Sustained Reduction in Third-generation Cephalosporin Usage in Adult Inpatients Following Introduction of an Antimicrobial Stewardship Program in a Large, Urban Hospital in Malawi

Background Third-generation cephalosporins (3GC) remain the first-choice empiric antibiotic for severe infection in many sub-Saharan African hospitals. In Malawi, limited availability of alternatives, mean that strategies to prevent spread of 3GC-resistance (3GC-R) are imperative, however suitable approaches to antimicrobial stewardship (AMS) in low-income settings are not well studied. Methods We introduced an AMS intervention to Queen Elizabeth Central Hospital (QECH) in Blantyre. The intervention consisted of a smartphone prescribing application and regular point-prevalence surveys (PPS) with prescriber feedback. We evaluate the effects of the intervention on 3GC usage and on cost of providing antibiotics. Using thematic analysis of semi-structured interviews and participant observations, we additionally evaluate the acceptability of the stewardship program. Results The proportion of antibiotic prescriptions for a 3GC reduced from 193/241 (80.1%) to 177/330 (53.6%) (percentage decrease 26.5% [95%CI; 18.7 to 34.1]) with no change in case-fatality rate. Cost analysis estimated annual savings of US$15,000. Qualitative research revealed trust in the guideline and found its accessibility through smartphones helpful to guide clinical decisions. Operational health-system barriers and hierarchal clinical relationships lead to continued reliance on 3GC. Conclusions We report the successful introduction of an antimicrobial stewardship approach in Malawi. By focusing on pragmatic interventions and simple aims, we demonstrate the feasibility, acceptability and cost-saving of a stewardship program where resources are limited. In doing so, we provide a suitable starting point for expansion of AMS interventions in this and other low-income settings

Roles of tau protein in health and disease

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons. We highlight the post-translational modifications of tau, which are pivotal in defining and modulating tau localisation and its roles in health and disease. We include discussion of other pathologically relevant changes in tau, including mutation and aggregation, and how these aspects impinge on the propensity of tau to propagate, and potentially drive neuronal loss, in diseased brain. Finally, we describe the cascade of pathological events that may be driven by tau dysfunction, including impaired axonal transport, alterations in synapse and mitochondrial function, activation of the unfolded protein response and defective protein degradation. It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease. Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies

Content validation of Texas State-Adopted life, earth, physical, and biological science textbooks

Typescript (photocopy).Passage of Texas House Bill 246 in 1981 has led to massive restructuring of the Texas educational system with the upgrading of the quality of textbooks an important part of the revisions. The purpose of this study was to determine whether or not the Texas State-Adopted science textbooks contained concepts, scientific attitudes, and process skills that were identified by Gibbons (1976) as minimum competencies for high school graduates to attain to be considered scientifically literate. The sample of textbooks examined was narrowed to the 25 textbooks under current adoption used in life science, earth science, physical science, introductory biology, and biology since it was assumed that most secondary students completed their last science course by grade ten. An evaluation instrument was developed along with a list of rules that was abided by all investigators when examining the textbooks. Five secondary science student teachers reviewed randomly selected chapters from the sample population of textbooks. Results indicated high inter-rater reliability. A total of 11,784 pages of narration were examined for concepts: 52 life science, 35 earth science, 41 physical science, and an additional 20 ecology. Concepts were coded as either defined, partially defined, explained, or example. The scientific attitudes and process skills were coded as present or not present. Based on the findings of this study, it is probable that the life, earth, physical, introductory biology, and biology students in the State of Texas are being exposed, to varying degrees, to concepts, scientific attitudes, and process skills necessary for scientific literacy. There was a significant difference in the presentations of the concepts. Very few concepts were defined or partially defined in the textbooks. The findings suggested that students had to learn concepts by understanding the explanations and examples and, through inductive reasoning, formulate the concepts in their minds. Scientific attitudes were sparse and mainly found in the chapter devoted to the scientific method. Process skills were abundant; however, some of the lab activities were ambiguously written so it was difficult to determine what process skills were being used

Content validation of Texas State-Adopted life, earth, physical, and biological science textbooks

Typescript (photocopy).Passage of Texas House Bill 246 in 1981 has led to massive restructuring of the Texas educational system with the upgrading of the quality of textbooks an important part of the revisions. The purpose of this study was to determine whether or not the Texas State-Adopted science textbooks contained concepts, scientific attitudes, and process skills that were identified by Gibbons (1976) as minimum competencies for high school graduates to attain to be considered scientifically literate. The sample of textbooks examined was narrowed to the 25 textbooks under current adoption used in life science, earth science, physical science, introductory biology, and biology since it was assumed that most secondary students completed their last science course by grade ten. An evaluation instrument was developed along with a list of rules that was abided by all investigators when examining the textbooks. Five secondary science student teachers reviewed randomly selected chapters from the sample population of textbooks. Results indicated high inter-rater reliability. A total of 11,784 pages of narration were examined for concepts: 52 life science, 35 earth science, 41 physical science, and an additional 20 ecology. Concepts were coded as either defined, partially defined, explained, or example. The scientific attitudes and process skills were coded as present or not present. Based on the findings of this study, it is probable that the life, earth, physical, introductory biology, and biology students in the State of Texas are being exposed, to varying degrees, to concepts, scientific attitudes, and process skills necessary for scientific literacy. There was a significant difference in the presentations of the concepts. Very few concepts were defined or partially defined in the textbooks. The findings suggested that students had to learn concepts by understanding the explanations and examples and, through inductive reasoning, formulate the concepts in their minds. Scientific attitudes were sparse and mainly found in the chapter devoted to the scientific method. Process skills were abundant; however, some of the lab activities were ambiguously written so it was difficult to determine what process skills were being used

Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer’s disease

Organotypic brain slice culture models provide an alternative to early stage in vivo studies as an integrated tissue system that can recapitulate key disease features, thereby providing an excellent platform for drug screening. We recently described a novel organotypic 3xTg-AD mouse brain slice culture model with key Alzheimer's disease-like changes. We now highlight the potential of this model for testing disease-modifying agents and show that results obtained following in vivo treatment are replicated in brain slice cultures from 3xTg-AD mice. Moreover, we describe novel effects of the amyloid-binding tetra (ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, on tau. BTA-EG4 significantly reduced tau phosphorylation in the absence of any changes in the amounts of amyloid precursor protein, amyloid-β or synaptic proteins. The reduction in tau phosphorylation was associated with inactivation of the Alzheimer's disease-relevant major tau kinase, GSK-3. These findings highlight the utility of 3xTg-AD brain slice cultures as a rapid and reliable in vitro method for drug screening prior to in vivo testing. Furthermore, we demonstrate novel tau-directed effects of BTA-EG4 that are likely related to the ability of this agent to inactivate GSK-3. Our findings support the further exploration of BTA-EG4 as a candidate therapeutic for Alzheimer's disease

A new TAO kinase inhibitor reduces tau phosphorylation at sites associated with neurodegeneration in human tauopathies

Abstract In Alzheimer’s disease (AD) and related tauopathies, the microtubule-associated protein tau is highly phosphorylated and aggregates to form neurofibrillary tangles that are characteristic of these neurodegenerative diseases. Our previous work has demonstrated that the thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more than 40 residues in vitro. Here we show that TAOKs are phosphorylated and active in AD brain sections displaying mild (Braak stage II), intermediate (Braak stage IV) and advanced (Braak stage VI) tau pathology and that active TAOKs co-localise with both pre-tangle and tangle structures. TAOK activity is also enriched in pathological tau containing sarkosyl-insoluble extracts prepared from AD brain. Two new phosphorylated tau residues (T123 and T427) were identified in AD brain, which appear to be targeted specifically by TAOKs. A new small molecule TAOK inhibitor (Compound 43) reduced tau phosphorylation on T123 and T427 and also on additional pathological sites (S262/S356 and S202/T205/S208) in vitro and in cell models. The TAOK inhibitor also decreased tau phosphorylation in differentiated primary cortical neurons without affecting markers of synapse and neuron health. Notably, TAOK activity also co-localised with tangles in post-mortem frontotemporal lobar degeneration (FTLD) brain tissue. Furthermore, the TAOK inhibitor decreased tau phosphorylation in induced pluripotent stem cell derived neurons from FTLD patients, as well as cortical neurons from a transgenic mouse model of tauopathy (Tau35 mice). Our results demonstrate that abnormal TAOK activity is present at pre-tangles and tangles in tauopathies and that TAOK inhibition effectively decreases tau phosphorylation on pathological sites. Thus, TAOKs may represent a novel target to reduce or prevent tau-associated neurodegeneration in tauopathies

Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain

Summary of postmortem brain characteristics (DOC 28 kb

Loss of BIN1 protein in Alzheimer’s disease promotes synaptic accumulation of phosphorylated tau and disrupts tau release:Tau-directed effects of BIN1 loss in AD

Polymorphisms associated with BIN1 (bridging integrator 1) confer the second greatest risk for developing late-onset Alzheimer’s disease. The biological consequences of this genetic variation are not fully understood; however, BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer’s disease, tau is abnormally phosphorylated and accumulates at synapses to exert synaptotoxicity. The purpose of this study was to determine whether alterations in BIN1 and tau in Alzheimer’s disease promote the damaging redistribution of tau to synapses, as a mechanism by which BIN1 polymorphisms may increase the risk of developing Alzheimer’s disease. We show that BIN1 is lost from the cytoplasmic fraction of Alzheimer’s disease cortex, and this is accompanied by the progressive mislocalization of phosphorylated tau to synapses. We confirmed proline 216 in tau as critical for tau interaction with the BIN1-SH3 domain and showed that the phosphorylation of tau disrupts this binding, suggesting that tau phosphorylation in Alzheimer’s disease disrupts tau–BIN1 associations. Moreover, we show that BIN1 knockdown in rat primary neurons to mimic BIN1 loss in Alzheimer’s disease brain causes the damaging accumulation of phosphorylated tau at synapses and alterations in dendritic spine morphology. We also observed reduced release of tau from neurons upon BIN1 silencing, suggesting that BIN1 loss disrupts the function of extracellular tau. Together, these data indicate that polymorphisms associated with BIN1 that reduce BIN1 protein levels in the brain likely act synergistically with increased tau phosphorylation to increase the risk of Alzheimer’s disease by disrupting cytoplasmic tau–BIN1 interactions, promoting the damaging mis-sorting of phosphorylated tau to synapses to alter synapse structure and reducing the release of physiological forms of tau to disrupt tau function

Genetic sampling identifies canid predators of koalas (Phascolarctos cinereus) in peri-urban areas

An understanding of the threats to threatened species in urban and peri-urban areas is essential to develop successful management approaches. Dog attacks are considered to be a major contributor to koala (Phascolarctos cinereus) mortalities in peri-urban areas of north-eastern Australia. Predation could be due to either domestic dogs or wild dogs (dingoes and dingo-domestic dog hybrids), gentically-identifiable groups of Canis familiaris. Here, we aimed to use genetic sampling methods to determine or verify the identity, number and successful removal of canid predators of koalas in a peri-urban environment in south-eastern Queensland. Genetic samples were taken from the remains of 12 koalas suspected to have died from predation. Canine genotypes were present on 11 of 12 predated koalas (∼92%) and were from wild dogs, not domestic dogs. Most koalas had only one canine genotype identified, suggesting they were killed by a single dog. Our results show that DNA samples collected from deceased prey species can be used to identify the predator, and distinguish between closely-related species, and hybrids of the two. Genetic methods confirmed the identification of the predator obtained through conventional necropsy and support growing evidence that wild dog predation is a significant cause of koala mortality in this region. Strategies to reduce predation on koalas should therefore focus on reducing the impact of free-ranging wild dog populations. This approach is important to identify and target those canids responsible for predation of threatened prey populations, particularly where multiple predators are present and/or predator removals may be controversial

Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy

Abstract Tau is normally a highly soluble phosphoprotein found predominantly in neurons. Six different isoforms of tau are expressed in the adult human CNS. Under pathological conditions, phosphorylated tau aggregates are a defining feature of neurodegenerative disorders called tauopathies. Recent findings have suggested a potential role of the gut-brain axis in CNS homeostasis, and therefore we set out to examine the isoform profile and phosphorylation state of tau in the enteric nervous system (ENS) under physiological conditions and in tauopathies. Surgical specimens of human colon from controls, Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) patients were analyzed by Western Blot and immunohistochemistry using a panel of anti-tau antibodies. We found that adult human ENS primarily expresses two tau isoforms, localized in the cell bodies and neuronal processes. We did not observe any difference in the enteric tau isoform profile and phosphorylation state between PSP, PD and control subjects. The htau mouse model of tauopathy also expressed two main isoforms of human tau in the ENS, and there were no apparent differences in ENS tau localization or phosphorylation between wild-type and htau mice. Tau in both human and mouse ENS was found to be phosphorylated but poorly susceptible to dephosphorylation with lambda phosphatase. To investigate ENS tau phosphorylation further, primary cultures from rat enteric neurons, which express four isoforms of tau, were pharmacologically manipulated to show that ENS tau phosphorylation state can be regulated, at least in vitro. Our study is the first to characterize tau in the rodent and human ENS. As a whole, our findings provide a basis to unravel the functions of tau in the ENS and to further investigate the possibility of pathological changes in enteric neuropathies and tauopathies