of the susceptible and not resistant genotypes when maternal plants were infected. The level of nutrients K, P and S was higher in the pistils of the infected maternal plants than the healthy ones. Pistil nutrient level did not affect pollen tube growth rates, as indicated by seed siring patterns along the fruit. We propose that the effect on the siring ability of pollen carrying the susceptible and resistant alleles occurred at the post-fertilization stage, possibly as an indirect result of different growth rates of the two embryo genotypes under elevated nutrient conditions. We discuss our results with respect to possibilities of differential selection, costs and reproductive implications

Garnet fracturing reveals ancient unstable slip events hosted in plate interface metasediments

A paradox exists between the great number of intermediate-depth earthquakes occurring along active subduction interfaces worldwide and the extreme scarcity of paleo-seismic events recorded in exhumed metasediments from ancient subducted slabs. Recrystallization associated with exhumation-related overprinting generally contributes to the nearly-complete erasing of markers of unstable slip events in metamorphic rocks. We herein focus on a sample from an ancient deep thrust from a Cretaceous High-Pressure paleo-accretionary complex in Chilean Patagonia. A representative, moderately foliated micaschist exhibits broken garnet crystals that host a dense network of healed micro-fractures. While garnet fragments appear thoroughly disaggregated along the main foliation, the rock matrix that completely recrystallized has lost the record of brittle deformation. We employ a 2D visco-elasto-plastic numerical modelling approach in order to investigate the mechanical conditions that enable the fracturing of isolated garnet grains in a relatively weak matrix. The rupture of these stiff grains is achieved in our models at strain rates faster than 10−10 /s to 10−12 /s for elevated pore fluid pressures (80 to 99 % of the lithostatic value, respectively). Since high pore fluid pressures prevail in deep subduction interface settings, it is suggested that the rupture of these garnet crystals occurred through cataclastic deformation via (transient) slip rate acceleration, perhaps as a consequence of localized slip associated with slow to conventional earthquakes. Upon slip rate deceleration, viscous disaggregation of the broken garnet clasts occurred along with the erasing of the matrix cataclastic fabric.</p

Garnet fracturing reveals ancient unstable slip events hosted in plate interface metasediments

International audienceA paradox exists between the great number of intermediate-depth earthquakes occurring along active subduction interfaces worldwide and the extreme scarcity of paleo-seismic events recorded in exhumed metasediments from ancient subducted slabs. Recrystallization associated with exhumation-related overprinting generally contributes to the nearly-complete erasing of markers of unstable slip events in metamorphic rocks. We herein focus on a sample from an ancient deep thrust from a Cretaceous High-Pressure paleo-accretionary complex in Chilean Patagonia. A representative, moderately foliated micaschist exhibits broken garnet crystals that host a dense network of healed micro-fractures. While garnet fragments appear thoroughly disaggregated along the main foliation, the rock matrix that completely recrystallized has lost the record of brittle deformation. We employ a 2D visco-elasto-plastic numerical modelling approach in order to investigate the mechanical conditions that enable the fracturing of isolated garnet grains in a relatively weak matrix. The rupture of these stiff grains is achieved in our models at strain rates faster than 10 -10 /s to 10 -12 /s for elevated pore fluid pressures (80 to 99 % of the lithostatic value, respectively). Since high pore fluid pressures prevail in deep subduction interface settings, it is suggested that the rupture of these garnet crystals occurred through cataclastic deformation via (transient) slip rate acceleration, perhaps as a consequence of localized slip associated with slow to conventional earthquakes. Upon slip rate deceleration, viscous disaggregation of the broken garnet clasts occurred along with the erasing of the matrix cataclastic fabric