Efficacy of species-specific protein antibiotics in a murine model of acute Pseudomonas aeruginosa lung infection

Protein antibiotics, known as bacteriocins, are widely produced by bacteria for intraspecies competition. The potency and targeted action of bacteriocins suggests that they could be developed into clinically useful antibiotics against highly drug resistant Gram-negative pathogens for which there are few therapeutic options. Here we show that Pseudomonas aeruginosa specific bacteriocins, known as pyocins, show strong efficacy in a murine model of P. aeruginosa lung infection, with the concentration of pyocin S5 required to afford protection from a lethal infection at least 100-fold lower than the most commonly used inhaled antibiotic tobramycin. Additionally, pyocins are stable in the lung, poorly immunogenic at high concentrations and efficacy is maintained in the presence of pyocin specific antibodies after repeated pyocin administration. Bacteriocin encoding genes are frequently found in microbial genomes and could therefore offer a ready supply of highly targeted and potent antibiotics active against problematic Gram-negative pathogens

Emerging concepts of shear stress in placental development and function.

Blood flow, and the force it generates, is critical to placental development and function throughout pregnancy. This mechanical stimulation of cells by the friction generated from flow is called shear stress (SS) and is a fundamental determinant of vascular homeostasis, regulating remodelling and vasomotor tone. This review describes how SS is fundamental to the establishment and regulation of the blood flow through the uteroplacental and fetoplacental circulations. Amongst the most recent findings is that alongside the endothelium, embryonic stem cells and the villous trophoblast are mechanically sensitive. A complex balance of forces is required to enable effective establishment of the uteroplacental circulation, whilst protecting the embryo and placental villi. SS also generates flow-mediated vasodilatation through the release of endothelial nitric oxide, a process vital for adequate placental blood flow. The identification of SS sensors and the mechanisms governing how the force is converted into biochemical signals is a fast-paced area of research, with multiple cellular components under investigation. For example, the Piezo1 ion channel is mechanosensitive in a variety of tissues including the fetoplacental endothelium. Enhanced Piezo1 activity has been demonstrated in response to the Yoda1 agonist molecule, suggesting the possibility for developing tools to manipulate these channels. Whether such agents might progress to novel therapeutics to improve blood flow through the placenta requires further consideration and research

Structural and biophysical analysis of nuclease protein antibiotics

© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society. Protein antibiotics (bacteriocins) are a large and diverse family of multidomain toxins that kill specific Gram-negative bacteria during intraspecies competition for resources. Our understanding of the mechanism of import of such potent toxins has increased significantly in recent years, especially with the reporting of several structures of bacteriocin domains. Less well understood is the structural biochemistry of intact bacteriocins and how these compare across bacterial species. Here, we focus on endonuclease (DNase) bacteriocins that target the genomes of Escherichia coli and Pseudomonas aeruginosa, known as E-Type colicins and S-Type pyocins, respectively, bound to their specific immunity (Im) proteins. First, we report the 3.2 Å structure of the DNase colicin ColE9 in complex with its ultra-high affinity Im protein, Im9. In contrast with Im3, which when bound to the ribonuclease domain of the homologous colicin ColE3 makes contact with the translocation (T) domain of the toxin, we find that Im9 makes no such contact and only interactions with the ColE9 cytotoxic domain are observed. Second, we report small-Angle X-ray scattering data for two S-Type DNase pyocins, S2 and AP41, into which are fitted recently determined X-ray structures for isolated domains. We find that DNase pyocins and colicins are both highly elongated molecules, even though the order of their constituent domains differs. We discuss the implications of these architectural similarities and differences in the context of the translocation mechanism of protein antibiotics through the cell envelope of Gram-negative bacteria

Socio-economic status influences the relationship between obesity and antenatal depression: Data from a prospective cohort study

Background Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression. Methods Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression. Results Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16–3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses. Limitations 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined. Conclusions Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category

Ten Years of Experience Training Non-Physician Anesthesia Providers in Haiti.

Surgery is increasingly recognized as an effective means of treating a proportion of the global burden of disease, especially in resource-limited countries. Often non-physicians, such as nurses, provide the majority of anesthesia; however, their training and formal supervision is often of low priority or even non-existent. To increase the number of safe anesthesia providers in Haiti, Médecins Sans Frontières has trained nurse anesthetists (NAs) for over 10 years. This article describes the challenges, outcomes, and future directions of this training program. From 1998 to 2008, 24 students graduated. Nineteen (79%) continue to work as NAs in Haiti and 5 (21%) have emigrated. In 2008, NAs were critical in providing anesthesia during a post-hurricane emergency where they performed 330 procedures. Mortality was 0.3% and not associated with lack of anesthesiologist supervision. The completion rate of this training program was high and the majority of graduates continue to work as nurse anesthetists in Haiti. Successful training requires a setting with a sufficient volume and diversity of operations, appropriate anesthesia equipment, a structured and comprehensive training program, and recognition of the training program by the national ministry of health and relevant professional bodies. Preliminary outcomes support findings elsewhere that NAs can be a safe and effective alternative where anesthesiologists are scarce. Training non-physician anesthetists is a feasible and important way to scale up surgical services resource limited settings

Inner Space Preserving Generative Pose Machine

Image-based generative methods, such as generative adversarial networks (GANs) have already been able to generate realistic images with much context control, specially when they are conditioned. However, most successful frameworks share a common procedure which performs an image-to-image translation with pose of figures in the image untouched. When the objective is reposing a figure in an image while preserving the rest of the image, the state-of-the-art mainly assumes a single rigid body with simple background and limited pose shift, which can hardly be extended to the images under normal settings. In this paper, we introduce an image "inner space" preserving model that assigns an interpretable low-dimensional pose descriptor (LDPD) to an articulated figure in the image. Figure reposing is then generated by passing the LDPD and the original image through multi-stage augmented hourglass networks in a conditional GAN structure, called inner space preserving generative pose machine (ISP-GPM). We evaluated ISP-GPM on reposing human figures, which are highly articulated with versatile variations. Test of a state-of-the-art pose estimator on our reposed dataset gave an accuracy over 80% on PCK0.5 metric. The results also elucidated that our ISP-GPM is able to preserve the background with high accuracy while reasonably recovering the area blocked by the figure to be reposed.Comment: http://www.northeastern.edu/ostadabbas/2018/07/23/inner-space-preserving-generative-pose-machine

What does the COVID-19 pandemic mean for the next decade of onchocerciasis control and elimination?

BACKGROUND: Mass drug administration (MDA) of ivermectin for onchocerciasis has been disrupted by the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modelling can help predict how missed/delayed MDA will affect short-term epidemiological trends and elimination prospects by 2030. METHODS: Two onchocerciasis transmission models (EPIONCHO-IBM and ONCHOSIM) are used to simulate microfilarial prevalence trends, elimination probabilities and age profiles of Onchocerca volvulus microfilarial prevalence and intensity for different treatment histories and transmission settings, assuming no interruption, a 1-y (2020) interruption or a 2-y (2020-2021) interruption. Biannual MDA or increased coverage upon MDA resumption are investigated as remedial strategies. RESULTS: Programmes with shorter MDA histories and settings with high pre-intervention endemicity will be the most affected. Biannual MDA is more effective than increasing coverage for mitigating COVID-19's impact on MDA. Programmes that had already switched to biannual MDA should be minimally affected. In high-transmission settings with short treatment history, a 2-y interruption could lead to increased microfilarial load in children (EPIONCHO-IBM) and adults (ONCHOSIM). CONCLUSIONS: Programmes with shorter (annual MDA) treatment histories should be prioritised for remedial biannual MDA. Increases in microfilarial load could have short- and long-term morbidity and mortality repercussions. These results can guide decision-making to mitigate the impact of COVID-19 on onchocerciasis elimination

Efficiency of Lift Production in Flapping and Gliding Flight of Swifts

Many flying animals use both flapping and gliding flight as part of their routine behaviour. These two kinematic patterns impose conflicting requirements on wing design for aerodynamic efficiency and, in the absence of extreme morphing, wings cannot be optimised for both flight modes. In gliding flight, the wing experiences uniform incident flow and the optimal shape is a high aspect ratio wing with an elliptical planform. In flapping flight, on the other hand, the wing tip travels faster than the root, creating a spanwise velocity gradient. To compensate, the optimal wing shape should taper towards the tip (reducing the local chord) and/or twist from root to tip (reducing local angle of attack). We hypothesised that, if a bird is limited in its ability to morph its wings and adapt its wing shape to suit both flight modes, then a preference towards flapping flight optimization will be expected since this is the most energetically demanding flight mode. We tested this by studying a well-known flap-gliding species, the common swift, by measuring the wakes generated by two birds, one in gliding and one in flapping flight in a wind tunnel. We calculated span efficiency, the efficiency of lift production, and found that the flapping swift had consistently higher span efficiency than the gliding swift. This supports our hypothesis and suggests that even though swifts have been shown previously to increase their lift-to-drag ratio substantially when gliding, the wing morphology is tuned to be more aerodynamically efficient in generating lift during flapping. Since body drag can be assumed to be similar for both flapping and gliding, it follows that the higher total drag in flapping flight compared with gliding flight is primarily a consequence of an increase in wing profile drag due to the flapping motion, exceeding the reduction in induced drag

Prevalence and predictors of alcohol use during pregnancy: findings from international multicentre cohort studies

Objectives To compare the prevalence and predictors of alcohol use in multiple cohorts. Design Cross-cohort comparison of retrospective and prospective studies. Setting Population-based studies in Ireland, the UK, Australia and New Zealand. Participants 17 244 women of predominantly Caucasian origin from two Irish retrospective studies (Growing up in Ireland (GUI) and Pregnancy Risk Assessment Monitoring System Ireland (PRAMS Ireland)), and one multicentre prospective international cohort, Screening for Pregnancy Endpoints (SCOPE) study. Primary and secondary outcome measures Prevalence of alcohol use pre-pregnancy and during pregnancy across cohorts. Sociodemographic factors associated with alcohol consumption in each cohort. Results Alcohol consumption during pregnancy in Ireland ranged from 20% in GUI to 80% in SCOPE, and from 40% to 80% in Australia, New Zealand and the UK. Levels of exposure also varied substantially among drinkers in each cohort ranging from 70% consuming more than 1–2 units/week in the first trimester in SCOPE Ireland, to 46% and 15% in the retrospective studies. Smoking during pregnancy was the most consistent predictor of gestational alcohol use in all three cohorts, and smokers were 17% more likely to drink during pregnancy in SCOPE, relative risk (RR)=1.17 (95% CI 1.12 to 1.22), 50% more likely to drink during pregnancy in GUI, RR=1.50 (95% CI 1.36 to 1.65), and 42% more likely to drink in PRAMS, RR=1.42 (95% CI 1.18 to 1.70). Conclusions Our data suggest that alcohol use during pregnancy is prevalent and socially pervasive in the UK, Ireland, New Zealand and Australia. New policy and interventions are required to reduce alcohol prevalence both prior to and during pregnancy. Further research on biological markers and conventions for measuring alcohol use in pregnancy is required to improve the validity and reliability of prevalence estimates