Rabies elimination research: juxtaposing optimism, pragmatism and realism

More than 100 years of research has now been conducted into the prevention, control and elimination of rabies with safe and highly efficacious vaccines developed for use in human and animal populations. Domestic dogs are a major reservoir for rabies, and although considerable advances have been made towards the elimination and control of canine rabies in many parts of the world, the disease continues to kill tens of thousands of people every year in Africa and Asia. Policy efforts are now being directed towards a global target of zero human deaths from dog-mediated rabies by 2030 and the global elimination of canine rabies. Here we demonstrate how research provides a cause for optimism as to the feasibility of these goals through strategies based around mass dog vaccination. We summarize some of the pragmatic insights generated from rabies epidemiology and dog ecology research that can improve the design of dog vaccination strategies in low- and middle-income countries and which should encourage implementation without further delay. We also highlight the need for realism in reaching the feasible, although technically more difficult and longer-term goal of global elimination of canine rabies. Finally, we discuss how research on rabies has broader relevance to the control and elimination of a suite of diseases of current concern to human and animal health, providing an exemplar of the value of a ‘One Health’ approach

Special Values of Generalized Polylogarithms

We study values of generalized polylogarithms at various points and relationships among them. Polylogarithms of small weight at the points 1/2 and -1 are completely investigated. We formulate a conjecture about the structure of the linear space generated by values of generalized polylogarithms.Comment: 32 page

National neonatal resuscitation training program in Nigeria (2008-2012): A preliminary report

Background: Routine institutional training of doctors and nurses on newborn resuscitation have commenced, to improve the quality of resuscitation available to high-risk babies, in Nigeria, as a means of reducing newborn deaths in the country. Perinatal asphyxia contributes to 26% of newborn deaths in Nigeria. Perinatal asphyxia results when babies have difficulty establishing spontaneous respiration after birth.Materials and Methods: Between 2008 and 2012, doctors and nurses drawn from all the geo.political zones were trained using the Neonatal  Resuscitation Training (NRT) manual of the American Heart Association and the American Academy of Pediatrics. Questionnaire.based, cross.sectional surveys of doctor and nurse trainees from the six geo.political zones in Nigeria were conducted eight months after the primary training, to evaluate the post.training  neonatal resuscitation activities.Results: Over the period of study, 357 doctors and 370 nurse/midwives were primarily trained in NRT. The overall ratio of step down training was 1:22 with 1:18 for doctors and 1:26 for nurses. In 2008, the delivery attendance rates were 11 per doctor and 9 per nurse/midwife. These rates increased to 30 per doctor and 47 per nurse in 2012. Between 88 and 94% of the doctors and between 72 and 93% of the nurses successfully used bag and mask to help babies breathe in the post.training period. The nurses used bag and mask for infant resuscitation more frequently,   compared to doctors, with the rate fluctuating between two.to.one and four.to.one. Over the years, 87 to 94% of the doctors and 92 to 97% of the nurses/midwives trained other birth attendants.Conclusion: The NRT in Nigeria is well.subscribed and the frequency of secondary training is good.Key words: Birth asphyxia, birth attendants, delivery room care, neonatal resuscitation training, perinatal mortalit

Reservoir dynamics of rabies in Southeast Tanzania and the roles of cross-species transmission and domestic dog vaccination

1) Understanding the role of different species in the transmission of multi-host pathogens, such as rabies virus, is vital for effective control strategies. Across most of sub-Saharan Africa domestic dogs (Canis familiaris) are considered the reservoir for rabies, but the role of wildlife has been long debated. Here we explore the multi-host transmission dynamics of rabies across southeast Tanzania. 2) Between January 2011 and July 2019 data on probable rabies cases were collected in the regions of Lindi and Mtwara. Hospital records of animal-bite patients presenting to healthcare facilities were used as sentinels for animal contact tracing. The timing, location and species of probable rabid animals was used to reconstruct transmission trees to infer who infected whom and the relative frequencies of within-and between-species transmission. 3) During the study, 688 probable human rabies exposures were identified, resulting in 47 deaths. Of these exposures, 389 were from domestic dogs (56.5%) and 262 from jackals (38.1%). Over the same period 549 probable animal rabies cases were traced: 303 in domestic dogs (55.2%) and 221 in jackals (40.3%). 4) Although dog-to-dog transmission was most commonly inferred (40.5% of transmission events), a third of inferred events involved wildlife-to-wildlife transmission (32.6%) and evidence suggested some sustained transmission chains within jackal populations. 5) A steady decline in probable rabies cases in both humans and animals coincided with the implementation of widespread domestic dog vaccination during the first six years of the study. Following the lapse of this programme dog rabies cases began to increase in one of the northernmost districts. 6) Synthesis and applications: in southeast Tanzania, despite a relatively high incidence of rabies in wildlife and evidence of wildlife-to-wildlife transmission, domestic dogs remain essential to the reservoir of infection. Continued dog vaccination alongside improved surveillance would allow a fuller understanding of the role of wildlife in maintaining transmission in this area. Nonetheless, dog vaccination clearly suppressed rabies in both domestic dog and wildlife populations, reducing both public health and conservation risks and, if sustained, has potential to eliminate rabies from this region

Blood-flow-restricted exercise: strategies for enhancing muscle adaptation and performance in the endurance-trained athlete

New Findings: What is the topic of this review? Blood-flow-restricted (BFR) exercise represents a potential approach to augment the adaptive response to training and improve performance in endurance-trained individuals. What advances does it highlight? When combined with low-load resistance exercise, low- and moderate-intensity endurance exercise and sprint interval exercise, BFR can provide an augmented acute stimulus for angiogenesis and mitochondrial biogenesis. These augmented acute responses can translate into enhanced capillary supply and mitochondrial function, and subsequent endurance-type performance, although this might depend on the nature of the exercise stimulus. There is a requirement to clarify whether BFR training interventions can be used by high-performance endurance athletes within their structured training programme. Abstract: A key objective of the training programme for an endurance athlete is to optimize the underlying physiological determinants of performance. Training-induced adaptations are governed by physiological and metabolic stressors, which initiate transcriptional and translational signalling cascades to increase the abundance and/or function of proteins to improve physiological function. One important consideration is that training adaptations are reduced as training status increases, which is reflected at the molecular level as a blunting of the acute signalling response to exercise. This review examines blood-flow-restricted (BFR) exercise as a strategy for augmenting exercise-induced stressors and subsequent molecular signalling responses to enhance the physiological characteristics of the endurance athlete. Focus is placed on the processes of capillary growth and mitochondrial biogenesis. Recent evidence supports that BFR exercise presents an intensified training stimulus beyond that of performing the same exercise alone. We suggest that this has the potential to induce enhanced physiological adaptations, including increases in capillary supply and mitochondrial function, which can contribute to an improvement in performance of endurance exercise. There is, however, a lack of consensus regarding the potency of BFR training, which is invariably attributable to the different modes, intensities and durations of exercise and BFR methods. Further studies are needed to confirm its potential in the endurance-trained athlete

Powering sub-Saharan Africa’s urban revolution: An energy transitions approach

This paper develops a geographic understanding of urban energy transitions in subSaharan African towns and cities. In doing so this paper seeks to critically reflect on the value and limits of urban transitions analysis as a framework for understanding energy networks beyond the largely integrated systems across the Global North. We explore how these potentials and deficits can be addressed by examining promising developments across a series of debates in urban studies that can help sensitise this approach to energyscapes in the African context. By reviewing urban transi- tions analysis through these debates the paper offers four important contributions to expand existing ways of understanding energy transition. These include the particular urbanisation dynamics of African towns ands cities, the need to locate the urban across energy regimes, the agencies of various intermediaries and urban actors and the contested politics inherent in the governing of energy networks. In the conclusion we reflect on the specific directions that have emerged from the paper in relation to our contributions, offering a geographically informed framework that allows us to better examine the challenges and specificities of transition across these rapidly growing urban regions

Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Graduate entry to medicine: widening psychological diversity

At Nottingham University more than 95% of entrants to the traditional 5-year medical course are school leavers. Since 2003 we have admitted graduate entrants (GEM) to a shortened (4-year) course to 'widen access to students from more disadvantaged backgrounds'. We have recently shown that the GEM course widens academic and socio-demographic diversity of the medical student population. This study explored whether GEM students also bring psychological diversity and whether this could be beneficial. We studied: a) 217 and 96 applicants to the Nottingham 5- and 4-year courses respectively, applying in the 2002-3 UCAS cycle, and, b) 246 school leavers starting the 5-year course and 39 graduate entrants to the 4-year course in October 2003. The psychological profiles of the two groups of applicants and two groups of entrants were compared using their performance in the Goldberg 'Big 5' Personality test, the Personal Qualities Assessment (PQA; measuring interpersonal traits and interpersonal values), and the Lovibond and Lovibond measure of depression, anxiety and stress. For the comparison of the Entrants we excluded the 33 school leavers and seven graduates who took the tests as Applicants. Statistical analyses were undertaken using SPSS software (version 16.0). Graduate applicants compared to school leaver applicants were significantly more conscientious, more confident, more self controlled, more communitarian in moral orientation and less anxious. Only one of these differences was preserved in the entrants with graduates being less anxious. However, the graduate entrants were significantly less empathetic and conscientious than the school leavers. This study has shown that school leaver and graduate entrants to medical school differ in some psychological characteristics. However, if confirmed in other studies and if they were manifest in the extreme, not all the traits brought by graduates would be desirable for someone aiming for a medical career

Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils