Study protocol of cost-effectiveness and cost-utility of a biopsychosocial multidisciplinary intervention in the evolution of non-specific sub-acute low back pain in the working population: cluster randomised trial.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain (LBP), with high incidence and prevalence rate, is one of the most common reasons to consult the health system and is responsible for a significant amount of sick leave, leading to high health and social costs. The objective of the study is to assess the cost-effectiveness and cost-utility analysis of a multidisciplinary biopsychosocial educational group intervention (MBEGI) of non-specific sub-acute LBP in comparison with the usual care in the working population recruited in primary healthcare centres. Methods/design: The study design is a cost-effectiveness and cost-utility analysis of a MBEGI in comparison with the usual care of non-specific sub-acute LBP.Measures on effectiveness and costs of both interventions will be obtained from a cluster randomised controlled clinical trial carried out in 38 Catalan primary health care centres, enrolling 932 patients between 18 and 65 years old with a diagnosis of non-specific sub-acute LBP. Effectiveness measures are: pharmaceutical treatments, work sick leave (% and duration in days), Roland Morris disability, McGill pain intensity, Fear Avoidance Beliefs (FAB) and Golberg Questionnaires. Utility measures will be calculated from the SF-12. The analysis will be performed from a social perspective. The temporal horizon is at 3 months (change to chronic LBP) and 12 months (evaluate the outcomes at long term. Assessment of outcomes will be blinded and will follow the intention-to-treat principle. Discussion: We hope to demonstrate the cost-effectiveness and cost-utility of MBEGI, see an improvement in the patients' quality of life, achieve a reduction in the duration of episodes and the chronicity of non-specific low back pain, and be able to report a decrease in the social costs. If the intervention is cost-effectiveness and cost-utility, it could be applied to Primary Health Care Centres. Trial registration: ISRCTN: ISRCTN5871969

Use of surrogate endpoints in healthcare policy : proposal for consistent adoption of a validation framework

We propose a three step framework for the evaluation of surrogate endpoints for health policy decisions on health technologies

A mixed methods approach to evaluating community drug distributor performance in the control of neglected tropical diseases

BACKGROUND: Trusted literate, or semi-literate, community drug distributors (CDDs) are the primary implementers in integrated preventive chemotherapy (IPC) programmes for Neglected Tropical Disease (NTD) control. The CDDs are responsible for safely distributing drugs and for galvanising communities to repeatedly, often over many years, receive annual treatment, create and update treatment registers, monitor for side-effects and compile treatment coverage reports. These individuals are 'volunteers' for the programmes and do not receive remuneration for their annual work commitment. METHODS: A mixed methods approach, which included pictorial diaries to prospectively record CDD use of time, structured interviews and focus group discussions, was used to triangulate data on how 58 CDDs allocated their time towards their routine family activities and to NTD Programme activities in Uganda. The opportunity costs of CDD time were valued, performance assessed by determining the relationship between time and programme coverage, and CDD motivation for participating in the programme was explored. RESULTS: Key findings showed approximately 2.5 working weeks (range 0.6-11.4 working weeks) were spent on NTD Programme activities per year. The amount of time on NTD control activities significantly increased between the one and three deliveries that were required within an IPC campaign. CDD time spent on NTD Programme activities significantly reduced time available for subsistence and income generating engagements. As CDDs took more time to complete NTD Programme activities, their treatment performance, in terms of validated coverage, significantly decreased. Motivation for the programme was reported as low and CDDs felt undervalued. CONCLUSIONS: CDDs contribute a considerable amount of opportunity cost to the overall economic cost of the NTD Programme in Uganda due to the commitment of their time. Nevertheless, programme coverage of at least 75 %, as required by the World Health Organisation, is not being achieved and vulnerable individuals may not have access to treatment as a consequence of sub-optimal performance by the CDDs due to workload and programmatic factors

Ectopic A-lattice seams destabilize microtubules

Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe

Connectomics Analysis Reveals First-, Second-, and Third-Order Thermosensory and Hygrosensory Neurons in the Adult Drosophila Brain.

Animals exhibit innate and learned preferences for temperature and humidity-conditions critical for their survival and reproduction. Leveraging a whole-brain electron microscopy volume, we studied the adult Drosophila melanogaster circuitry associated with antennal thermo- and hygrosensory neurons. We have identified two new target glomeruli in the antennal lobe, in addition to the five known ones, and the ventroposterior projection neurons (VP PNs) that relay thermo- and hygrosensory information to higher brain centers, including the mushroom body and lateral horn, seats of learned and innate behavior. We present the first connectome of a thermo- and hygrosensory neuropil, the lateral accessory calyx (lACA), by reconstructing neurons downstream of heating- and cooling-responsive VP PNs. A few mushroom body-intrinsic neurons solely receive thermosensory input from the lACA, while most receive additional olfactory and thermo- and/or hygrosensory PN inputs. Furthermore, several classes of lACA-associated neurons form a local network with outputs to other brain neuropils, suggesting that the lACA serves as a hub for thermo- and hygrosensory circuitry. For example, DN1a neurons link thermosensory PNs in the lACA to the circadian clock via the accessory medulla. Finally, we survey strongly connected downstream partners of VP PNs across the protocerebrum; these include a descending neuron targeted by dry-responsive VP PNs, meaning that just two synapses might separate hygrosensory inputs from motor circuits. These data provide a comprehensive first- and second-order layer analysis of Drosophila thermo- and hygrosensory systems and an initial survey of third-order neurons that could directly modulate behavior.MRC LMB Graduate Studentship to M.W.P. Boehringer Ingelheim Fonds PhD Fellowship and a Herchel Smith Studentship to A.S.B. Cambridge Neuroscience-PSL collaborative grant supported by the Embassy of France in London to G.S.X.E.J

Dynamics of Molecular Evolution and Phylogeography of Barley yellow dwarf virus-PAV

Barley yellow dwarf virus (BYDV) species PAV occurs frequently in irrigated wheat fields worldwide and can be efficiently transmitted by aphids. Isolates of BYDV-PAV from different countries show great divergence both in genomic sequences and pathogenicity. Despite its economical importance, the genetic structure of natural BYDV-PAV populations, as well as of the mechanisms maintaining its high diversity, remain poorly explored. In this study, we investigate the dynamics of BYDV-PAV genome evolution utilizing time-structured data sets of complete genomic sequences from 58 isolates from different hosts obtained worldwide. First, we observed that BYDV-PAV exhibits a high frequency of homologous recombination. Second, our analysis revealed that BYDV-PAV genome evolves under purifying selection and at a substitution rate similar to other RNA viruses (3.158×10−4 nucleotide substitutions/site/year). Phylogeography analyses show that the diversification of BYDV-PAV can be explained by local geographic adaptation as well as by host-driven adaptation. These results increase our understanding of the diversity, molecular evolutionary characteristics and epidemiological properties of an economically important plant RNA virus

Novel insights into host-fungal pathogen interactions derived from live-cell imaging

Acknowledgments The authors acknowledge funding from the Wellcome Trust (080088, 086827, 075470 and 099215) including a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377 and FP7-2007–2013 grant agreement HEALTH-F2-2010-260338–ALLFUN to NARG.Peer reviewedPublisher PD

Phylogeography of the Microcoleus vaginatus (Cyanobacteria) from Three Continents – A Spatial and Temporal Characterization

It has long been assumed that cyanobacteria have, as with other free-living microorganisms, a ubiquitous occurrence. Neither the geographical dispersal barriers nor allopatric speciation has been taken into account. We endeavoured to examine the spatial and temporal patterns of global distribution within populations of the cyanobacterium Microcoleus vaginatus, originated from three continents, and to evaluate the role of dispersal barriers in the evolution of free-living cyanobacteria. Complex phylogeographical approach was applied to assess the dispersal and evolutionary patterns in the cyanobacterium Microcoleus vaginatus (Oscillatoriales). We compared the 16S rRNA and 16S-23S ITS sequences of strains which had originated from three continents (North America, Europe, and Asia). The spatial distribution was investigated using a phylogenetic tree, network, as well as principal coordinate analysis (PCoA). A temporal characterization was inferred using molecular clocks, calibrated from fossil DNA. Data analysis revealed broad genetic diversity within M. vaginatus. Based on the phylogenetic tree, network, and PCoA analysis, the strains isolated in Europe were spatially separated from those which originated from Asia and North America. A chronogram showed a temporal limitation of dispersal barriers on the continental scale. Dispersal barriers and allopatric speciation had an important role in the evolution of M. vaginatus. However, these dispersal barriers did not have a permanent character; therefore, the genetic flow among populations on a continental scale was only temporarily present. Furthermore, M. vaginatus is a recently evolved species, which has been going through substantial evolutionary changes

Multi-Locus Phylogeographic and Population Genetic Analysis of Anolis carolinensis: Historical Demography of a Genomic Model Species

The green anole (Anolis carolinensis) has been widely used as an animal model in physiology and neurobiology but has recently emerged as an important genomic model. The recent sequencing of its genome has shed new light on the evolution of vertebrate genomes and on the process that govern species diversification. Surprisingly, the patterns of genetic diversity within natural populations of this widespread and abundant North American lizard remain relatively unknown. In the present study, we use 10 novel nuclear DNA sequence loci (N = 62 to 152) and one mitochondrial locus (N = 226) to delimit green anole populations and infer their historical demography. We uncovered four evolutionarily distinct and geographically restricted lineages of green anoles using phylogenetics, Bayesian clustering, and genetic distance methods. Molecular dating indicates that these lineages last shared a common ancestor ∼2 million years ago. Summary statistics and analysis of the frequency distributions of DNA polymorphisms strongly suggest range-wide expansions in population size. Using Bayesian Skyline Plots, we inferred the timing of population size expansions, which differ across lineages, and found evidence for a relatively recent and rapid westward expansion of green anoles across the Gulf Coastal Plain during the mid-Pleistocene. One surprising result is that the distribution of genetic diversity is not consistent with a latitudinal shift caused by climatic oscillations as is observed for many co-distributed taxa. This suggests that the most recent Pleistocene glacial cycles had a limited impact on the geographic distribution of the green anole at the northern limits of its range

Genetic Signature of Rapid IHHNV (Infectious Hypodermal and Hematopoietic Necrosis Virus) Expansion in Wild Penaeus Shrimp Populations

Infectious hypodermal and hematopoietic necrosis virus (IHHNV) is a widely distributed single-stranded DNA parvovirus that has been responsible for major losses in wild and farmed penaeid shrimp populations on the northwestern Pacific coast of Mexico since the early 1990's. IHHNV has been considered a slow-evolving, stable virus because shrimp populations in this region have recovered to pre-epizootic levels, and limited nucleotide variation has been found in a small number of IHHNV isolates studied from this region. To gain insight into IHHNV evolutionary and population dynamics, we analyzed IHHNV capsid protein gene sequences from 89 Penaeus shrimp, along with 14 previously published sequences. Using Bayesian coalescent approaches, we calculated a mean rate of nucleotide substitution for IHHNV that was unexpectedly high (1.39×10−4 substitutions/site/year) and comparable to that reported for RNA viruses. We found more genetic diversity than previously reported for IHHNV isolates and highly significant subdivision among the viral populations in Mexican waters. Past changes in effective number of infections that we infer from Bayesian skyline plots closely correspond to IHHNV epizootiological historical records. Given the high evolutionary rate and the observed regional isolation of IHHNV in shrimp populations in the Gulf of California, we suggest regular monitoring of wild and farmed shrimp and restriction of shrimp movement as preventative measures for future viral outbreaks