Modeling 18F−FDG^{18}F-FDG Kinetics during Acute Lung Injury: Experimental Data and Estimation Errors

Background: There is increasing interest in Positron Emission Tomography (PET) of 2-deoxy-2-[18F]flouro-D-glucose ($^{18}F-FDG$) to evaluate pulmonary inflammation during acute lung injury (ALI). We assessed the effect of extra-vascular lung water on estimates of $^{18}F-FDG$-kinetics parameters in experimental and simulated data using the Patlak and Sokoloff methods, and our recently proposed four-compartment model. Methodology/Principal Findings Eleven sheep underwent unilateral lung lavage and 4 h mechanical ventilation. Five sheep received intravenous endotoxin (10 ng/kg/min). Dynamic $^{18}F-FDG$ PET was performed at the end of the 4 h period. $^{18}F-FDG$ net uptake rate (Ki), phosphorylation rate (k3), and volume of distribution (Fe) were estimated in three isogravitational regions for each method. Simulations of normal and ALI $^{18}F-FDG$-kinetics were conducted to study the dependence of estimated parameters on the transport rate constants to (k5) and from (k6) the extra-vascular extra-cellular compartment. The four-compartment model described 85.7% of the studied $^{18}F-FDG$-kinetics better than the Sokoloff model. Relative to the four-compartment model the Sokoloff model exhibited a consistent positive bias in Ki (3.32 [1.30–5.65] 10−4/min, p<0.001) and showed inaccurate estimates of the parameters composing Ki (k3 and Fe), even when Ki was similar for those methods. In simulations, errors in estimates of Ki due to the extra-vascular extra-cellular compartment depended on both k5 and k5/k6, with errors for the Patlak and Sokoloff methods of 0.02 [−0.01–0.18] and 0.40 [0.18–0.60] 10−3/min for normal lungs and of −0.47 [−0.89–0.72] and 2.35 [0.85–3.68] 10−3/min in ALI. Conclusions/Significance: $^{18}F-FDG$ accumulation in lung extra-vascular fluid, which is commonly increased during lung injury, can result in substantial estimation errors using the traditional Patlak and Sokoloff methods. These errors depend on the extra-vascular extra-cellular compartment volume and its transport rates with other compartments. The four-compartment model provides more accurate quantification of $^{18}F-FDG$-kinetics than those methods in the presence of increased extra-vascular fluid

Viscosities of the Gay-Berne nematic liquid crystal

We present molecular dynamics simulation measurements of the viscosities of the Gay-Berne phenomenological model of liquid crystals in the nematic and isotropic phases. The temperature dependence of the rotational and shear viscosities, including the nonmonotonic behavior of one shear viscosity are in good agreement with experimental data. The bulk viscosities are significantly larger than the shear viscosities, again in agreement with experiment.Comment: 11 pages, 4 Postscript figures, Revte

Polydispersity and ordered phases in solutions of rodlike macromolecules

We apply density functional theory to study the influence of polydispersity on the stability of columnar, smectic and solid ordering in the solutions of rodlike macromolecules. For sufficiently large length polydispersity (standard deviation $\sigma>0.25$) a direct first-order nematic-columnar transition is found, while for smaller $\sigma$ there is a continuous nematic-smectic and first-order smectic-columnar transition. For increasing polydispersity the columnar structure is stabilized with respect to solid perturbations. The length distribution of macromolecules changes neither at the nematic-smectic nor at the nematic-columnar transition, but it does change at the smectic-columnar phase transition. We also study the phase behaviour of binary mixtures, in which the nematic-smectic transition is again found to be continuous. Demixing according to rod length in the smectic phase is always preempted by transitions to solid or columnar ordering.Comment: 13 pages (TeX), 2 Postscript figures uuencode

‘That is because we are alone’:A relational qualitative study of socio-spatial inequities in maternal and newborn health programme coverage in rural Uttar Pradesh, India

This qualitative study was conducted in Uttar Pradesh state, India to explore how interrelated socio-economic position and spatial characteristics of four diverse villages may have influenced equity in coverage of community-based maternal and newborn health (MNH) services. We conducted social mapping and three focus group discussions in each village, among women of lower and higher socio-economic position who recently gave birth, and with community health workers (n = 134). Data were analysed in NVivo 11.0 using thematic framework analysis. The extent of socio-economic hierarchies and spatial disparateness within the village, combined with distance to larger centers, together shaped villages’ level of socio-spatial remoteness. Disadvantaged socio-economic groups expressed being more often spatially isolated, with less access to infrastructure, resources or services, which was heightened if the village was physically distant from larger centers. In more socio-spatially remote villages, inequities in coverage of MNH services that disadvantaged lower socio-economic position groups were compounded as these groups more often experienced ASHA vacancies, as well as greater distance to and poorer perceived quality of health services nearest the village. The results inform a conceptual framework of ‘socio-spatial remoteness’ that can guide public health research and programmes to more comprehensively address health inequities within India and beyond.</p

‘That is because we are alone’:A relational qualitative study of socio-spatial inequities in maternal and newborn health programme coverage in rural Uttar Pradesh, India

This qualitative study was conducted in Uttar Pradesh state, India to explore how interrelated socio-economic position and spatial characteristics of four diverse villages may have influenced equity in coverage of community-based maternal and newborn health (MNH) services. We conducted social mapping and three focus group discussions in each village, among women of lower and higher socio-economic position who recently gave birth, and with community health workers (n = 134). Data were analysed in NVivo 11.0 using thematic framework analysis. The extent of socio-economic hierarchies and spatial disparateness within the village, combined with distance to larger centers, together shaped villages’ level of socio-spatial remoteness. Disadvantaged socio-economic groups expressed being more often spatially isolated, with less access to infrastructure, resources or services, which was heightened if the village was physically distant from larger centers. In more socio-spatially remote villages, inequities in coverage of MNH services that disadvantaged lower socio-economic position groups were compounded as these groups more often experienced ASHA vacancies, as well as greater distance to and poorer perceived quality of health services nearest the village. The results inform a conceptual framework of ‘socio-spatial remoteness’ that can guide public health research and programmes to more comprehensively address health inequities within India and beyond.</p

Model-based geostatistical mapping of the prevalence of onchocerca volvulus in West Africa.

Background: The initial endemicity (pre-control prevalence) of onchocerciasis has been shown to be an important determinant of the feasibility of elimination by mass ivermectin distribution. We present the first geostatistical map of microfilarial prevalence in the former Onchocerciasis Control Programme in West Africa (OCP) before commencement of antivectorial and antiparasitic interventions. Methods and Findings: Pre-control microfilarial prevalence data from 737 villages across the 11 constituent countries in the OCP epidemiological database were used as ground-truth data. These 737 data points, plus a set of statistically selected environmental covariates, were used in a Bayesian model-based geostatistical (B-MBG) approach to generate a continuous surface (at pixel resolution of 5 km x 5km) of microfilarial prevalence in West Africa prior to the commencement of the OCP. Uncertainty in model predictions was measured using a suite of validation statistics, performed on bootstrap samples of held-out validation data. The mean Pearson’s correlation between observed and estimated prevalence at validation locations was 0.693; the mean prediction error (average difference between observed and estimated values) was 0.77%, and the mean absolute prediction error (average magnitude of difference between observed and estimated values) was 12.2%. Within OCP boundaries, 17.8 million people were deemed to have been at risk, 7.55 million to have been infected, and mean microfilarial prevalence to have been 45% (range: 2–90%) in 1975. Conclusions and Significance: This is the first map of initial onchocerciasis prevalence in West Africa using B-MBG. Important environmental predictors of infection prevalence were identified and used in a model out-performing those without spatial random effects or environmental covariates. Results may be compared with recent epidemiological mapping efforts to find areas of persisting transmission. These methods may be extended to areas where data are sparse, and may be used to help inform the feasibility of elimination with current and novel tools

Integrating Multiple Lines of Evidence into Historical Biogeography Hypothesis Testing: A Bison bison Case Study

One of the grand goals of historical biogeography is to understand how and why species’ population sizes and distributions change over time. Multiple types of data drawn from disparate fields, combined into a single modelling framework, are necessary to document changes in a species’s demography and distribution, and to determine the drivers responsible for change. Yet truly integrated approaches are challenging and rarely performed. Here, we discuss a modelling framework that integrates spatio-temporal fossil data, ancient DNA, palaeoclimatological reconstructions, bioclimatic envelope modelling and coalescence models in order to statistically test alternative hypotheses of demographic and potential distributional changes for the iconic American bison (Bison bison). Using different assumptions about the evolution of the bioclimatic niche, we generate hypothetical distributional and demographic histories of the species. We then test these demographic models by comparing the genetic signature predicted by serial coalescence against sequence data derived from subfossils and modern populations. Our results supported demographic models that include both climate and human-associated drivers of population declines. This synthetic approach, integrating palaeoclimatology, bioclimatic envelopes, serial coalescence, spatio-temporal fossil data and heterochronous DNA sequences, improves understanding of species’ historical biogeography by allowing consideration of both abiotic and biotic interactions at the population level

Evidence of two deeply divergent co-existing mitochondrial genomes in the Tuatara reveals an extremely complex genomic organization

Animal mitochondrial genomic polymorphism occurs as low-level mitochondrial heteroplasmy and deeply divergent co-existing molecules. The latter is rare, known only in bivalvian mollusks. Here we show two deeply divergent co-existing mt-genomes in a vertebrate through genomic sequencing of the Tuatara (Sphenodon punctatus), the sole-representative of an ancient reptilian Order. The two molecules, revealed using a combination of short-read and long-read sequencing technologies, differ by 10.4% nucleotide divergence. A single long-read covers an entire mt-molecule for both strands. Phylogenetic analyses suggest a 7–8 million-year divergence between genomes. Contrary to earlier reports, all 37 genes typical of animal mitochondria, with drastic gene rearrangements, are confirmed for both mt-genomes. Also unique to vertebrates, concerted evolution drives three near-identical putative Control Region non-coding blocks. Evidence of positive selection at sites linked to metabolically important transmembrane regions of encoded proteins suggests these two mt-genomes may confer an adaptive advantage for an unusually cold-tolerant reptile

A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts.

INTRODUCTION The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. METHODS To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. RESULTS Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. CONCLUSION Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target