Therizinosauria is one of the most enigmatic and peculiar clades among theropod dinosaurs, exhibiting an unusual suite of characters, such as lanceolate teeth, a rostral rhamphotheca, long manual claws, and a wide, opisthopubic pelvis. This specialized anatomy has been associated with a shift in dietary preferences and an adaptation to herbivory. Despite a large number of discoveries in recent years, the fossil record for Therizinosauria is still relatively poor, and cranial remains are particularly rare.Erlikosaurus andrewsi, as well as partial braincases of two other therizinosaurian taxa, the endocranial anatomy is reconstructed and described. The wider phylogenetic range of the described specimens permits the evaluation of sensory and cognitive capabilities of Therizinosauria in an evolutionary context. The endocranial anatomy reveals a mosaic of plesiomorphic and derived characters in therizinosaurians. The anatomy of the olfactory apparatus and the endosseous labyrinth suggests that olfaction, hearing, and equilibrium were well-developed in therizinosaurians and might have affected or benefited from an enlarged telencephalon.Based on computed tomographic (CT) scanning of the nearly complete and articulated skull of This study presents the first appraisal of the evolution of endocranial anatomy and sensory adaptations in Therizinosauria. Despite their phylogenetically basal position among maniraptoran dinosaurs, therizinosaurians had developed the neural pathways for a well developed sensory repertoire. In particular olfaction and hearing may have played an important role in foraging, predator evasion, and/or social complexity. Therizinosauria comprises an enigmatic clade of Cretaceous (Barremian – Maastrichtian) maniraptoran dinosaurs found in Asia and North American As the neurocranium and the brain are closely associated during growth, the endocranial cavity constitutes a representation of the gross surficial structure of the brain itself. A cast of the endocranial cavity, thus can provide the means to reconstruct the brain anatomy and associated structures A variety of cranial endocasts  of dinosaurs in general have been described in recent years Erlikosaurus andrewsi (IGM 100/111) from the Late Cretaceous of Mongolia includes the only complete, articulated, and three-dimensionally preserved skull (including the braincase) of any therizinosaurian Nothronychus mckinleyi (AZMNH-2117) from the Upper Cretaceous (Turonian) Moreno Hill Formation of New Mexico Falcarius utahensis (UMNH VP 15000 & 15001) from the Lower Cretaceous (Barremian) Cedar Mountain Formation of Utah Although cranial remains are still rare, numerous discoveries have expanded our knowledge of therizinosaurians in the last 20 years. To date, the holotype of Based on the endocasts of these four specimens, we present an extensive description of the endocranial anatomy of therizinosaurians . The widErlikosaurus andrewsi (IGM 100/111) was CT scanned at X-Tek Systems Ltd. (now Nikon Metrology), Tring, Hertfordshire, using a XT-H-225ST CT scanner fitted with a special steel honeycomb support to minimize object movement. Scan parameters were set at 180 kV and 145 µA for the complete skull. Additional scans were performed for the braincase region at 180 kV and 135 µA. The resulting rotational projections were processed with custom-built software provided by X-Tek Systems Ltd. creating.vgi and.vol files containing 1998 slices with a slice thickness of 145 µm for the complete skull and 1000 slices with a slice thickness of 108 µm for the braincase region.The skull of Falcarius utahensis  and a partial braincase of Nothronychus mckinleyi (AZMNH-2117) were performed at Ohio University using a General Electric eXplore Locus in vivo Small Animal MicroCT Scanner at 80 kV and 498 µA. Scans of the holotype and referred specimens of Falcarius yielded 781 and 960 slices, respectively, both with a slice thickness of 92 µm, whereas the Nothronychus scans yielded 1008 slices with a slice thickness of 88 µm. The respective scan data are part of an ongoing doctoral dissertation of the first author and will be deposited in an electronic archive and with the respective museum collections after completion of the dissertation.CT scans of two partial braincases of The final data files were subsequently imported into Avizo , running on a Hewlett-Packard workstation with 72 GB RAM and an nVidia Quadro 4000 2 GB graphics card under Windows 7 Professional (64 bit). Anatomical structures of interest  were highlighted and separately labeled using Avizo's segmentation editor. 3D surface models and volumes were created to visualize the highlighted structures and illustrate this article. Additionally, all measurements presented in this article and used for various calculations were derived from the digital models using Avizo see . A 3d pdErlikosaurus, it was not possible to completely reconstruct this part of the endocast. To obtain a complete endocast, the individual slices of the data set were mirrored and the missing part of the endocast was created and registered for the left side separately. To automate these steps two tcl (tool command language) scripts were created for Avizo. The endocast description is therefore mostly based on the original right side, unless specified otherwise. This method was also applied to acquire and supplement data for some parts of the endosseous labyrinths of Falcarius and Nothronychus. Following Sampson and Witmer Erlikosaurus andrewsi, as its endocast is the most complete and shows the majority of anatomical features. The phylogenetic and taxonomic classifications follow Zanno Falcarius utahensis, whereas the terms Therizinosauroidea and therizinosauroid, and Therizinosauridae and therizinosaurid define more exclusive clades within Therizinosauria.Due to some extensive damage to the caudal left braincase wall  of No permits were required for the described study, which complied with all relevant regulations.Relative and correlated measures of sensory capabilities are typically scaled to body mass. In the case of therizinosaurians, the general lack of preserved fossil remains usable for body-mass calculations poses a considerable problem. Moreover, the exceptional body morphology and proportions, which differ from those of other theropods, make comparisons to better-known theropod groups difficult. For example, although Therrien and Henderson Erlikosaurus andrewsi, who estimated its body mass at approximately 160 kg. This value was obtained by calculating a mass estimate of 380 kg for the more complete Alxasaurus elesitaiensis using Anderson et al.’s Erlikosaurus, by applying the principle of geometrically similar bodies Of the three therizinosaurian taxa discussed here, the only published mass estimate was given by Russell and Dong Erlikosaurus, Nothronychus mckinleyi, and Falcarius  measures 403 mm, yielding an estimated mass of 128 kg. However, femora are unknown for Erlikosaurus and Nothronychus mckinleyi. In order to estimate femoral length for these taxa, we performed bivariate regression analyses on log-transformed data to describe the relationship between femoral length (FL) and humeral length (HL) in six therizinosauriod taxa . Although not a weight-bearing element, we chose the humerus because, among the fragmentary materials known for ErlikosaurusErlikosaurus and Nothronychus mckinleyi allowing interpolated prediction of FL and minimizing potential error. The resulting equation (log10 HL = −0.2218±0.2753+1.158±0.1116× log10 FL) produced a high correlation coefficient (r = 0.96). Applying the maximum humeral length of 300 mm for Erlikosaurus given by Perle Nothronychus mckinleyi, results in a FL of 651 mm and a mass value of 599 kg. Given the large uncertainty inherent in our approach and in body-mass estimates in general, we assume a range of 150–250 kg for Erlikosaurus and 550–650 for Nothronychus mckinleyi  alcarius . The larsee also .AZMNH, Arizona Museum of Natural History, Mesa, Arizona, USA.IGM, Geological Institute of the Mongolian Academy of Sciences, Ulaan Bataar, Mongolia.UMNH, Natural History Museum of Utah, Salt Lake City, USA.Erlikosaurus andrewsi. Its endocast is relatively elongate and straight. The individual parts of the brain  are arranged in the same horizontal plane and do not show an obvious angulation, indicating only slight cephalic and pontine flexures. This is in contrast to more basal theropods, where the angulation of the midbrain can be up to 45–60 degrees Falcarius utahensis (UMNH VP 15000). Although incomplete, its morphology suggests a more pronounced angulation between the hindbrain and the midbrain. Smith et al. Falcarius. However, this only applies to the holotype specimen (UMNH VP 15000)  . The exckosaurus . HoweverErlikosaurus , for which endocranial casts are available Falcarius, two incomplete frontals  in all the therizinosaurian endocasts project caudolaterally from the cerebellar region and enter the space between the semicircular canals of the endosseous labyrinth. The floccular lobes are enlarged and have a round to oval cross-section in communis . They exErlikosaurus, and only partially for Falcarius and Nothronychus. It is most complete in one of the specimens of Falcarius (UCMP 15001), where it is dorsoventrally elongated and oval with a slight constriction dorsally. The canals for the cerebral carotid artery are positioned ventrally on each side of the pituitary fossa and are small in Falcarius. In Nothronychus they are enlarged and situated close together, projecting caudally.Due to the lack of preservation of bony correlates, the pituitary fossa could not be faithfully reconstructed for Erlikosaurus, where the braincase is the most complete, the rostromedial parts of the laterosphenoids and orbitosphenoids are only fragmentarily preserved. In the partial braincases of Falcarius and Nothronychus, this region is completely missing. The canal for the trigeminal nerve (CN V) is large and originates from the endocast ventrolaterally of the cerebellum and between the abducens and facial nerve canal in Erlikosaurus. The trigeminal nerve canal splits up into a rostrally directed smaller ophthalmic branch (CN V1), which passes through a separate ophthalmic foramen, and a larger branch exiting the braincase laterally. The latter branch subsequently divides into a more dorsally oriented maxillary branch (CN V2) and a ventral mandibular branch (CN V3), each passing through a separate foramen. Due to preservation, the osteological correlates of the trigeminal nerve canals are less clear in Nothronychus and Falcarius. However, in both taxa a split of the trigeminal nerve into three separate branches as in Erlikosaurus is evident. The CT scans confirm the trigeminal foramen identified by Kirkland et al. Nothronychus , oculomotor (CN III) and trochlear (CN IV) nerves could not be reconstructed for any of the discussed specimens. In ronychus . The sinronychus  is a bliErlikosaurus. It originates ventrolaterally from the endocast rostromedial to the trigeminal nerve canal, passing through a medium sized abducens foramen in the orbitosphenoid. This part of the braincase is only fragmentarily preserved and for some parts crushed. Therefore the exact distal course of the abducens nerve canal cannot be traced with certainty, but the lateral position of both canals indicate that they did not pass through the pituitary fossa, which is a derived condition found in most coelurosaurs Erlikosaurus, the abducens nerve canal in Falcarius originates rostrally to the trigeminal nerve canal bypassing the pituitary fossa. Smith et al. Falcarius or Nothronychus braincases. In Nothronychus, the abducens nerve canal originates from the endocast caudal to the trigeminal nerve canal. It exits the braincase rostrolaterally to the pituitary fossa without passing through the latter. The abducens foramen however is filled with matrix and not clearly visible in the actual specimen. The abducens foramen identified by Kirkland et al. The abducens nerve (CN VI) canal is only incompletely preserved in Erlikosaurus. It originates from the endocast in close association with the vestibulocochlear nerve (CN VIII), but both canals are clearly separated. The facial nerve canal exits the braincase through a small foramen ventral to the floccular fossa and caudal to the large foramen for the trigeminal nerve canal  in ve canal . LateralNothronychus the facial nerve canal is comparable to that of Erlikosaurus in both location and size. A split into two branches is not visible. This is either due to the lower resolution of the CT scans and/or the preservation or the fact that the division of the facial nerve into a hyomandibular and a palatine ramus could have occurred lateral to the braincase. The latter option is more widely observed , although detailed information on the peripheral branching of the facial nerve is rare Falcarius is only visible in the holotype specimen. Compared to Erlikosaurus and Nothronychus, it is larger and positioned more rostrally, closer to the trigeminal nerve canal. It concurs with the respective foramina identified by Kirkland et al. In Erlikosaurus, caudal to the facial nerve canal. It leaves the braincase through a small foramen caudal to the foramen for the facial nerve canal  originates from the lateral side of the endocast of ve canal . The vesErlikosaurus most likely housed the glossopharyngeal (CN IX), the vagus (CN X), and the spinal accessory (CN XI) nerve, as no further nerve canals are visible on the endocast for the separation of these three nerves. The same canal probably also housed the jugular vein. The canal exits the braincase on the medial side through a large and dorsoventrally elongated foramen. The foramen is not divided internally and appears again on the caudal (outside) surface of the braincase between the basioccipital and the exoccipital, lateral to the occipital condyle and the dorsal foramen (details see below) of the hypoglossal nerve. A separate foramen vagi, illustrated by Clark et al. A large nerve canal on the ventrolateral part of the endocast of Nothronychus a similar nerve canal originates from the caudolateral side of the endocast and exits the braincase through an enlarged, slit-like foramen lateral to the occipital condyle and two smaller foramina  hypoglossal foramina are present in several derived theropods In foramina . WhereasFalcarius, and is presumed to have housed all three cranial nerves (CN IX–XI). However, as inferred for the troodontid Zanabazaar juniorFalcarius, as well as in Erlikosaurus and Nothronychus.A single large nerve canal is present in the endocasts of Erlikosaurus is represented by two thin nerve canals, originating on the lower ventrolateral side of the endocast. Both canals are distinctly separated and exit the braincase through two foramina lateral to the occipital condyle on the medial side of the braincase. Although both foramina were illustrated on the inside of the braincase by Clark et al. The hypoglossal nerve (CN XII) of Nothronychus. As discussed above, they probably transmitted the two branches of the hypoglossal nerve instead of single vagus and hypoglossal nerves as suggested by Kirkland et al. Two distinct nerve canals are also present in the endocast of Erlikosaurus and Nothronychus. The roots of a large and prominent vascular canal are located slightly dorsal and rostral to the floccular lobes on the lateral surface of the cerebellar region  is surprising and could mean two things: (1) moderate to high olfactory abilities played an important role in foraging or (2) relatively large olfactory ratios are an ancestral feature retained in this group. The Aptian and Albian are characterized by the radiation of flowering plants The sensorineural calculations for the endocasts under study here indicate that the sensory capabilities were relatively high in therizinosaurians. In particular, olfaction was well developed in at least A similar pattern can be found in the auditory capabilities. Our results indicate that therizinosaurians were able to discriminate a comparably wide range of frequencies in a low to middle frequency domain. The auditory capabilities were similar or even higher in these taxa than in other herbivorous dinosaur groups, such as ornithischians Erlikosaurus, showing a transitional stage in the evolution of a more birdlike brain.Regarding the visual abilities in therizinosaurians, the lack of prominent and ventrolaterally displaced optic tecta would suggest that their visual capabilities were only low to moderately developed. However, due to equivocal data in tyrannosaurs, Witmer and Ridgely Erlikosaurus had probably a lower visual sensitivity than other theropods. Ornithomimus edmonticus and Garudimimus brevipes, as well as most herbivores in their study Erlikosaurus was photopic. Still, the enlarged floccular lobes and elongated semicircular canals indicate that vision was at least moderately developed in terms of coordination between eye and head movement. Witmer and Ridgely Erlikosaurus and Nothronychus, it can be assumed that these taxa were capable of keeping their gaze focused on a target during rapid head and neck movements–a requirement typically associated with predation and/or flight. Alternatively, refined gaze stabilization mechanisms might have been advantageous for other behaviors  or may simply be plesiomorphic reflections of their coelurosaurian heritage. In this context, it is worth noting that extant flightless herbivorous birds such as ostrich (Struthio camelus) likewise retain elongate semicircular canals.Schmitz and Motani Erlikosaurus would have had a nearly horizontal head posture, which could be linked to allow an optimal overlap of the visual fields and binocular vision. The low cephalic and pontine flexure of the brain observed in Erlikosaurus might thus be an adaptation to the osteological requirements in keeping a horizontal deportment of the head and upper neck Struthiomimus altus in contrast, has a relatively straight endocast similar to that of Erlikosaurus. Low pontine flexure is also present in Nothronychus and the referred specimen of Falcarius (UMNH VP 15001), whereas the holotype specimen of Falcarius (UMNH VP 15000) shows a pronounced pontine flexure. Although the forebrain and partly the midbrain regions in the latter taxa are unknown, the amounts of pontine and cephalic flexure are generally directly correlated in dinosaurs Falcarius could be explained by different ontogenetic stages, as the holotype specimen most likely represent a juvenile individual Inferred from the position of the lateral semicircular canal, Erlikosaurus falls within the range of basal theropods and coelurosaurs  , with the exception of Archaeopteryx lithographica (3.41–4.85), which shows only a slightly higher ratio.Wharton .3–3.23) . AlthougTyrannosaurus rex (32.6%) and Archaeopteryx lithographica (44.6%), they assumed an intermediate stage of forebrain enlargement was present in derived maniraptorans, such as Troodon and Caudipteryx. The value for Erlikosaurus also falls within that range, indicating that forebrain enlargement must have occurred very close to the base of Maniraptora.Considering the large uncertainties in body mass, allometric factors, and the extent to which the actual brain filled the endocranial cavity, Larsson et al. This study presents the first reconstruction and visualization of the endocranial anatomy of therizinosaurians and sheds light on the sensory adaptations within this group. Phylogenetically positioned between basal coelurosaurs and derived maniraptoran dinosaurs, the brain anatomy of therizinosaurians represents a mixture between plesiomorphic and derived characteristics. Although situated near the base of Maniraptora, therizinosaurians had developed the neural pathways for a well-developed sensory repertoire. The anatomy of the olfactory apparatus and the endosseous labyrinth suggests that olfaction, hearing, and equilibrium were well developed in therizinosaurians and might have affected or benefited from an enlarged telencephalon. The high acuity of the individual senses further indicates that they may have played an important role in foraging, predator evasion, and/or social complexity. However, it is important to note that, although a variety of osteological adaptations provide good evidence for derived dietary preferences in Therizinosauria, the sensory abilities could constitute a retention of plesiomorphic traits, rather than a direct result of an ecological transformation. Considering the wider distribution of these sensory and neural characteristics among basal coelurosaurs, therizinosaurians could thus simply have utilized an already existing sensory repertoire inherited from their carnivorous ancestors for different dietary strategies. Further investigations of sensory capabilities in Maniraptora are needed to differentiate between phylogenetic and ecological signals in the evolution of these traits.Figure S1Interactive figure of the cranial endocast of Erlikosaurus andrewsi (IGM 100/111).(PDF)Click here for additional data file.Figure S2Interactive figure of the cranial endocast and braincase of Nothronychus mckinleyi (AZMNH-2117).(PDF)Click here for additional data file.Figure S3Interactive figure of the cranial endocast and braincase of Falcarius utahensis .(PDF)Click here for additional data file.Figure S4Interactive figure of the cranial endocast and braincase of Falcarius utahensis .(PDF)Click here for additional data file.Figure S5Interactive figure of the endosseous labyrinths (right side) of Erlikosaurus andrewsi (IGM 100/111), Nothronychus mckinleyi (AZMNH-2117), and Falcarius utahensis .(PDF)Click here for additional data file.


The persistence of rural-urban disparities in child nutrition outcomes in developing countries alongside rapid urbanisation and increasing incidence of child malnutrition in urban areas raises an important health policy question - whether fundamentally different nutrition policies and interventions are required in rural and urban areas. Addressing this question requires an enhanced understanding of the main drivers of rural-urban disparities in child nutrition outcomes especially for the vulnerable segments of the population. This study applies recently developed statistical methods to quantify the contribution of different socio-economic determinants to rural-urban differences in child nutrition outcomes in two South Asian countries – Bangladesh and Nepal.Using DHS data sets for Bangladesh and Nepal, we apply quantile regression-based counterfactual decomposition methods to quantify the contribution of (1) the differences in levels of socio-economic determinants (covariate effects) and (2) the differences in the strength of association between socio-economic determinants and child nutrition outcomes (co-efficient effects) to the observed rural-urban disparities in child HAZ scores. The methodology employed in the study allows the covariate and coefficient effects to vary across entire distribution of child nutrition outcomes. This is particularly useful in providing specific insights into factors influencing rural-urban disparities at the lower tails of child HAZ score distributions. It also helps assess the importance of individual determinants and how they vary across the distribution of HAZ scores.There are no fundamental differences in the characteristics that determine child nutrition outcomes in urban and rural areas. Differences in the levels of a limited number of socio-economic characteristics – maternal education, spouse’s education and the wealth index (incorporating household asset ownership and access to drinking water and sanitation) contribute a major share of rural-urban disparities in the lowest quantiles of child nutrition outcomes. Differences in the strength of association between socio-economic characteristics and child nutrition outcomes account for less than a quarter of rural-urban disparities at the lower end of the HAZ score distribution.Public health interventions aimed at overcoming rural-urban disparities in child nutrition outcomes need to focus principally on bridging gaps in socio-economic endowments of rural and urban households and improving the quality of rural infrastructure. Improving child nutrition outcomes in developing countries does not call for fundamentally different approaches to public health interventions in rural and urban areas. A substet al. in a stuet al.. This peet al.. In suchet al.,10. SuchObserved rural-urban differences in indicators of child nutritional outcomes such as Height-for-Age Z scores (HAZ) may arise because of:levels of determinants of nutrition outcomes, such as mother’s education and household wealth – which may be termed as ‘covariate’ effects in a regression context; or(i) rural-urban differences in the strength of association between particular determinants and nutrition outcomes – which may be termed as coefficient effects in a regression context. For example, an additional year of mother’s education may have a larger impact on nutrition outcomes in an urban or a rural population relative to the other, all else held equal.(ii) rural-urban differences in the levels of determinants, similar policy frameworks and tools could be applied across urban and rural areas [Rural-urban disparities in child nutrition may also arise from a combination of covariate and coefficient effects. If rural-urban differences arise largely due to covariate effects, or differing al areas . If diffe.g., what proportion of rural-urban HAZ score differentials may be explained by differential wealth or maternal education levels, and how does this proportion vary across the HAZ distribution? QR-CD methods are well-validated and have been applied in a variety of regression modelling contexts, including labour remuneration, health outcomes and public finance. There have also been several applications to modelling under as well as over nutrition outcomes in recent years [A small literature ,11 has ent years -15. Our The literature on rural-urban nutrition and health disparities discussed in the previous section has largely modelled the mean/median of nutrition outcomes such as height for age z-scores (HAZ), or the prevalence of stunting or wasting. It has, however, been recognised in the literature that comparisons of means of child nutrition indicators is not adequate for understanding rural-urban disparities. Inequalities of socio-economic endowments tend to be much greater in urban areas. The differing patterns of inequalities in urban and rural areas may imply that rural-urban disparities in the upper and lower tails of the distribution of child nutrition outcomes may be very different from what is suggested by a comparison of means ,8. Our iOnly a few studies have attempted to quantify the contribution of socio-economic or ecological variables, individually or in the aggregate, to rural-urban differences in child nutrition outcomes. Garrett and Ruel  investigFor the empirical application of this approach, we have chosen two country case studies in South Asia – Bangladesh and Nepal. Both countries are developing countries with a high incidence of poverty-31.5% in Bangladesh (2010) and 25.2% in Nepal (2011)  - and sihttp://measuredhs.com/) which collects and disseminates nationally representative demographic, health and nutrition information based on household surveys for 90 countries. The datasets are freely accessible to the public and researchers subject to a prescribed registration and approval process. Permission to access and use the datasets relevant to this study was obtained by the authors from the MEASURE-DHS archive. The most recent datasets from the Demographic and Health Surveys for Bangladesh (2007) and Nepal (2006) were used in the study. The datasets include data from a nationally representative sample of urban and rural households. Units for observation for this study were all children aged below five years in the households surveyed. After deletion of observations with incomplete information, the sample for Bangladesh had 5267 children, with 1842 (35%) living in urban households and 3425 (65%) living in rural households, while Nepal had 5219 children with 1168 (22%) living in urban households 4051 (78%) living in rural households.We have used datasets from the Demographic and Health Surveys of the MEASURE-DHS project (We used height-for-age Z-scores (HAZ) as indicators of child nutrition in rural and urban households. Stunting, defined as HAZ less than two standard deviations of the NCHS/CDC/WHO International Reference Standard , is a goa. For the construction of the Index, these variables are broken into sets of dichotomous variables and indicator weights are assigned using principal component analysis (PCA) as suggested by Filmer and Pritchett [b.The DHS wealth index  is a comritchett . The indThe conceptual framework underpinning our empirical analysis is the widely-applied UNICEF framework  outlininTo assess the rural-urban differentials in HAZ scores, we first estimate the distributions of HAZ scores separately for rural and urban children in each country using kernel smoothing techniques. From the kernel density estimates of HAZ scores, the rural-urban differential is computed at each quantile and provides the raw difference in HAZ scores across the distribution.e.g., HAZ, into subsets based on outcomes values, e.g., deciles of HAZ values, and run standard regressions on these segments separately, since this introduces sample selectivity problems. Estimating categorical dependent variables models is one option, e.g., probit or logit models to explain stunting status. However, apart from constraining the effect of explanatory covariates to be the same across the distribution of outcomes, these models sacrifice statistical information in grouping continuously distributed variables like HAZ into small numbers of categories. QR methods offer the most robust approach to flexibly model the shifts in HAZ distribution associated with changes to covariates.A major objective of this study is to decompose the rural-urban differences in child nutrition outcomes into the covariate (or composition) effect, i.e., the differences in HAZ scores due to differences in levels of characteristics of urban and rural households, and the co-efficient (or structure) effect, i.e., the differences in HAZ scores due to the differences in the returns to those characteristics, across the entire distribution of HAZ scores. Linear or logistic regression approaches assess the mean response of the outcome variable to changes in covariates and the effect of covariates is constrained to be the same along the entire distribution of the outcome variable. Decompositions based on linear regression results ,31 wouldThe quantile regression method developed by Koenker and Bassett  estimateFollowing Firpo et al. , the decet al.[Although our set of chosen covariates excludes proximate determinants in order to minimize endogeneity problems, and is consistent with variables used in previous literature ,11,13, tTable The estimates of the unconditional RIF quantile regressions (QR) separately for rural and urban areas are shown for Bangladesh and Nepal in Tables The distribution-wide relationship between age of the child and HAZ scores in rural and urban areas in Nepal is similar to that of Bangladesh. Again, mother’s education has a consistently positive relationship with HAZ scores across the distribution in both rural and urban areas. There are two key differences between the Nepal and Bangladesh results. In contrast to Bangladesh, in Nepal, education of the spouse has only a weak and largely insignificant relationship with child nutrition. However, child vaccination has a positive and significant association with HAZ scores. In both rural and urban areas, this relationship strengthens as we move up the HAZ score distribution.Figures Figures increasing the rural-urban disparity in HAZ scores, while positive figures show a contribution to reducing it. A large proportion of the covariate effect is accounted for by a limited number of characteristics. In Bangladesh, in the lowest quantile (Q10), wealth (39%), mother’s education (26%) and spouse’s education (22%) account for 87% of the covariate effect which is explained by socio-economic characteristics included in the model. The contribution of other characteristics like child vaccination, working status of the mother, number of children below five years, dependency ratio and living in extended families is relatively small and is significant only in some quantiles. As we move from the lower to the higher quantiles, the contribution of mother’s education decreases while that of wealth increases. The contribution of spouse’s education to the covariate effect is nearly 20% across all quantiles. In Nepal, in the lowest quantile, wealth (38%), mother’s education (22%) and spouse’s education (22%) account for nearly 72% of the covariate effect. The contributions of child vaccination and the working status of the mother are significant in all quantiles, while the dependency ratio is significant in some of the higher quantiles. However, in Nepal, the contribution of mother’s education increases as we move up the quantiles, while that of wealth decreases. The contribution of spouse’s education is much lower than in Bangladesh.The further decomposition of the covariate and co-efficient effects into the contribution of individual covariates in Bangladesh and Nepal is also presented in Tables Tables . We discuss below the implications for the design of policies and programmes in public health and complementary areas.The QR-based decomposition methods provide specific insight into the drivers of disparities in the lowest quantiles of HAZ scores, which is useful for designing interventions aimed at vulnerable households with the highest levels of stunting. The quantification of the contribution of individual socio-economic determinants to rural-urban disparities can be used to assess the “returns” to different types of interventions. In both countries, rural-urban gaps in the lower half of the distribution are largely accounted for by differing levels of covariates, suggesting that bridging rural-urban inequality in undernutrition is largely a matter of equalizing endowments of the determinants of nutrition. Our results also suggest that much of this can be achieved by focussing on just three determinants: maternal education, spouse’s education and the wealth index. Other variables, child vaccination, age of mother, mother’s working status, extended family dummy and the dependency ratio make a relatively small contribution to explaining rural-urban disparities, especially in the lower quantilesThe preeminent role of maternal education in child nutrition in the region is emphasised by our results. The contribution of improved maternal education to bridging rural-urban disparities is the largest in the lowest quantiles of HAZ scores and is comparable in magnitude to the contribution of the wealth index (improvements in economic status) Plugging the maternal education gap is, therefore, particularly important for alleviating rural-urban disparity at the lower tail of HAZ. Bangladesh has already made great strides in improving rural women’s education over the last two decades. The Female Secondary Stipend (FSS) programme, a conditional cash transfer programme introduced in 1994, provided impetus for a rapid and substantial expansion in female secondary school enrolment that saw enrolment proportion increase from 35% to more than 50% within a decade . The FFSAn important caveat to bear in mind regarding public policymaking in the education sphere is the potential for gender-targeted education programmes to encourage the development of reverse gender-gaps. There is evidence to show that boys’ enrolment in co-educational schools in Bangladesh has been falling relative to girls , and thaBridging the gap in spouse’s education is also important for reducing rural-urban inequality across the HAZ distribution in Bangladesh, and for the most nutritionally vulnerable children in Nepal. In Bangladesh our results are consistent with a scenario wherein investments in improving the education level of spouses  have large impacts on child nutrition outcomes across the distribution of HAZ scores. This probably highlights the role of the spouse in a context where women may be constrained by social norms in accessing public health messages or services. However, in Nepal, investments in improving the education levels of spouses may have large impact only in the lower end of the HAZ score distribution. Similarly, measures to mitigate the adverse effects of mothers’ working status in rural areas can be expected to have a substantial impact on reducing rural-urban disparities in Nepal. But in Bangladesh, such measures are likely to have only a very limited impact. The decomposition exercise can, therefore, provide useful inputs for decisions on the relative priorities for different types of interventions in specific contexts.The difference in relative endowments of wealth is the single most important factor in explaining rural-urban disparities in our case study countries. Given the wealth index is a composite of several variables, as discussed before, it is difficult to interpret wealth effects in terms of specific interventions or policies. However, we note that sanitation (toilet facilities) and water (source of supply) are two of the key components of the wealth index in the two countries. Recent research in the region  has highquality of rural services in the region relevant to nutrition, such as in health care, have been called into question [The question ,10. The question . The lacWe have used QR-CD methods to assess the relative importance of covariate and coefficient effects in explaining rural-urban disparities in child nutrition using cross-sectional data sets for two countries that are at different stages of development and urbanisation. The efficacy of socio-economic endowments and public health infrastructure in promoting improved child nutrition may change as a country develops. QR-CD methods can provide more insights into the changes in the efficacy of public health interventions if they can be applied to repeated cross-section datasets within a country. This is an extension of the study that we intend to explore subject to the availability of data. It must be noted that QR-CD methods are computationally intensive and require large datasets. The method cannot be applied to smaller datasets such as those available from intervention studies or RCTs. The CD exercise can provide reliable results only if the basic quantile regression includes all the important determinants of child nutrition outcomes and is well specified. While our choice of determinants has been constrained by the coverage of the DHS surveys, we have included the key exogenous demographic and economic determinants considered in the previous literature ,11,13. TUsing DHS datasets we examined rural-urban differences in child nutrition outcomes using HAZ scores for two South Asian countries – Bangladesh and Nepal which differ substantially in the extent of urbanisation. The similarity in the pattern of rural-urban differentials in these two countries suggests that these differentials persist even as urbanisation and economic development proceed. The methodology employed in this paper allows us to decompose rural-urban differences in child nutrition outcomes into covariate and co-efficient effects and further enables us to quantify the contribution of individual explanatory variables (socio-economic characteristics) to rural-urban differences via these effects. The decomposition of rural-urban differences into covariate and co-efficient effects shows that the covariate effect is dominant. A core set of determinants – wealth index (which incorporates ownership of assets and access to sanitation and drinking water), maternal education and spouse’s education – accounts for a very large proportion of the covariate effects in both countries, which suggests that there are no fundamental differences in the socio-economic determinants of child nutrition outcomes in rural and urban areas. The dominance of covariate effects confirms findings from earlier studies ,11 that a The DHS surveys generally cover water supply, electricity, sanitation, flooring type, ownership of assets such as radio, television, telephone, and refrigerator, ownership of agricultural land and livestock, persons sleeping per room and country specific items. Ownership of agricultural land and livestock is not used in the calculation of the DHS Wealth Index as these assets are not generally available in urban areas.b There have been some concerns that the DHS Wealth Index is too “urban” in its construction depending on assets and services that the urban population may have but the rural population may not have. This has been sought to be addressed in more recent DHS surveys by inclusion of more items mainly rural in character . A number of alternative approaches to construction of rural and urban wealth indices using DHS data are possible [possible  includinThe authors have no competing interests to declare.CSS contributed to the literature review, design of the study, interpretation of results and prepared the drafts of the manuscript. GZ managed the DHS datasets, ran the econometric models for unconditional quantile regressions and counterfactual decompositions and contributed to the interpretation of results. BS conceived of the study, participated in its design, provided oversight and co-ordination and helped in revisions of the manuscript. All authors read and approved the final manuscript.Dr C.S. Srinivasan is a Senior Lecturer in the Department of Food Economics and Marketing, School of Agriculture, Policy and Development at the University of Reading, UK. Dr Giacomo Zanello is a Research Officer in the Oxford Department of International Development, Queen Elizabeth House, University of Oxford, UK. Professor Bhavani Shankar is Professor of International Agriculture, Food and Health in the Centre for Development, Environment and Policy in the School of Oriental and African Studies, University of London and the Leverhulme Centre for Integrative Research on Agriculture and Health.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/581/prepubCounterfactual Decomposition Procedure Using Unconditional Recentred Influence Function (RIF) Quantile Regression.Click here for file


Phosphoproteomics is a powerful analytical platform for identification and quantification of phosphorylated peptides and assignment of phosphorylation sites. Bioinformatics tools to identify phosphorylated peptides from their tandem mass spectra and protein sequence databases are important part of phosphoproteomics. In this work, we discuss general informatics aspects of mass-spectrometry-based phosphoproteomics. Some of the specifics of phosphopeptide identifications stem from the labile nature of phosphor groups and expanded peptide search space. Allowing for modifications of Ser, Thr, and Tyr residues exponentially increases effective database size. High mass resolution and accuracy measurements of precursor mass-to-charge ratios help to restrict the search space of candidate peptide sequences. The higher-order fragmentations of neutral loss ions enhance the fragment ion mass spectra of phosphorylated peptides. We show an example of a phosphopeptide identification where accounting for fragmentation from neutral loss species improves the identification scores in a database search algorithm by 50%. PhospMass-spectrometry-based proteomics has emerged as a powerful platform for the analysis of protein phosphorylations . In partLu and coworkers , 21 haveN times.Here, we describe the informatics aspects of phosphopeptide identifications using protein sequence databases and mass spectral data from high mass accuracy and resolution instruments. Database identifications of phosphorylated peptides are done in a dynamic mode—assuming that in a peptide sequence Ser, Thr, and Tyr may or may not be are modified. For database searches, it effectively means exponential increase in the size of database. About 17% of amino acid residues   in humanLTQ-Orbitrap mass spectrometer  stores tNormally, the full MS scan is recorded in the Orbitrap mass analyzer which is a high resolution and mass accuracy mass analyzer. The routine mass accuracy of intact peptides is in the range of ±5–10 part-per-million (ppm). This is a very high mass accuracy and is very important for reducing false discovery rates of peptide identifications. The accuracy of the intact peptide's mass affects the number of candidate peptides from the database that will be considered in matching to the spectra. The candidate peptides are filtered based on the mass of the intact peptide and accuracy with which the mass has been measured. The higher the accuracy, the smaller the number of candidate peptides, and as a result the smaller the possibility of false positives. Fragment ion masses are recorded in ion trap mass analyzer. This is a very sensitive mass analyzer. However, the mass accuracy of measured ions is nominal, and normally in the range of ±0.5 Da. Peptide identification using tandem mass spectra and protein databases is an integral part of proteomics. It is important that peptide assignments are determined with high accuracy and are verifiable. In high-throughput experiments, when thousands of tandem mass spectra are searched, it is not practical for an expert user to manually assign every spectrum and the assignments are made by software. The software uses a concept, either heuristic or probabilistic model, to measure similarity between experimental tandem mass spectrum and an amino acid sequence. For high quality spectra, when signal-to-noise ratio is high and spectra contains clearly defined ion series, most of the programs and concepts perform very well. However, when the peptide fragmentation is poor and the spectrum contains very few distinguishable peaks, or if the peptide amino acid sequence is not in the database, a number of factors lead to a wrong peptide assignment—a false identification. Depending on the software, sometimes false identifications may yield high assignment scores. High mass accuracy may substantially reduce the false identification by restricting the search space of allowed candidate sequences.Another important aspect of the database search algorithm is the modeling of the fragmentation pattern. This is especially true for cases when there is significant difference from the routine fragmentation pattern, caused, for example, by posttranslational modifications. Thus, it is known that, in CID, peptides containing phosphorylated amino acid residues, Ser or Thr, tend to lose the phosphor group(s) before they fragment along the peptide backbone. We show here that accounting for product ions in this pathway significantly improves the identification scores of phosphopeptides in SEQUEST database search algorithm.It is often difficult to differentiate between possible phosphorylation sites in a peptide and to uniquely assign phosphorylated amino acid residues. It has to do with the presence of several Ser, Thr, and Tyr residues in a peptide and low overall intensity of peaks from product ions of phosphorylated peptides. To address this problem, Beausoleil and coworkers  have devThere are several mass spectral characteristics of phosphorylated peptides. Thus, in collision-induced dissociation reactions, one of the most prevalent pathways of the molecular dissociation is the neutral loss of the labile phosphor group of Ser or Thr residues. The presence of the relevant ion often serves as a diagnostic feature for phosphorylated peptides . Often tIn general, fragmentation of peptides via CID produces strong b- and y-ion series . Therefo2 are further dissociated generating MS3 spectra. In spectra collected with this approach, there are number of ions corresponding to phosphoric acid group losses from b- and y-ions. An example of such a tandem mass spectrum is shown in n experiments to enhance fragmentation spectra of phosphopeptides.The interpretations of the tandem mass spectra of phosphorylated peptides may be complicated. The main reason for this is the low abundance of fragment ions due to the alternative fragmentations. One experimental approach used for enhancing phosphopeptide identifications is to do a higher-order mass spectrometry on the fragment ions of original precursor. In these experiments, neutral loss fragment ions generated during CID in MSIncreased mass accuracy for precursor ions combined with enhanced fragmentation pathways helps bioinformatics methods to improve phosphopeptide identifications from tandem mass spectra and protein sequence databases. Normally identifications of phosphorylated peptides yield small cross-correlation scores. This has partially to do with the theoretical fragmentation models, which take into account only b- and y-ions generated from the peptide bond fragmentations of phosphorylated precursor peptides. We augmented the fragmentation pattern (in SEQUEST)  introduc


The ergotamine tartrate associated with certain categories of drugs can lead to critical ischemia of the extremities. Discontinuation of taking ergotamine is usually sufficient for the total regression of ischemia, but in some cases it could be necessary thrombolytic and anticoagulant therapy to avoid amputation.A woman of 62 years presented with a severe pain left forearm appeared 10 days ago, with a worsening trend. The same symptoms appeared after 5 days also in the right forearm. Physical examination showed the right arm slightly hypothermic, with radial reduced pulse in presence of reduced sensitivity. The left arm was frankly hypothermic, pulse less on radial and with an ulnar humeral reduced pulse, associated to a decreased sensitivity and motility.Clinical history shows a chronic headache for which the patient took a daily basis for years Cafergot suppository .From about ten days had begun therapy with itraconazole for vaginal candidiasis. The Color-Doppler ultrasound shown arterial thrombosis of the upper limbs , with minimal residual flow to the right and no signal on the humeral and radial left artery.Angiography revealed progressive reduction in size of the axillary artery and right humeral artery stenosis with right segmental occlusions and multiple hypertrophic collateral circulations at the elbow joint. At the level of the right forearm was recognizable only the radial artery, decreased in size. Does not recognize the ulnar, interosseous artery was thin. To the left showed progressive reduction in size of the distal subclavian and humeral artery, determined by multiple segmental steno-occlusion with collateral vessels serving only a thin hypotrophic interosseous artery.Arteriographic findings were compatible with systemic drug-induced disease. The immediate implementation of thrombolysis, continued for 26 hours, with heparin in continuous intravenous infusion and subsequent anticoagulant therapy allowed the gradual disappearance of the symptoms with the reappearance of peripheral pulses.Angiography showed regression of vasospasm and the resumption of flow in distal vessels. The patient had regained sensitivity and motility in the upper limbs and bilaterally radial and ulnar were present. A 62 years woman was admitted in our Institute complaining a strong bilateral forearm pain. The pain left upper limb had appeared 10 days ago and after 5 days was also presented on the right side.® (ergotamine) for 5-6 years, 2-4 mg/day. The patient, with these doses of ergotamine, could control the headaches that immediately recurred in case of drug withdrawal.The history revealed that the patient was suffering from migraine with aura and therefore she took Cafergot® (itraconazole) for a vaginal candidiasis.Moreover, 10 days before she had started taking 4 tablets per day of SporanoxThe pain was first discontinuous, associated with effort, and only after become continuous. Physical examination showed the right arm hypothermic, with reduced radial pulse, in the absence of motility deficiency and loss of sensation.The left arm was frankly hypothermic in the absence of radial and ulnar humeral loss of pulse.At the CW-Doppler control: absence of signal in the left radial and ulnar artery and demodulated signal at humeral artery; on the right, demodulated signal at the radial and ulnar arteries.After a Color-Doppler ultrasound of the upper limbs, which showed bilateral humerus thrombosis with minimal residual flow on the right radial artery and no signal on the left radial artery, the patient was subjected to emergency upper limb angiography for possible thrombolytic therapy.Under local anesthesia, a right femoral approach was performed through a 4F introducer sheath. Angiography revealed a progressive reduction of caliber at the right axillary artery with a steno-occlusions of the right humeral artery and multiple segmental hypertrophic collateral circulation in the elbow joint. At the level of the right forearm was recognizable only the radial artery, decreased in size. To the left, showed progressive reduction in size of the distal subclavian and humeral arteries, determined by multiple segmental steno-occlusion with collateral hypotrophic vessels that belatedly revascularized only a thin interosseous artery Figure .The arteriographic findings were compatible with systemic drug induced disease: ergotamine therapy was suddently suspended.The thrombolytic treatment was performed through a 4F catheter with the tip placed at the origin of the brachial artery: after a 60.000 urokinase U.I injection, a slow intra-arterial infusion of urokinase and heparin during the following hours was performed.At the end of the procedure, after the administration of about 1.300.000 U.I of urokinase, patency of the brachial and ulnar artery was re-established, obtaining a good perfusion of the hand; however, a concentric stenosis was still detectable in the distal brachial artery and in the ulnar and radial arteries. The immediate implementation of thrombolysis, continued for 26 hours, keeping the patient anticoagulation with heparin infusion pump  led to the gradual disappearance of the symptoms of patients with recurrence of the peripheral pulses.Serial angiograms during the procedure shew a gradual thrombolytic recanalization of the artery occluded, in the presence of angiographic signs of concentric wall thickening of vasculitic nature.The final angiographic control shew regression of vasospasm and the resumption of flow in distal vessels Figure .®, maintaining an INR between 2.0 and 3.0), and supported for 12 days with intravenous prostaglandin treatment (Prostavasin® 20 mg/day).Treatment with heparin during hospitalization was imbricate with oral anticoagulant therapy ; genetic testing (factors II and V Leiden) and homocysteine assay for exclude metabolic diseases with genetic etiology ; aortic arch arteriography allowed to exclude a primary disease like Takayasu arthritis type. Moreover, we proposed to test antithrombin, protein C/S deficiency and the prothrombin mutation (20210A) and all results were negative.During hospitalization, three days after ergotamine discontinuation, the patient presented a strong trend to worsening headache accompanied by nausea and vomiting that required an implemented treatment with benzodiazepines , inhibitors of re-uptake of serotonin  and an associated steroid (Bentelan) in case of resistance.The patient was discharged completely asymptomatic after two weeks of hospitalization. At two weeks, three and six months the patient was in subjective well-being, in absence of motility and sensitivity deficiency. Radial and ulnar pulses were present bilaterally and a Color-Doppler ultrasound showed a normal blood supply of the upper limbs. Even the patient's headache was controlled by the new implemented therapy after ergot discontinuation.The Ergotamine is an alkaloid produced by a fungus, Claviceps purpurea , describErgotamine induced ischemia is rare but potentially serious complications may lead through two mechanisms: vasospasm and thrombosis. Toxicity arises from chronic therapeutic doses, acute ingestion of excessive doses of the drug and acute ingestion of therapeutic doses in patients with hypersensitivity.The literature shows a surprisingly low number of clinical cases using angiographic evidence of arterial stenosis showed a rapidly reversible after discontinuation of ergotamine -7.McKiernan et al reported a case of severe vasospasm of the lower extremities  induced by ergotamine tartrate .Martinet et al. used the Duplex ultrasound showing multiple areas of vasospasm in the lower limbs in a woman of 38 years who suffered from "chronic migraine" treated with ergotamine tartrate and resolved after infusion of sodium nitroprusside and epidural analgesia .D'Amore et al. showed a severe arterial stenosis to load the lower extremities in a patient taking Cafergot for migraine headaches .Regarding the treatment of limb ischemia upper and lower drug discontinuation is certainly the first procedure to be implemented, but not always sufficient to reverse the disease in place.In severe forms of ischemia refractory to therapy surgical sympathectomy with balloon dilatation or arterial dilation can be effective, however the patient management depends on clinical and instrumental monitoring of vasospasm, especially in cases of advanced ischemia.Bongard and Bounameaux infused sodium nitroprusside in 6 patients with severe acute lower limb ischemia due to ergotamine tartrate or dihydroergotamine recruitment, the vasospasm was relieved within 48 hours in all patients except one .Thrombolysis was effective in the patient described by D'Amore et al. . In refrThe ergotamine discontinuation with the infusion of nitroprusside or nitroglycerin appears to solve the problem in most cases .In our case the patient took ergotamine chronically for about three years without any reported problems, the addition of an antifungal (itraconazole) has caused the artery vasospasm and thrombosis of the upper limbs. The interaction of erythromycin and ergotamine at low doses can cause ischemia of the lower extremities . SimilarIn our case, we decided to start thrombolytic therapy continued for 26 hours maintaining the patient on anticoagulation with heparin infusion (maintaining a PTT of 50-55 sec) for 3 days, then overlapped with an oral anticoagulant therapy. At the same time a vasoactive therapy was also carried out for 15 days. This attitude has led to the gradual resolution of the ischemic and the clinical point of view with the reappearance of peripheral pulses, both in terms of radiological with complete resolution of vasospasm and thrombotic process. In conclusion in the literature has not documented any cases of ischemia with the combination of ergotamine and itraconazole, should we believe an aggressive therapeutic approach in cases of significant clinical impairment and instrumental. We believe that in cases of vasospasm associated with arterial thrombosis thrombolytic treatment, when necessary, PTA and vaso-active therapy provides an excellent immediate result avoiding prolonged ischemic pain related complications.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.EC, GB and SB had the primary role in patient care, EC and FG wrote the manuscript, FG made the literature research, SB, SMG and RM revised the manuscript. All authors read and approved the final version.


According to the practice guidelines of the American Burn Association on burn shock resuscitation, intravenous (IV) fluid therapy is the standard of care for the replacement of fluid and electrolyte losses in burn injury of ≥20% of the total body surface area. However, in mass burn casualties, IV fluid resuscitation may be delayed or unavailable. Oral rehydration therapy (ORT), which has been shown to be highly effective in the treatment of dehydration in epidemics of cholera, could be an alternate way to replace fluid losses in burns. A prospective case series of three patients was carried out as an initial step to establish whether oral Ceralyte®90 could replace fluid losses requiring IV fluid therapy in thermal injury. The requirement of the continuing IV fluid therapy was reduced by an average of 58% in the first 24 hours after the injury (range 37-78%). ORT may be a feasible alternative to IV fluid therapy in the resuscitation of burns. It could also potentially save many lives in mass casualty situations or in resource-poor settings where IV fluid therapy is not immediately available. Further studies are needed to assess the efficacy of this treatment and to determine whether the present formulations of ORT for cholera need modification. Oral rehydration therapy (ORT) was formulated for treating cholera in the 1960s . It was A prospective study of three patients with burn wounds (20-40% of TBSA) was performed. Fluid requirements were calculated according to the Parkland Formula  . For theAll the patients tolerated the administration of ORT with gastric residuals of less than 300 cc which were monitored every two hours. The characteristics of the patients are defined in We reviewed the literature on oral fluid replacement in burns but found only one report on the use of ORT in burns in humans, which treated burns 10-20%) in children. Resuscitation of IV fluid is the current standard of care for the treatment of patients with burns of ≥20% of the TBSA. Without intervention, the loss of fluids and electrolytes into burned tissues rapidly leads to hypotension and shock. In major burns, early resuscitation fluid is required to maintain circulation and adequate tissue perfusion. Volume losses occur most rapidly in the first 6-8 hours but continue for 18-36 hours or longer ,10. Howe-20% in cORT is a proven safe and effective alternative to IV resuscitation in epidemic cholera, a disease which causes rapid loss of fluids from the gut, leading to circulatory collapse and death. Oral rehydration solutions (ORS) take advantage of a robust back-up mechanism for intestinal absorption of salts and water, in addition to the normal absorption which is mediated by a sodium chloride-linked transport system at the brush border of the intestinal epithelium. This active transport moves sodium with chloride from the intestinal lumen into the cell. Cellular sodium potassium ATPase extrudes sodium into the lateral cell spaces, creating an osmotic and electrochemical gradient that produces a net flow of water and solutes from the lumen into the bloodstream ,12.This sodium-glucose transporter of the intestinal epithelium allows absorption of sufficient water and electrolytes to restore the large fluid losses even in severe diarrhoeal diseases when the normal absorptive mechanism is impaired . The WorIn the present limited case series, we have shown that ORT decreased the amount of IV fluids needed to maintain adequate hydration in patients with severe burn wounds. By introducing a rice-based ORT—Ceralyte®90, there is the potential to substantially decrease the IV fluid requirement in the resuscitation of the thermally-injured patient, thereby decreasing the risk of such complications as line infection. Furthermore, the absorption offluid and electrolyte from the intestine is autoregulated by homeostatic mechanisms, including endocrine and mechano receptors. ORT is, therefore, less likely to result in fluid overload which can cause significant complications, such as compartment syndrome and pulmonary oedema, occasionally observed in burned patients receiving IV fluid therapy .JAMA stated that “The use of oral saline is adopted as standard procedure in the treatment of shock due to burns, in the event of large scale civilian catastrophe”  used in this study.


The purpose of this article is to report on the quality of the existing evidence base regarding the effectiveness of clinical pathway (CPW) research in the hospital setting. The analysis is based on a recently published Cochrane review of the effectiveness of CPWs.An integral component of the review process was a rigorous appraisal of the methodological quality of published CPW evaluations. This allowed the identification of strengths and limitations of the evidence base for CPW effectiveness. We followed the validated Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria for randomized and non-randomized clinical pathway evaluations. In addition, we tested the hypotheses that simple pre-post studies tend to overestimate CPW effects reported.Out of the 260 primary studies meeting CPW content criteria, only 27 studies met the EPOC study design criteria, with the majority of CPW studies (more than 70 %) excluded from the review on the basis that they were simple pre-post evaluations, mostly comparing two or more annual patient cohorts. Methodologically poor study designs are often used to evaluate CPWs and this compromises the quality of the existing evidence base.Cochrane EPOC methodological criteria, including the selection of rigorous study designs along with detailed descriptions of CPW development and implementation processes, are recommended for quantitative evaluations to improve the evidence base for the use of CPWs in hospitals. Clinical pathways (CPWs) are evidence-based multidisciplinary care plans which describe the essential steps needed in the care of patients with a specific clinical problem. They are used to translate clinical guidelines into local protocols and clinical practice . WhereasClinical pathways have been proposed as a strategy to optimise resource allocation in a climate of increasing healthcare costs . Other tThe first objective of this article is to report on the methodological quality of the existing evidence base regarding the effectiveness of CPW research in the hospital setting. An international, multidisciplinary team of researchers conducted a systematic review of the effectiveness of CPWs in hospitals, with the findings recently published in the Cochrane library . The secWe followed the validated Cochrane Effective Practice and Organisation of Care Group (EPOC) methodology for considering and analysing studies . The priFor the purpose of the systematic review on CPWs in hospitals, four study designs were considered for inclusion: randomized controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series analysis (ITS).While there are many well developed and well accepted critical appraisal criteria for experimental studies, fewer exist for non-experimental studies such as CBAs and ITS. Both designs are subject to a lack of control and high risk of bias so EPOC developed criteria to facilitate their quality assessment and inclusion (where appropriate) in systematic reviews. For example, CBAs are required to have more than one control group and ITS require at least three time points before and after an intervention. Validated criteria for the assessment of these designs have been developed by EPOC and are available from the EPOC website  and the We developed a quality assessment and data abstraction instrument incorporating the EPOC risk of bias criteria . QualityWe compared patients managed according to CPW to those managed by usual care, and patients treated within a multifaceted intervention including a CPW compared to usual care.The aim of the secondary analysis was to determine whether pre-post study design was associated with an overestimate of the effects of CPW. Other researchers also compared the findings of randomized evaluations vs. non-randomized study designs and concluded that such studies potentially overestimate the effects reported and there were systematic differences between effects estimated -9. To te2)).A Cochrane web-based program, Review Manager (RevMan), was used to calculate a pooled estimate of the combined intervention effect on LOS, called weighted mean difference (WMD) . We usedAll potentially relevant studies were assessed using the CPW definition  and EPOCThe majority (79.1 %) of the rejected studies (2335 out of 2954) had to be excluded because they failed to meet our definition of CPW. Table Out of 27 CPW evaluations included, nineteen of the included studies were randomised controlled trials (RCTs) -22,41-48Of the original studies which met the CPW content criteria, more than 70 % were excluded from the review as they were simple pre-post evaluations, mostly comparing two or more yearly patient cohorts ), versus the pooled LOS data recently published in the Cochrane library ) [We followed the validated Cochrane EPOC criteria for randomized and non-randomized CPW evaluations ,6. The fMany of such excluded CPW evaluations claimed to provide evidence for the effectiveness of the pathway intervention under consideration but, with a methodologically weak study design, it remains unclear if the reported effect was really attributable to the CPW effectiveness or any other unknown factors. Possible confounding factors might have been the case-mix introduction, hospital quality improvement initiatives or changes in hospital policy . The uncBased on our review experience, we reaffirm that uncontrolled pre-post designs are commonly used to evaluate the effectiveness of CPWs. Such designs are likely to be misleading and contribute little to understanding the reported effects of pathways. Considering the second objective of this article, the meta-analytic comparison supports other evidence -9 that sThere is a place for well designed process-evaluations also referred to as interrupted time series (ITS) to explore and provide more insights into the varying pathway components and their causal effectiveness to determine how CPW interventions actually work. Carefully designed time series studies are less resource-intensive than RCTs, do not require a control group, and allow for the use of retrospective data. While requiring more advanced statistical techniques than simple pre-post studies, ITS supports research outcomes that are more likely to contribute to the evidence base, including systematic reviews. Better designed, conducted and reported CPW evaluations will contribute to a better understanding of the key elements of CPWs that impact on patient, provider and economic outcomes.The majority of included studies employed LOS as a performance measure. Hence, we compared the magnitudes of CPW effects on length of stay (n = 14 primary studies) rather than patient outcomes such as mortality (n = 4 studies) or in-hospital complications (n = 5 studies) . The lowCochrane EPOC methodological inclusion criteria should be considered for quantitative evaluations into the impact of CPWs in hospitals. Based on our review experience, the EPOC methodological gold standard is infrequently transferred into research practice. Future evaluators could hereby contribute significantly to the understanding of factors associated with the reported effects of clinical pathways in hospitals by incorporating EPOC criteria into study design. Whilst experimental methods such as randomised trials are recommended they may be considered beyond the capacity of many clinicians and researchers. A well designed evaluation such as ITS or CBA that meets the EPOC gold standard methodological criteria can produce meaningful, rigorous results with the use of relatively few resources. In terms of the second study objective, the methodological comparison of Cochrane vs. non Cochrane study designs (see Figure The authors declare that they have no competing interests.TR, LK, EJ and AM participated equally to the development and preparation of the manuscript. TR, LK and EWS contributed to study design and writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/12/80/prepubEPOC risk of bias criteria.Click here for file


Saccharomyces cerevisiae strains and inferred the underlying recombination landscape at a fine genomic resolution (mean segregating site distance 0.22 kb). Comparison was made with landscapes inferred for a similar cross between four yeast strains, and with a previous single-generation, intra-strain cross . Moderate congruence was identified between landscapes (correlation 0.58–0.77 at 5 kb resolution), albeit with variance between mean genome-wide recombination rates. The multiple generations of mating undergone in the AILs gave more precise inference of recombination rates than could be achieved from a single-generation cross, in particular in identifying recombination cold-spots. The recombination landscapes we describe have particular utility; both AILs are part of a resource to study complex yeast traits . Our results will enable future applications of this resource to take better account of local linkage structure heterogeneities. Our method has general applicability to other crossing experiments, including a variety of experimental designs.Accurate estimates of recombination rates are of great importance for understanding evolution. In an experimental genetic cross, recombination breaks apart and rejoins genetic material, such that the genomes of the resulting isolates are comprised of distinct blocks of differing parental origin. We here describe a method exploiting this fact to infer genome-wide recombination profiles from sequenced isolates from an advanced intercross line (AIL). We verified the accuracy of the method against simulated data. Next, we sequenced 192 isolates from a twelve-generation cross between West African and North American yeast  Accurate estimates of bare rates of evolutionary processes such as mutation and recombination are important building blocks in our understanding of evolution. These rates are known to vary across genomes; in the case of recombination, changes of orders of magnitude can occur between nearby loci at recombination hotspots We consider an experiment in which a population of Saccharomyces cerevisiae strains. This was denoted the “two-way” cross, or by the sub-index We applied our method to two different examples of advanced intercross lines. The first example, described in detail in Ref. In a further step, we applied our method to data from the crossing experiment of Mancera et al. We start by describing results obtained from the application of our inference method to simulated crosses. We then report the results of our genome-wide analysis of the cross-specific recombination profiles, and of our comparisons between them, in detail.Our method gave accurate inferences of recombination rates for simulated systems. Inferences of recombination were made for simulated data of an ion rate . The infhotspots ; again tOur method was extended to cover finite populations by estimating the likelihoods of observing given haplotypes see , Eq. 3 v see . However see . This coOur results from simulated data demonstrate the basic ability of the method to infer simple recombination profiles from offspring sequences of genetic crosses. Later in the text, we return to the issue of the consistency of results obtained with our model when applied to biological recombination landscapes.We first used our method to infer recombination rates for each of the two advanced yeast intercross lines. The mean recombination rate, measured genome-wide, was substantially higher in the four-way cross, at Analysis of data from the s-way cross of Mancera et al. Investigating recombination across chromosomes revealed substantial variability in mean rates  with theLDhatSequence polymorphisms between the parental strains gave more than fifty thousand segregating sites for the two-way cross, and more than eighty thousand for the four-way cross. Segregating sites were dispersed fairly uniformly across the genome , which are resolved into recombination events. DSBs are themselves non-randomly distributed across the genome We took a DSB map The DSB map is extremely reproducible and thus has little statistical noise associated with it Application of our inference method to the two advanced intercross datasets allowed us to investigate both the coldest and hottest regions of recombination with satisfactory true positive rates. Inferred landscapes from sets of ten simulated replicate experiments were used to measure the accuracy with which the hottest and coldest regions of recombination could be annotated. For each simulation, the two-way cross landscape was used as an input. Relative to a single generation cross, the advanced intercross design performed substantially better in identifying both the hottest and coldest regions see . From thHere we have described a bespoke method for recombination rate estimation in advanced intercross lines. Whereas a coalescent-based calculation for the haplotype likelihoods arises naturally in the context of wild populations with unknown histories, our “forward-in-time” analysis is intuitive for a crossing experiment with known initial population. Comparing our approach to that applied by Mancera et al. When studying recombination rates in the setting of a genetic cross, there are several experimental parameters and tradeoffs to consider. Key among these are the number of isolates (with associated cost in sequencing and isolate generation), the number of crossing rounds, typical inter-marker distances, the number of parental lines, and the population size. In order for the inference method to be able to faithfully capture the statistics of the whole range of recombination rates over the genome at the level of the histograms shown in These two advanced intercrosses form part of a yeast resource to systematically study complex traits. We hope that the cross specific recombination landscapes that we inferred here will help future studies utilising this resource. For example, any quantitative trait loci (QTL) mapping study .Considering loci We note that, in the above equations, all except two of the parameters are known from the locus positions and the structure of the cross, the exceptions being the recombination rate, LDhat) are used in the computation to improve the speed of calculation) LDhatEstimation of recombination rates across regions spanning multiple loci was conducted using a composite likelihood approach. For multi-locus systems, deriving analytical probability functions equivalent to Details on isolation and sequencing of individual segregants and variant calling can be found in ftp://ftp.sanger.ac.uk/pub/teams/153/AIL-yeast/. Sequence data is available from European Nucleotide Archive (ENA) under access number ERP000780.The inference program, haplotype data, and inferred yeast landscape are available from Text S1Details of isolation and sequencing of individual segregants, calling of segregating sites, and genotyping from sequencing data.(PDF)Click here for additional data file.


Previous studies have demonstrated that cancer registrations and hospital discharge rate are closely correlated with census data-based socioeconomic deprivation indices. We hypothesized that communities with higher degrees of socioeconomic deprivation tend to have a higher ratio of metastatic to non-metastatic cancer cases . In this study, we investigate the potential link between this ratio and the Wellbeing Index (WI) among Texas counties.r2 = 0.84, p = 0.0002), all-type cancers  and lung cancer  at diagnosis were positively correlated with WI.Cancer data in 2000 were provided by the Texas Cancer Registry, while data on the ten socioeconomic variables among the 254 Texas counties in 2000 for building the WI were obtained from U.S. Census Bureau. The ten socioeconomic status variables were subjected to the principal component analysis, and the first principal component scores were grouped into deciles for the WI (1 to 10) and the 254 Texas counties were classified into 10 corresponding groups. Weighted linear regression analyses and a Cochran-Armitage trend test were performed to determine the relationship between the ratio of age-adjusted metastatic to non-metastatic cancer incidence cases and WI. The ratios of metastatic to non-metastatic cases of female genital system cancer (The ratios of metastatic to non-metastatic cases of all-type, female genital system and lung cancers at diagnosis were statistically correlated with socioeconomic deprivation. Potential mediators for the correlation warrant further investigation in order to reduce health disparities associated with socioeconomic inequality. Socioeconomic status is one of the major determinants of health status and health disparities among different social and ethnic groups , and mayThe study reported here was undertaken to test a specific hypothesis that the ratio of metastatic to non-metastatic cancer cases  would be positively correlated with the degree of socioeconomic deprivation among Texas counties. Identifying cancer in its relatively earlier non-metastatic stages leads to substantially higher success in treatment and fewer cancer deaths. Such a difference is likely to exist among communities with different levels of socioeconomic deprivation as measured by a deprivation index. Texas is the second largest state in the United States of America with 261,797 square miles, larger than France .This study was approved by Texas Tech University Health Science Center Institutional Review Board with exemption for review because of its use of published data. The present study used the Wellbeing Index (WI) developed by Albrecht and Ramasubramanian , which iData for the ten socioeconomic status variables for each of the 254 counties of Texas in 2000 were obtained from the U.S. Census Bureau . Data foThe ten socioeconomic status variables listed in Table Before estimating the model, we compute the Moran's I statistic  and GearIn addition, we performed principal component analysis with the percentages of people with cars, etc. rather than without cars etc. to construct a "reverse" WI, and found no correlation with the ratio of metastatic to non-metastatic cases of any cancer studied, suggesting that the WI is scaling deprivation but not wellbeing.Table r2 = 0.839, p = 0.0002), all types of cancer  and lung cancer  were significantly and positively correlated with WI . The ratios for breast, prostate or colorectal cancers were not significantly correlated with WI . The test for the existence of spatial autocorrelation using Moran's I and Geary's C statistics fail to detect spatial correlation in all the regressions of interest in this study and are shown in table The ratio of metastatic to non-metastatic cases of the female genital system cancer  is very effective . After dThis study demonstrates the utility of the WI as a novel tool for identifying health disparities across large geographic areas. Further, this method can be accomplished in a relatively quick and reproducible fashion using readily available and standard census data. It would be of interest to apply the method to other disease pathologies.Specific results for cancer pathologies show that the ratios of metastatic to non-metastatic cases of all-type cancers, lung cancer and the female genital cancer at diagnosis were significantly and positively correlated to WI among Texas counties. Hence, the WI is a useful indicator at least for the ratios of metastatic to non-metastatic cancer cases at county level. Further studies are needed to determine the actual sources and solutions for cancer in economically deprived areas. In particular, barriers for the early detection of cancers among communities with higher degree of socioeconomic deprivation should be examined in order to reduce health disparities.The authors declare that they have no competing interests.BUP conceived the idea that the ratio of metastatic to non-metastatic cancer cases would be correlated with the WI. KAH interacted with Texas Cancer Registry and obtained the Texas cancer data. BUP, KAH and GG worked collaboratively on the data analysis. KAH performed the GIS mapping and GG performed principal component analysis, regression analysis and Cochran-Armitage trend test. BUP and GG interpreted the results and wrote the manuscript. KAH assisted GG in extracting data using SEER software, participated in the discussion of the methodology and interpretation of the results, and drew the WI map. EB and KAH used ArcGIS to obtain spatial weights followed by Moran's I and Geary's C test for spatial autocorrelation using the spdep package in R software. CL participated in revising the manuscript according to reviewers' comments, and choosing appropriate statistical approaches, and editing the entire text. All authors read and approved the final manuscript.


We report the case of a true hermaphrodite with testicular seminoma with resulting metastases to the inguinal lymph nodes eight months after radical orchidectomy. This is an unusual presentation of testicular cancer and, to the best of our knowledge, the first report of this kind in the literature.A 45-year-old Caucasian true hermaphrodite, raised as a male, developed a testicular seminoma. He had undergone a left orchidopexy at the age of 10 for undescended testes. Metastases from testicular tumors to inguinal lymph nodes are a rare occurrence. It has been suggested that previous inguinal or scrotal surgery may alter the pattern of nodal metastasis of testicular cancer. We review the literature to evaluate the incidence of inguinal lymph node involvement in early stage testicular cancer and discuss possible routes of metastases to this unusual site. We also discuss the management of the inguinal lymph nodes in patients with testicular tumors and a previous history of inguinal or scrotal surgery, as this remains controversial.Inguinal lymph node metastases from testicular cancer are rare. A history of inguinal or scrotal surgery may predispose involvement of the inguinal nodes. During radical inguinal orchidectomy, the surgeon should be careful to minimize the handling of the testis and ensure high ligation of the spermatic cord up to the internal inguinal ring to reduce the risk of inguinal lymph node metastasis. Testicular cancer is a relatively rare cancer and is responsible for one to two percent of all male cancer. In the UK, around 2000 new cases are diagnosed every year . SeminomUsually, the testicular lymphatics drain along the gonadal vessels to the retroperitoneal nodes, which are located between the lower thoracic and lumbar vertebrae, including the renal hili and around the inferior vena cava and the aorta . The lymPrimary involvement of the iliac and inguinal nodes is rare and associated with tumor extension into the epididymis, breaching of the tunica vaginalis through to the scrotal wall or extension to the vas deferens. Direct inguinal metastases are also reported as a result of previous surgical manipulation of the inguinoscrotal region , as in oUsually the superficial inguinal nodes drain the skin from the lower abdomen, part of the buttocks and scrotum, the perineum and the penis. The deep inguinal nodes, which can be found under the fascia lata, are drained from the superficial nodes, legs and deep penile structures. However, following surgery where the testicular lymphatics are damaged and disrupted as a result of dissection of the spermatic cord during orchidopexy, orchidectomy, hydrocele repair, varicocelectomy or hernia repair, these lymphatics seek new collateral vessels for drainage. Injured lymphatics from scrotal incisions re-anastomose with the testicular lymphatics and can therefore provide a direct route of spread to the inguinal nodes .et al. postulated in his report that seminoma may have spread along a similar subepithelial capillary network along the vas [Ohtani and Gannon studied the microvasculature of the rat vas deferens and have described the arterial and venous drainage in great detail . They fo the vas . For theA 45-year-old Caucasian true hermaphrodite, who has been raised as a male, presented with a hard left testicular mass which had significantly increased in size over the preceding few months. His past medical history included a left orchidopexy at the age of 10 years. He had also previously undergone a hysterectomy and a right oophorectomy and no testicular tissue had ever been identified on the right side. On examination, he had a left-sided inguinoscrotal scar. His left testis was enlarged and hard. We could detect no other abnormality. His human chorionic gonadotrophin (HCG) level was elevated (11 mIU/ml) and the other tumor markers, including lactate dehydrogenase LDH - 240 U/L) and alpha-fetoprotein AFP - 3 ng/ml), were normal. A staging computed tomography (CT) scan showed no evidence of metastatic disease. A left radical orchidectomy was performed. Intra-operatively, his whole testis was found to be hard and no distinct mass was identified. A histopathology examination revealed a homogenous friable testis with no epididymis identified. The tumor breached the tunica albuginea and tunica vaginalis. Microscopic examination showed a classical seminoma with vascular and perineural invasion  in patients with testicular tumors and a previous history of inguinal or scrotal surgery remains controversial, as a result of insufficient data . Prophylocedures .et al. also suggested that prophylactic ipsilateral inguinal dissection is not necessary in patients with non-seminomatous testicular tumors with a history of inguinal or scrotal surgery, owing to the efficacy of primary and secondary chemotherapy [Another series in which 20 cases of testicular tumor and previous scrotal surgery were presented, failed to document the incidence of inguinal lymphadenopathy . They cootherapy . HoweverInguinal lymph node metastases from testicular cancer are rare. A history of inguinal or scrotal surgery may predispose involvement of the inguinal nodes as a result of altered patterns of lymphatic drainage. The routine management of inguinal lymphatics  in patients with testicular tumors and a previous history of inguinal or scrotal surgery remains controversial, with no consensus amongst those treating these patients. During radical inguinal orchidectomy, the surgeon should be careful to minimize the handling of the testis and ensure high ligation of the spermatic cord up to the internal inguinal ring to reduce the risk of inguinal lymph node metastasis.(AFP): Alpha-fetoprotein; (CT): Computed tomography; (FNA): Fine needle aspiration; (GCTs): Germ cell tumors; (HCG): Human chorionic gonadotrophin; (LDH): Lactate dehydrogenaseWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.MI wrote the original manuscript. FZ and JP analyzed and interpreted the patient data with regard to the hematological and radiological diagnosis. SB performed the histological examination of the testis. VN and JM were major contributors in writing the manuscript. All authors read and approved the final manuscript.