Mineralization of cancellous bone after alendronate and sodium fluoride treatment: a quantitative backscattered electron imaging study on minipig ribs.
Fluoride stimulates bone formation, whereas bisphosphonates reduce bone resorption. In clinical trials, both treatments increase bone density, although sodium fluoride (NaF) increases and alendronate (bisphosphonate, ALN) decreases bone turnover. In a comparative study using minipigs an inverse correlation has been reported between bone turnover and elastic modulus. Small-angle X-ray scattering (SAXS) measurements of these bones revealed no structural deterioration of the collagen/mineral composite at the nanometer range for ALN-treated vertebra, whereas a slight increase of the average thickness of the mineral crystals as well as changes of the structure of the collagen/mineral composite were found in the bones of NaF-treated animals. In this study we used quantitative backscattered electron imaging (qBSE) to investigate the cancellous bones from ribs of minipigs treated with vehicle, NaF, or ALN. This method provides information on the local mineral concentration in the micrometer range. Mineralization spectra were obtained from each treatment group, and statistically significant differences between ALN and controls were found for the peak position, the peak height, the peak width, and the average calcium (Ca) concentration of the mineral distribution. The results reveal that the cancellous bone matrix was more uniformly mineralized after ALN treatment. The reduced bone turnover induced by ALN, documented histomorphometrically could be at the origin of this phenomenon. No significant differences were detected between NaF and control. Together with the earlier SAXS data these results may explain in part the increase in bone density and the improvement of biomechanical properties observed after ALN treatment in animals and in osteoporotic patients.


Endogenous opioids modulate neuronal survival in the developing avian ciliary ganglion.
Most studies on the trophic regulation of the normal neuronal competition for survival have focused on interactions between neurons and their target environment. However, it is also likely that trophic modulators are released from premotor inputs onto motoneurons. We have examined the developmental distribution of endogenous enkephalin-like immunoreactivity and the role that these endogenous opioid peptides play in normal neuronal degeneration. During the early portion of the normal cell death period, enkephalin-like immunoreactivity is highest within preganglionic cell bodies in the midbrain and their nerve terminals in the ciliary ganglion. Exogenous daily morphine administration to the chick embryo has previously been shown to delay most of the normal neuronal death in the ciliary ganglion (see Meriney et al., 1985). We hypothesized that opiate receptor activation increases the probability that ciliary ganglion neurons will survive their developmental competition and, further, that the endogenous opioid peptides in the ciliary ganglion normally modulate this competition. However, in our previous report (Meriney et al., 1985), we noted that daily administration of the antagonist naloxone to the chorioallantoic membrane did not significantly alter neuronal survival, as would have been expected if endogenous opioids were involved in regulating cell death. In contrast, in this report we show that three times daily application of naltrexone (a long-lasting opiate antagonist) significantly decreased neuronal survival among the ciliary ganglion cells, and that the surviving cells were not ultrastructurally different than neurons from controls of the same developmental stage. To control for toxic effects of naltrexone, we performed cell counts following naltrexone, we performed cell counts following naltrexone treatment in another population of cholinergic motoneurons (lumbar spinal motoneurons). In this population of cells, the total number of motoneurons remains unchanged following naltrexone treatment. To test for a specific toxic effect on the neurons of the ciliary ganglion, we generated a dose-response curve for toxicity in vitro and determined that naltrexone was not toxic over concentration ranges that are likely to exist in vivo. It appears, therefore, that a multiple daily antagonist application protocol blocks opiate receptors sufficiently in the ciliary ganglion to decrease an endogenous opiate influence significantly. We tested the possibility that endogenous opioids exert their effect by modifying transmission at peripheral and ganglionic synapses. In the generally accepted hypothesis, paralysis at the peripheral nerve-striated muscle synapse would rescue cells, while paralysis of ganglionic synapses would decrease survival. Iris neuromuscular junctions onto striated muscle cells were not blocked by opioids, but neuromuscular transmission in the smooth muscle of the choroid coat was blocked.(ABSTRACT TRUNCATED AT 400 WORDS)


Three-dimensional distortion-tolerant object recognition using photon-counting integral imaging.
This paper addresses three-dimensional distortion-tolerant object recognition using photon-counting integral imaging (II). A photon-counting linear discriminant analysis (LDA) is proposed for classification photonlimited images. In the photon-counting LDA, classical irradiance images are used to train the classifier. The unknown objects used to test the classifier are labeled by the number of photons detected. The optimal solution of the Fisher's LDA for photon-limited images is found to be different from the case when irradiance values are used. This difference results in one of the merits of a photon-counting LDA, namely that the high dimensionality of the image can be handled without preprocessing. Thus, the singularity problem of the Fisher's LDA encountered in the use of irradiance images can be avoided. By using photon-counting II, we build a compact distortiontolerant recognition system that makes use of the multiple-perspective imaging of II to enhance the recognition performance. Experimental and simulation results are presented to classify out-of-plane rotated objects. The performance is analyzed in terms of mean-squared distance (MSD) between the irradiance images. It is shown that a low level of photons is sufficient in the proposed technique.


Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes.
The relation of ventilatory impairment and chronic mucus hypersecretion to death from all causes and death from obstructive lung disease (chronic bronchitis, emphysema and asthma) was studied in 13,756 men and women randomly selected from the general population of the City of Copenhagen. During the 10 year follow up 2288 subjects died. In 164 subjects obstructive lung disease was considered to be an underlying or a contributory cause of death (obstructive lung disease related death); in 73 subjects it was considered to be the underlying cause of death (obstructive lung disease death). Forced expiratory volume in one second, expressed as a percentage of the predicted value (FEV1% pred), and the presence of chronic phlegm were used to characterise ventilatory function and chronic mucus hypersecretion respectively. For mortality analysis the proportional hazards regression model of Cox was used; it included age, sex, pack years, inhalation habit, body mass index, alcohol consumption, and the presence or absence of asthma, heart disease, and diabetes mellitus as confounding factors. By comparison with subjects with an FEV1 of 80% pred or more, subjects with an FEV1 below 40% pred had increased risk of dying from all causes (relative risk (RR) = 5.0 for women, 2.7 for men), a higher risk of obstructive lung disease related death (RR = 57 for women, 34 for men), and a higher risk of obstructive lung disease death (RR = 101 for women, 77 for men). Chronic mucus hypersecretion was associated with only a slightly higher risk of death from all causes (RR = 1.1 for women, 1.3 for men). The association between chronic mucus hypersecretion and obstructive lung disease death varied with the level of ventilatory function, being weak in subjects with normal ventilatory function (for an FEV1 of 80% pred the RR was 1.2), but more pronounced in subjects with reduced ventilatory function (for an FEV1 of 40% pred the RR was 4.2). A similar though statistically non-significant trend was observed with regard to obstructive lung disease related death. This study shows that impaired lung function is very strongly related to total mortality, obstructive lung disease related mortality, and obstructive lung disease mortality and suggests that chronic mucus hypersecretion, in those with impaired ventilatory function, is also a significant risk factor for death from obstructive lung disease.


Composition of tissue fatty acids of phospholipids depends on tumor localization and disease progression in colorectal patients.
Fatty acids play a role in development and progression of colon cancer. The aim of this study was to assess the relation between tissue fatty acids (saturated fatty acids, unsaturated fatty acids, the ratio of C18 to C18:1 - index of fatty acids saturation, SI), colorectal tumor localization and disease progression. Total of 49 patients (14 with proximal colon, 13 with distal colon and 22 with rectal tumor localization) were studied. One year after surgery 24 patients had the disease progression. Tissue levels of saturated fatty acids and unsaturated fatty acids were measured before surgery by gas-chromatography. These fatty acids were determined in cancerous tissue (CA) and non-cancerous tissue (NCA). The most significant differences in the mean values of fatty acids of phospholipids between CA and NCA in patients with proximal tumor localization were noted. The mean value of C18 was significantly lower while C18:1 was significantly higher in CA as compared to NCA in patients without disease progression (p<0.02; p<0.03; respectively). SI was significantly lower in CA as compared to NCA only in patients without disease progression (p<0.02). Fatty acids of tissue phospholipids' fraction, as well as SI, strongly depend on tumor localization and might be useful as potential markers of the disease progression in colorectal cancer patients.


Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans.
It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. However, it is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We investigate a number of questions pertaining to the distribution of mutations using more than 130,000 DNMs from three large datasets. We demonstrate that the amount and pattern of variation differs between datasets at the 1MB and 100KB scales probably as a consequence of differences in sequencing technology and processing. In particular, datasets show different patterns of correlation to genomic variables such as replication time. Never-the-less there are many commonalities between datasets, which likely represent true patterns. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that cannot be explained by variation at smaller scales, however the level of this variation is modest at large scales-at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome. We demonstrate that variation in the mutation rate does not generate large-scale variation in GC-content, and hence that mutation bias does not maintain the isochore structure of the human genome. We find that genomic features explain less than 40% of the explainable variance in the rate of DNM. As expected the rate of divergence between species is correlated to the rate of DNM. However, the correlations are weaker than expected if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered.


A pseudo-tetragonal tungsten bronze superstructure: a combined solution of the crystal structure of K6.4(Nb,Ta)(36.3)O94 with advanced transmission electron microscopy and neutron diffraction.
The crystal structure of the K6.4Nb28.2Ta8.1O94 pseudo-tetragonal tungsten bronze-type oxide was determined using a combination of X-ray powder diffraction, neutron diffraction and transmission electron microscopy techniques, including electron diffraction, high angle annular dark field scanning transmission electron microscopy (HAADF-STEM), annular bright field STEM (ABF-STEM) and energy-dispersive X-ray compositional mapping (STEM-EDX). The compound crystallizes in the space group Pbam with unit cell parameters a = 37.468(9) Å, b = 12.493(3) Å, c = 3.95333(15) Å. The structure consists of corner sharing (Nb,Ta)O6 octahedra forming trigonal, tetragonal and pentagonal tunnels. All tetragonal tunnels are occupied by K(+) ions, while 1/3 of the pentagonal tunnels are preferentially occupied by Nb(5+)/Ta(5+) and 2/3 are occupied by K(+) in a regular pattern. A fractional substitution of K(+) in the pentagonal tunnels by Nb(5+)/Ta(5+) is suggested by the analysis of the HAADF-STEM images. In contrast to similar structures, such as K2Nb8O21, also parts of the trigonal tunnels are fractionally occupied by K(+) cations.


Individual and combined effects of postpartum depression in mothers and fathers on parenting behavior.
Pediatric anticipatory guidance has been associated with parenting behaviors that promote positive infant development. Maternal postpartum depression is known to negatively affect parenting and may prevent mothers from following anticipatory guidance. The effects of postpartum depression in fathers on parenting is understudied. Our purpose with this work was to examine the effects of maternal and paternal depression on parenting behaviors consistent with anticipatory guidance recommendations. The 9-month-old wave of data from a national study of children and their families, the Early Childhood Longitudinal Study, provided data on 5089 2-parent families. Depressive symptoms were measured with a short form of the Center for Epidemiologic Studies Depression Scale. Interviews with both parents provided data on parent health behaviors and parent-infant interactions. Logistic and linear regression models were used to estimate the association between depression in each parent and the parenting behaviors of interest. These models were adjusted for demographic and socioeconomic status indicators. In this national sample, 14% of mothers and 10% of fathers exhibited levels of depressive symptoms on the Center for Epidemiologic Studies Depression Scale that have been associated with clinical diagnoses, confirming other findings of a high prevalence of postpartum maternal depression but highlighting that postpartum depression is a significant issue for fathers as well. Mothers who were depressed were approximately 1.5 times more likely to engage in less healthy feeding and sleep practices with their infant. In both mothers and fathers, depressive symptoms were negatively associated with positive enrichment activity with the child (reading, singing songs, and telling stories). Postpartum depression is a significant problem in both mothers and fathers in the United States. It is associated with undesirable parent health behaviors and fewer positive parent-infant interactions.


Concentration of enteroviruses from estuarine water.
Pleated cartridge filters readily adsorb viruses in estuarine water at low pH containing aluminum chloride. Adsorbed viruses are efficiently recovered by treating filters with glycine buffer at high pH. By using these procedures, it was possible to recover approximately 70% of the poliovirus added to 400 liters of estuarine water in 3 liters of filter eluate. Reconcentration of virus in the filter eluate in small volumes that are convenient for viral assays was more difficult. Reconcentration methods described previously for eluates from filters that process tap water or treated wastewater were inadequate when applied to eluates from filters used to process estuarine water containing large amounts of organic compounds. Two methods were found to permit efficient concentration of virus in filter eluates in small volumes. In both methods, virus in 3 liters of filter eluate was adsorbed to aluminum hydroxide flocs and then recovered in approximately 150 ml of buffered fetal calf serum. Additional reductions in volume were achieved by ultrafiltration or hydroextraction. By using these procedures 60 to 80% of the virus in 3 liters of filter eluate could be recovered in a final volume of 10 to 40 ml.


Mosaic analysis of stem cell function and wound healing in the mouse corneal epithelium.
The mouse corneal epithelium is a continuously renewing 5-6 cell thick protective layer covering the corneal surface, which regenerates rapidly when injured. It is maintained by peripherally located limbal stem cells (LSCs) that produce transient amplifying cells (TACs) which proliferate, migrate centripetally, differentiate and are eventually shed from the epithelial surface. LSC activity is required both for normal tissue maintenance and wound healing. Mosaic analysis can provide insights into LSC function, cell movement and cell mixing during tissue maintenance and repair. The present study investigates cell streaming during corneal maintenance and repair and changes in LSC function with age. The initial pattern of corneal epithelial patches in XLacZ+/- X-inactivation mosaics was replaced after birth by radial stripes, indicating activation of LSCs. Stripe patterns (clockwise, anticlockwise or midline) were independent between paired eyes. Wound healing in organ culture was analysed by mosaic analysis of XLacZ+/- eyes or time-lapse imaging of GFP mosaics. Both central and peripheral wounds healed clonally, with cells moving in from all around the wound circumference without significant cell mixing, to reconstitute striping patterns. Mosaic analysis revealed that wounds can heal asymmetrically. Healing of peripheral wounds produced stripe patterns that mimicked some aberrant striping patterns observed in unwounded corneas. Quantitative analysis provided no evidence for an uneven distribution of LSC clones but showed that corrected corneal epithelial stripe numbers declined with age (implying declining LSC function) but stabilised after 39 weeks. Striping patterns, produced by centripetal movement, are defined independently and stochastically in individual eyes. Little cell mixing occurs during the initial phase of wound healing and the direction of cell movement is determined by the position of the wound and not by population pressure from the limbus. LSC function declines with age and this may reflect reduced LSCs numbers, more quiescent LSCs or a reduced ability of older stem cells to maintain tissue homeostasis. The later plateau of LSC function might indicate the minimum LSC function that is sufficient for corneal epithelial maintenance. Quantitative and temporal mosaic analyses provide new possibilities for studying stem cell function, tissue maintenance and repair.


Utilization of sepiolite materials as a bottom liner material in solid waste landfills.
Landfill bottom liners are generally constructed with natural clay soils due to their high strength and low hydraulic conductivity characteristics. However, in recent years it is increasingly difficult to find locally available clay soils that satisfy the required engineering properties. Fine grained soils such as sepiolite and zeolite may be used as alternative materials in the constructions of landfill bottom liners. A study was conducted to investigate the feasibility of using natural clay rich in kaolinite, sepiolite, zeolite, and their mixtures as a bottom liner material. Unconfined compression tests, swell tests, hydraulic conductivity tests, batch and column adsorption tests were performed on each type of soil and sepiolite-zeolite mixtures. The results of the current study indicate that sepiolite is the dominant material that affects both the geomechanical and geoenvironmental properties of these alternative liners. An increase in sepiolite content in the sepiolite-zeolite mixtures increased the strength, swelling potential and metal adsorption capacities of the soil mixtures. Moreover, hydraulic conductivity of the mixtures decreased significantly with the addition of sepiolite. The utilization of sepiolite-zeolite materials as a bottom liner material allowed for thinner liners with some reduction in construction costs compared to use of a kaolinite-rich clay.


Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons.
The mood-stabilizing drug valproic acid (VPA) exerts a neurotrophic effect on the human neuroblastoma cell line, SH-SY5Y. We aimed to establish whether other mood-stabilizing drugs have a similar action and which signalling pathways mediate this process. We analysed the effects of the mood stabilizers VPA, lithium, carbamazepine and lamotrigine on proliferation, survival, neurite outgrowth and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) activation using the SH-SY5Y cell line. We also compared their effects in primary neurons. We found that VPA promotes neurite outgrowth and prevents cell death in SH-SY5Y cells, but has no effect on cell proliferation. This neurotrophic effect does not involve inhibition of glycogen synthase kinase-3, histone deacetylase or prolyl oligopeptidase; the effect also does not seem to involve protein kinase C. In contrast, VPA activates ERK/MAPK and the survival effect of VPA is blocked by inhibition of the ERK/MAPK signalling pathway. Moreover, other activators of ERK/MAPK, such as epidermal growth factor and phorbol 12-myristate 13-acetate, mimic the neurotrophic effects of VPA. Other mood stabilizers do not activate ERK/MAPK and do not promote neurite outgrowth or survival of SH-SY5Y cells. In contrast, both lithium and VPA activate ERK/MAPK in rat primary cortical neurons. We investigated four mood stabilizers that are effective in the treatment of bipolar disorder. Our results suggest that, while some mood stabilizers may have additional neuroprotective effects, activation of ERK/MAPK does not appear to be a mechanism common to all mood-stabilizing drugs.


Planarity and multiple components promote organic photovoltaic efficiency by improving electronic transport.
Establishing how the conformation of organic photovoltaic (OPV) polymers affects their electronic and transport properties is critical in order to determine design rules for new OPV materials and in particular to understand the performance enhancements recently reported for ternary blends. We report coupled classical and ab initio molecular dynamics simulations showing that polymer linkage twisting significantly reduces optical absorption efficiency, as well as hole transport rates in donor polymers. We predict that blends with components favoring planar geometries contribute to the enhancement of the overall efficiency of ternary OPVs. Furthermore, our electronic structure calculations for the PTB7-PID2-PC71BM system show that hole transfer rates are enhanced in ternary blends with respect to their binary counterpart. Finally, our results point at thermal disorder in the blend as a key reason responsible for device voltage losses and at the need to carry out electronic structure calculations at finite temperature to reliably compare with experiments.


The single Andigenum origin of Neo-Tuberosum potato materials is not supported by microsatellite and plastid marker analyses.
Neo-Tuberosum refers to cultivated potato adapted to long-day tuberization and a syndrome of related morphological and physiological traits, developed by intercrossing and selection of short-day adapted potatoes of the Solanum tuberosum Andigenum Group, native from the Andes of western Venezuela to northern Argentina. This re-creation of the modern potato helped support the theory of an Andigenum Group origin of potato in temperate regions and the possibility to access the largely untapped diversity of the Andigenum Group germplasm by base broadening breeding. This Neo-Tuberosum derived theory, the re-creation of the modern potato from Andigenum germplasm, has been universally accepted for almost 40 years, and has had tremendous impact in planning some breeding programs and supporting phylogenetic conclusions in cultivated potato. We show, with microsatellite (simple sequence repeat, SSR) and plastid DNA marker data, that Neo-Tuberosum germplasm is closely related to Chilotanum Group landraces from lowland south-central Chile rather than to Andigenum Group germplasm. We interpret this quite unexpected result to be caused by strong rapid selection against the original Andigenum clones after unintended hybridization with Chilotanum Group germplasm. In addition, we show that Neo-Tuberosum and Andigenum Group germplasm did not serve to broaden the overall genetic diversity of advanced potato varieties, but rather that Neo-Tuberosum lines and lines not using this germplasm are statistically identical with regard to genetic diversity as assessed by SSRs. These results question the long-standing Neo-Tuberosum derived theory and have implications in breeding programs and phylogenetic reconstructions of potato.


The training for health equity network evaluation framework: a pilot study at five health professional schools.
The Training for Health Equity Network (THEnet), a group of diverse health professional schools aspiring toward social accountability, developed and pilot tested a comprehensive evaluation framework to assess progress toward socially accountable health professions education. The evaluation framework provides criteria for schools to assess their level of social accountability within their organization and planning; education, research and service delivery; and the direct and indirect impacts of the school and its graduates, on the community and health system. This paper describes the pilot implementation of testing the evaluation framework across five THEnet schools, and examines whether the evaluation framework was practical and feasible across contexts for the purposes of critical reflection and continuous improvement in terms of progress towards social accountability. In this pilot study, schools utilized the evaluation framework using a mixed method approach of data collection comprising of workshops, qualitative interviews and focus group discussions, document review and collation and analysis of existing quantitative data. The evaluation framework allowed each school to contextually gather evidence on how it was meeting the aspirational goals of social accountability across a range of school activities, and to identify strengths and areas for improvement and development. The evaluation framework pilot study demonstrated how social accountability can be assessed through a critically reflective and comprehensive process. As social accountability focuses on the relationship between health professions schools and health system and health population outcomes, each school was able to demonstrate to students, health professionals, governments, accrediting bodies, communities and other stakeholders how current and future health care needs of populations are addressed in terms of education, research, and service learning.


Brain injury in sports.
Helmets are used for sports, military, and transportation to protect against impact forces and associated injuries. The common belief among end users is that the helmet protects the whole head, including the brain. However, current consensus among biomechanists and sports neurologists indicates that helmets do not provide significant protection against concussion and brain injuries. In this paper the authors present existing scientific evidence on the mechanisms underlying traumatic head and brain injuries, along with a biomechanical evaluation of 21 current and retired football helmets. The National Operating Committee on Standards for Athletic Equipment (NOCSAE) standard test apparatus was modified and validated for impact testing of protective headwear to include the measurement of both linear and angular kinematics. From a drop height of 2.0 m onto a flat steel anvil, each football helmet was impacted 5 times in the occipital area. Skull fracture risk was determined for each of the current varsity football helmets by calculating the percentage reduction in linear acceleration relative to a 140-g skull fracture threshold. Risk of subdural hematoma was determined by calculating the percentage reduction in angular acceleration relative to the bridging vein failure threshold, computed as a function of impact duration. Ranking the helmets according to their performance under these criteria, the authors determined that the Schutt Vengeance performed the best overall. The study findings demonstrated that not all football helmets provide equal or adequate protection against either focal head injuries or traumatic brain injuries. In fact, some of the most popular helmets on the field ranked among the worst. While protection is improving, none of the current or retired varsity football helmets can provide absolute protection against brain injuries, including concussions and subdural hematomas. To maximize protection against head and brain injuries for football players of all ages, the authors propose thresholds for all sports helmets based on a peak linear acceleration no greater than 90 g and a peak angular acceleration not exceeding 1700 rad/sec(2).


Addressing and proposing solutions for unmet clinical needs in the management of myeloproliferative neoplasm-associated thrombosis: A consensus-based position paper.
This article presents the results of a group discussion among an ad hoc constituted Panel of experts aimed at highlighting unmet clinical needs (UCNs) in the management of thrombotic risk and thrombotic events associated with Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs). With the Delphi technique, the challenges in Ph-neg MPN-associated thrombosis were selected. The most clinically relevant UCNs resulted in: (1) providing evidence of the benefits and risks of direct oral anticoagulants, (2) providing evidence of the benefits and risks of cytoreduction in patients with splanchnic vein thrombosis without hypercythemia, (3) improving knowledge of the role of the mutated endothelium in the pathogenesis of thrombosis, (4) improving aspirin dosing regimens in essential thrombocythemia, (5) improving antithrombotic management of Ph-neg MPN-associated pregnancy, (6) providing evidence for the optimal duration of anticoagulation for prophylaxis of recurrent VTE, (7) improving knowledge of the association between somatic gene mutations and risk factors for thrombosis, and (8) improving the grading system of thrombosis risk in polycythemia vera. For each of these issues, proposals for advancement in research and clinical practice were addressed. Hopefully, this comprehensive overview will serve to inform the design and implementation of new studies in the field.


Resolution of diminished olfactory sensation after treatment of bilateral ophthalmic segment aneurysms with flow diversion: case report.
Olfactory tract dysfunction due to an unruptured intracranial aneurysm is rare. We present a case in which a patient with impaired olfaction related to bilateral internal carotid artery aneurysms experienced subjective and quantitative objective improvement of olfactory sensation after treatment of ophthalmic segment aneurysms with flow diversion. A 44-year-old woman presented with hyposmia and bilateral ophthalmic segment internal carotid artery aneurysms. The symptom of hyposmia, worsening over a period of several months, was suspected to be due to mass effect from bilateral unruptured ophthalmic segment aneurysms pressing on the olfactory tracts. Each aneurysm was treated with a Pipeline embolization device (PED). Follow-up angiography at 5 months showed occlusion of both aneurysms. The patient experienced subjective improvement in olfaction and complete objective resolution of her hyposmia as measured by the validated University of Pennsylvania Smell Identification Test (UPSIT). Intracranial aneurysms causing dysfunction of olfactory sensation due to mass effect upon the olfactory tract can be successfully treated with flow diversion. Flow diversion should be considered as one of the treatment options for patients with cranial nerve dysfunction due to unruptured intracranial aneurysms.


Hidden diversity of the most basal tapeworms (Cestoda, Gyrocotylidea), the enigmatic parasites of holocephalans (Chimaeriformes).
Gyrocotylideans are evolutionary ancient parasitic flatworms, and like their hosts-a relict group of holocephalan fishes (Chimaeriformes)-they are considered to be "living fossils" of a vanished past. However, the species diversity, host associations and biogeography of these most basal tapeworms are poorly known. Herein, we provide evidence of a conspicuous contrast between the genetic and morphological data based on an examination of newly collected and properly processed Gyrocotyle specimens (hologenophores) isolated from holocephalans off Taiwan and Argentina. Our molecular data, inferred from three genes (COI, 28S rRNA, 18S rRNA), showed unexpected genetic interrelationships among isolates of the genus Gyrocotyle, because each of the four genotypes from Taiwan clustered with isolates of distinct gyrocotylideans from the North Atlantic. Three genotypes of Gyrocotyle from Taiwan were morphologically almost indistinguishable from each other but represented distinct genetic lineages; a single specimen of Gyrocotyle sp. genotype 4 exhibited a clear genetic and morphological distinctness, though its formal description as a new species would be premature. Additionally, specimens of Gyrocotyle rugosa Diesing, 1850, from the type host Callorhinchus callorynchus from Argentina, provided the first genetic data on the type species of the genus and enabled us to characterise it, which is necessary for future taxonomic studies. The finding of some specimens of Gyrocotyle sp. genotype 3 in Chimaera phantasma, and another one in C. cf. argiloba, together with the putative conspecificity of an unidentified gyrocotylidean from Callorhinchus milii off Australia and G. rugosa from C. callorynchus off Argentina, represent evidence that one gyrocotylidean species may parasitise more than one holocephalan host species. Existing taxonomic problems and conflicts between morphological and molecular data on species of Gyrocotyle can only be resolved if hologenophores from type hosts and localities of nominal taxa are properly characterised genetically and morphologically.


HIV-1 subtypes and drug resistance mutations among female sex workers varied in different cities and regions of the Democratic Republic of Congo.
Complex mosaic structures of HIV-1 were found in the Democratic Republic of Congo (DRC). Currently, there is limited information on the circulating HIV-1 strains, the distribution of these strains and antiretroviral (ART) resistant viruses in different regions of the country, and the HIV-1 strains harbored by the high-risk groups like female sex workers (FSW) reported to be the source of recombinant and ART resistant viruses. Dried Blood Spots (DBS), collected from 325 infected FSWs in ten cities from 2012 DRC HIV/STI Integrated Biological and Behavioral Surveillance Survey, were tested for HIV-1 genotypes and antiretroviral resistance mutations. Regional segregation of HIV-1 clades was detected using phylogenetics. The significance for differences in HIV-1 subtype and drug resistance mutations were evaluated using Chi-square tests. There were 145 (env) and 93 (pol) sequences analyzed. Based on env sequences, the predominant subtype was A1 (44%), and recombinants as defined pol sequences comprised 35% of the total sample. Paired sequences of pol and env from DRC FSW revealed mosaic recombinant in 54% of the sequences. Distinct geographic distributions of different HIV-1 subtypes and recombinants were observed. Subtype A1 was prevalent (40%) in Goma located in the East and significantly higher than in Mbuji-Mayi (p<0.05) in the South-central region, or in Lubumbashi in the South. Antiretroviral resistance was detected in 21.5% of 93 pol sequences analyzed, with the M184I/V and K103N mutations that confer high-level resistance to NRTI and NNRTI, respectively, being the most frequent mutations. However, the K103N mutant viruses were found only in the East. HIV-1 variants found in DRC FSW reflect those reported to circulate in the general population from the corresponding geographical locations. HIV-1 mosaic genetics were readily detected in FSW. Importantly, ART resistance mutations to NNRTI and NRTI were common in the DRC sex workers.


Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.
Recent advances in inflammatory bowel disease (IBD) therapeutics include novel medical, surgical, and endoscopic treatments. Among these, stem cell therapy is still in its infancy, although multiple studies suggest that the immunomodulatory effect of stem cell therapy may reduce inflammation and tissue injury in patients with IBD. This review discusses the novel avenue of stem cell therapy and its potential role in the management of ulcerative colitis and Crohn's disease. We conducted a comprehensive literature search to identify studies examining the role of stem cell therapy (without conditioning and immunomodulatory regimens) in IBD. Taken together, these studies suggest a promising role for stem cell therapy in IBD although the substantial challenges, such as cost and inadequate/incomplete characterization of effect, limit their current use in clinical practice.


Automated Respiratory Rate Counter to Assess Children for Symptoms of Pneumonia: Protocol for Cross-Sectional Usability and Acceptability Studies in Ethiopia and Nepal.
Manually counting a child's respiratory rate (RR) for 60 seconds using an acute respiratory infection timer is the World Health Organization (WHO) recommended method for detecting fast breathing as a sign of pneumonia. However, counting the RR is challenging and misclassification of an observed rate is common, often leading to inappropriate treatment. To address this gap, the acute respiratory infection diagnostic aid (ARIDA) project was initiated in response to a call for better pneumonia diagnostic aids and aimed to identify and assess automated RR counters for classifying fast breathing pneumonia when used by front-line health workers in resource-limited community settings and health facilities. The Children's Automated Respiration Monitor (ChARM), an automated RR diagnostic aid using accelerometer technology developed by Koninklijke Philips NV, and the Rad-G, a multimodal RR diagnostic and pulse oximeter developed by Masimo, were the two devices tested in these studies conducted in the Southern Nations, Nationalities, and Peoples' Region in Ethiopia and in the Karnali region in Nepal. In these studies, we aimed to understand the usability of two new automated RR diagnostic aids for community health workers (CHWs; health extension workers [Ethiopia] and female community health volunteers [Nepal]) and their acceptability to CHWs in Ethiopia and Nepal, first-level health facility workers (FLHFWs) in Ethiopia only, and caregivers in both Ethiopia and Nepal. This was a prospective, cross-sectional study with a mixed methods design. CHWs and FLHFWs were trained to use both devices and provided with refresher training on all WHO requirements to assess fast breathing. Immediately after training, CHWs were observed using ARIDA on two children. Routine pneumonia case management consultations for children aged 5 years and younger and the device used for these consultations between the first and second consultations were recorded by CHWs in their patient log books. CHWs were observed a second time after 2 months. Semistructured interviews were also conducted with CHWs, FLHFWs, and caregivers. The proportion of consultations with children aged 5 years and younger where CHWs using an ARIDA and adhered to all WHO requirements to assess fast breathing and device manufacturer instructions for use after 2 months will be calculated. Qualitative data from semistructured interviews will be analyzed using a thematic framework approach. The ARIDA project was funded in November 2015, and data collection was conducted between April and December 2018. Data analysis is currently under way and the first results are expected to be submitted for publication in 2020. This is the first time the usability and acceptability of automated RR counters in low-resource settings have been evaluated. Outcomes will be relevant for policy makers and are important for future research of this new class of diagnostic aids for the management of children with suspected pneumonia. DERR1-10.2196/14405.


Development of primary and secondary immune responses to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms.
Human anti-mouse immunoglobulin immune responses were studied in ten patients, eight with ovarian cancer and two with grade IV gliomas, diagnosed and treated with radiolabeled (123I, 131I) murine monoclonal antibodies. It was found that serum from these patients before treatment and from 18 control healthy individuals contained detectable antibodies to antigenic determinants on the Fc but not the F(ab')2 portion of mouse immunoglobulin. No change in this reactivity occurred after the initial (imaging) dose of monoclonal antibodies. However, repeated administration of mouse immunoglobulins for therapy resulted in an elevated immune response directed against determinants on both Fc and F(ab')2 regions of mouse immunoglobulin. This response contained increased levels of immunoglobulin M as well as immunoglobulin G and showed a marked prozone effect in our enzyme linked immunosorbent assay system. None of the immunized patients developed a detectable antiidiotypic response.


A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency.
Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Mutations in the gene encoding Pit-1 have been found in two dwarf mouse strains displaying hypoplasia of growth hormone, prolactin, and thyroid-stimulating, hormone-secreting cell types in the anterior pituitary. A point mutation in this gene was identified on one allele in a patient with combined pituitary hormone deficiency. Mutant Pit-1 binds DNA normally but acts as a dominant inhibitor of Pit-1 action in the pituitary.


Efficacy of pancreatoscopy for pancreatic duct stones: A systematic review and meta-analysis.
Pancreatic duct stones can lead to significant abdominal pain for patients. Per oral pancreatoscopy (POP)-guided intracorporal lithotripsy is being increasingly used for the management of main pancreatic duct calculi (PDC) in chronic pancreatitis. POP uses two techniques: Electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL). Data on the safety and efficacy are limited for this procedure. We performed a systematic review and meta-analysis with a primary aim to calculate the pooled technical and clinical success rates of POP. The secondary aim was to assess pooled rates of technical success, clinical success for the two individual techniques, and adverse event rates. To perform a systematic review and meta-analysis of POP, EHL and LL for management of PDC in chronic pancreatitis. We conducted a comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Cochrane, Google Scholar and Web of Science databases (from 1999 to October 2019) to identify studies with patient age greater than 17 and any gender that reported on outcomes of POP, EHL and LL. The primary outcome assessed involved the pooled technical success and clinical success rate of POP. The secondary outcome included the pooled technical success and clinical success rate for EHL and LL. We also assessed the pooled rate of adverse events for POP, EHL and LL including a subgroup analysis for the rate of adverse event subtypes for POP: Hemorrhage, post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), perforation, abdominal pain, fever and infections. Technical success was defined as the rate of clearing pancreatic duct stones and clinical success as the improvement in pain. Random-effects model was used for analysis. Heterogeneity between study-specific estimates was calculated using the Cochran Q statistical test and I 2 statistics. Publication bias was ascertained, qualitatively by visual inspection of funnel plot and quantitatively by the Egger test. A total of 16 studies including 383 patients met the inclusion criteria. The technical success rate of POP was 76.4% (95%CI: 65.9-84.5; I 2 = 64%) and clinical success rate was 76.8% (95%CI: 65.2-85.4; I 2 = 66%). The technical success rate of EHL was 70.3% (95%CI: 57.8-80.3; I 2 = 36%) and clinical success rate of EHL was 66.5% (95%CI: 55.2-76.2; I 2 = 19%). The technical success rate of LL was 89.3% (95%CI: 70.5-96.7; I 2 = 70%) and clinical success rate of LL was 88.2% (95%CI: 66.4-96.6; I 2 = 77%). The incidence of pooled adverse events for POP was 14.9% (95%CI: 9.2-23.2; I 2 = 49%), for EHL was 11.2% (95%CI: 5.9-20.3; I 2 = 15%) and for LL was 13.1% (95%CI: 6.3-25.4; I 2 = 31%). Subgroup analysis of adverse events showed rates of PEP at 7% (95%CI: 3.5-13.6; I 2 = 38%), fever at 3.7% (95%CI: 2-6.9; I 2 = 0), abdominal pain at 4.7% (95%CI: 2.7-7.8; I 2 = 0), perforation at 4.3% (95%CI: 2.1-8.4; I 2 = 0), hemorrhage at 3.4% (95%CI: 1.7-6.6; I 2 = 0) and no mortality. There was evidence of publication bias based on funnel plot analysis and Egger's test. Our study highlights the high technical and clinical success rates for POP, EHL and LL. POP-guided lithotripsy could be a viable option for management of chronic pancreatitis with PDC.


Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya.
An epidemiologic study of hyperendemic malaria in Arso PIR, a village in northeastern Irian Jaya (Indonesian New Guinea), revealed evidence suggesting suppression of gametocytemia independent of immune control of the asexual parasitemia. A total of 240 people, representing ages between 2 and 60 years, were followed by biweekly blood film examination for 16 weeks beginning in November 1987. Two distinct subpopulations were represented--1) life-long residents of Irian Jaya, and 2) transmigrants from Java who arrived in Irian Jaya 20 months before the surveillance effort began. Twenty-five percent of blood films from natives and 31% from Javanese were positive for falciparum malaria; of these, the rate of gametocytemia was 21% for natives, and 42% for the Javanese transmigrants (P less than 0.001). This difference could not be explained by differences in the frequency or grade of parasitemia, illness, or by known patterns of antimalarial consumption. Similarly, in Wor, a village near Arso PIR, the gametocyte rate for P. falciparum diminished from 83% to 25% in transmigrants from Java between their eleventh and twenty-fifth month of residence in Irian Jaya, a period during which the falciparum malaria rate remained stable between 30% and 50%. An immunofluorescent antibody test using whole, acetone-fixed gametocytes as substrate revealed correlation between antibody titer and protection from gametocytemia among the semi-immune natives of Arso PIR, but not among the Javanese. Specific immune suppression of gametocytes, independent of immune control of asexual parasites, can explain all of these observations.


Testing the role of phenotypic plasticity for local adaptation: growth and development in time-constrained Rana temporaria populations.
Phenotypic plasticity can be important for local adaptation, because it enables individuals to survive in a novel environment until genetic changes have been accumulated by genetic accommodation. By analysing the relationship between development rate and growth rate, it can be determined whether plasticity in life-history traits is caused by changed physiology or behaviour. We extended this to examine whether plasticity had been aiding local adaptation, by investigating whether the plastic response had been fixed in locally adapted populations. Tadpoles from island populations of Rana temporaria, locally adapted to different pool-drying regimes, were monitored in a common garden. Individual differences in development rate were caused by different foraging efficiency. However, developmental plasticity was physiologically mediated by trading off growth against development rate. Surprisingly, plasticity has not aided local adaptation to time-stressed environments, because local adaptation was not caused by genetic assimilation but on selection on the standing genetic variation in development time.


Occupational therapists' perceptions of occupation in practice: An exploratory study.
The World Federation of Occupational Therapists' minimum standards state occupation and its relationship with health must be concepts covered in occupational therapy education. Therefore, it is assumed that Australian graduates have sound knowledge of the principles of occupation-based practice. In some practice settings, the link to occupation may not be explicit and graduates could face challenges to being occupation-based. The aims of this pilot study were to explore graduates' perceptions of occupation in their practice and to investigate whether graduates felt sufficiently prepared for occupation-based practice. Two focus groups with eight therapists in total were employed to uncover experiences and perceptions of occupation. Themes were synthesised using Braun and Clarke's method of thematic analysis, where line by line coding was employed to inductively build themes. Participants believed that occupation-based practice was important but did not necessarily need to be implemented as a means of intervention. From the participants' perspective, simply striving for occupation as the end goal of therapy was acceptable. A strong focus on impairment-based practice hindered some therapists from exploring the use of occupation-based practice. For recent graduates, workplace culture was pervasive and inhibited the use of occupation. In addition, participants felt university educators did not provide an integrated or consistent approach when teaching how to apply occupation in practice. Workplace expectations and limited power to influence practice are impeding graduates from authentically applying occupation in practice. Insights from recently graduated therapists about occupation have the potential to inform future directions of occupation-based practice.


Intention-to-Treat Analysis of Radical Trachelectomy for Early-Stage Cervical Cancer With Special Reference to Oncologic Failures: Single-Institutional Experience in Hungary.
The aim of our study was to evaluate clinical and pathological data in order to draw eligibility criteria for oncologically sufficient radical trachelectomy (RT) in early-stage cervical cancer. Reviewing all cases of attempted RT performed at our unit, we focused attention on prognostic indicators of the need for additional oncologic treatment following RT. The analysis was extended by extensive literature review to include previously published cases of oncologic failures. The authors retrospectively analyzed data of patients who underwent RT at the Department of Obstetrics and Gynecology, University of Debrecen. Electronic records and case notes of RT cases were reviewed to determine the incidence of abdominal and vaginal route, distribution of clinicopathologic data, and follow-up results of individual cases. Individual procedures were categorized as oncologically insufficient if additional oncologic treatment was necessary following RT. Theoretical eligibility criteria for RT in early-stage cervical cancer were determined retrospectively by selecting prognostic features that were associated with oncologic insufficiency from clinicopathologic indicators of the complete series. Twenty-four cases of RT were performed by the authors, 15 vaginal RTs with laparoscopic pelvic lymphadenectomy and 9 abdominal RTs with open pelvic lymphadenectomy. Fifteen of 24 cases proved oncologically sufficient. Three cases required immediate conversion to radical hysterectomy because of positive sentinel nodes and/or positive isthmic disc on frozen section. In further 5 cases, final pathology results indicated additional oncologic treatment, that is, radical hysterectomy (n = 2), chemoradiotherapy (n = 2), or chemotherapy (n = 1). One patient among immediately converted cases and another 3 among those who required additional oncologic treatment died of their disease later. There were no other cases of recurrences over a median follow-up of 34 months (range, 12-188 months). Factors that may predict oncologic insufficiency of RT were stage IB1 or greater, tumor size of greater than 2 cm in 1 dimension or greater than 15 mm in 3 dimensions, G3, nonsquamous/adeno histological type, stromal invasion of greater than 9 mm, and lymphovascular space involvement in the primary tumor. Most cases of oncologically insufficient RTs have significant risk features that can be identified preoperatively. There is a need for more clinicopathologic data on oncologic failure of RT cases in order to improve patient selection.


Magnetic compression anastomosis for the stricture of the choledochocholedochostomy after ABO-incompatible living donor liver transplantation.
Biliary complications, such as stricture or obstruction after living donor liver transplantation (LDLT), are still major problems. Magnetic compression anastomosis (MCA) is a minimally invasive and nonsurgical procedure in patients with biliary structure or obstruction. A 49-year-old woman who had had ABO-incompatible LDLT 16 months previously presented with obstructive jaundice. After sufficient improvement of obstructive jaundice by percutaneous transhepatic cholangiodrainage (PTCD), the rendezvous technique between PTCD and endoscopic retrograde cholangiopancreatography was attempted in order to break through the stricture, but this was not successful. Therefore, MCA was performed. A parent magnet was endoscopically placed at the common bile duct side of the stricture, and the daughter magnet, attached to a guidewire, was also inserted to the intrahepatic bile duct. Both magnets were advanced to positions immediately prior to the biliary obstruction, and it was confirmed that the two magnets attracted each other magnetically, sandwiching the stricture. Twenty-four days after MCA, as recanalization could be achieved without any adverse events, the magnets were removed via the PTCD fistula. MCA enabled us to create a fistula without complications. In conclusion, when a conventional endoscopic or percutaneous approach, including the rendezvous technique, has failed, MCA is a novel method for patients with the stricture of the choledochocholedochostomy after LDLT.


Accuracy of frozen section diagnosis in ovarian tumors: Is there a change in the course of time?
A retrospective study of 222 ovarian biopsy results between January 1, 2000 and August 31, 2002 was examined to determine the accuracy of frozen section diagnosis. In addition we reviewed all previous studies that examined the accuracy rates of frozen section diagnosis in ovarian tumors. Histopathologic examination results of frozen section biopsies were concordant with paraffin diagnosis in 92% of all cases. The sensitivity rates for benign, malignant, and borderline ovarian tumors were 98%, 88.7%, and 61%, respectively. There were five (2.2%) false-positive (overdiagnosed), and 13 (5.4%) false-negative (underdiagnosed) patients in frozen section examination. Frozen section examination of mucinous tumors showed higher underdiagnosis rates (20%). Review of previous studies showed no significant variation in accuracy rates of frozen section diagnosis for benign and malignant ovarian tumors, in relation with time. We found low accuracy rates for borderline ovarian tumors which was similar with the previous studies. However, there were consistent and relatively higher sensitivity rates for borderline ovarian tumors in the recent studies. As a result, we conclude that frozen section evaluation in identifying a malignant or benign ovarian tumor is accurate enough for the correct diagnosis. Since accuracy rates for borderline ovarian tumors are low, we should have more improvement in the correct diagnosis.


[Osteogenesis imperfecta: Treatment and results of a case series].
To describe our experience in the management of patients with osteogenesis imperfect (OI). We conducted a retrospective study of a series of cases affected with OI treated in the Clínica Univesidad de Navarra from 1980 to 2007, with a mean follow up of 17.3 years (7-27 years). We collected descriptive data of the sample, the fractures and the deformities, and the treatments given. The complications presented and the functional outcomes at the end of follow-up were also reviewed. The sample included ten patients. Approximately two-thirds (65%) of fractures were sustained in the lower limbs. One patient received medical treatment only. Three patients had combined medical and surgical treatment. Some type of surgical treatment was performed on 6 patients. The most common surgery was the Sofield-Millar performed on 37 occasions, with a third of them requiring revision surgery due to migration of the nails. There were 17 episodes of re-fracture. Complications such as non-union, iatrogenic fractures, and infections, were also observed. The functional outcome, according to the Hoffer-Bullock scale, at the end of follow-up was grade I/II in 7 patients. Despite the need for multiple interventions and complications presented during follow up, the appropriate treatment of patients with OI can provide acceptable functional outcomes.


Evaluation of a new Transmural Trauma Care Model (TTCM) for the rehabilitation of trauma patients: a study protocol.
Improved organization of trauma care in the acute phase has reduced mortality of trauma patients. However, there has been limited attention for the optimal organization of post-clinical rehabilitation of trauma patients. Therefore we developed a Transmural Trauma Care Model (TTCM). This TTCM consists of four equally important components: 1) intake and follow up consultations by a multidisciplinary team consisting of trauma surgeon and hospital based trauma physical therapist, 2) coordination and individual goal setting for each patient by this team, 3) primary care physical therapy by specialized physical therapists organized in a network and 4) E-health support for transmural communication and treatment according to protocols. The aim of the current study is to assess the cost-effectiveness of the TTCM. Patients will be recruited from the outpatient clinic for trauma patients of the VU University Medical Center (VUmc) if they have at least one fracture and were discharged home. A controlled-before-and-after study design will be used to compare the TTCM with regular care. Measurements will take place after the first outpatient clinical visit and after 3, 6 and 9 months. Prior to the implementation of the TTCM, 200 patients (50 patients per time point) will be included in the control group. After implementation 100 patients will be included in the intervention group and prospectively followed. Between-group comparisons will be made separately for each time point. In addition, the recovery pattern of patients in the intervention group will be studied using longitudinal data analysis methods. Effectiveness will be evaluated in terms of health-related quality of life (HR-QOL), pain, functional status, patient satisfaction, and perceived recovery. Cost-effectiveness will be assessed from a societal perspective, meaning that all costs related to the TTCM will be taken into account including intervention, health care, absenteeism, presenteeism and unpaid productivity. Additionally, a process evaluation will be performed to explore the extent to which the TTCM was implemented as intended, and to identify possible facilitators and barriers associated with its implementation. This planned research will give insight into the feasibility of the TTCM model in clinical practice and will give a first indication of the cost-effectiveness of the TTCM and help us to further develop post-clinical trauma care. Trial registration number: NTR5474 . The Netherlands National Trial Register (NTR). Registered 12 October 2015.


Sparse PDF Volumes for Consistent Multi-Resolution Volume Rendering.
This paper presents a new multi-resolution volume representation called sparse pdf volumes, which enables consistent multi-resolution volume rendering based on probability density functions (pdfs) of voxel neighborhoods. These pdfs are defined in the 4D domain jointly comprising the 3D volume and its 1D intensity range. Crucially, the computation of sparse pdf volumes exploits data coherence in 4D, resulting in a sparse representation with surprisingly low storage requirements. At run time, we dynamically apply transfer functions to the pdfs using simple and fast convolutions. Whereas standard low-pass filtering and down-sampling incur visible differences between resolution levels, the use of pdfs facilitates consistent results independent of the resolution level used. We describe the efficient out-of-core computation of large-scale sparse pdf volumes, using a novel iterative simplification procedure of a mixture of 4D Gaussians. Finally, our data structure is optimized to facilitate interactive multi-resolution volume rendering on GPUs.


Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management.
About 30% of patients with cirrhosis have diabetes mellitus (DM). Nowadays, it is a matter for debate whether type 2 DM in the absence of obesity and hypertriglyceridemia may be a risk factor for chronic liver disease. DM, which develops as a complication of cirrhosis, is known as "hepatogenous diabetes". Insulin resistance in muscular and adipose tissues and hyperinsulinemia seem to be the pathophysiologic bases of diabetes in liver disease. An impaired response of the islet beta-cells of the pancreas and hepatic insulin resistance are also contributory factors. Non-alcoholic fatty liver disease, alcoholic cirrhosis, chronic hepatitis C (CHC) and hemochromatosis are more frequently associated with DM. Insulin resistance increases the failure of the response to treatment in patients with CHC and enhances progression of fibrosis. DM in cirrhotic patients may be subclinical. Hepatogenous diabetes is clinically different from that of type 2 DM, since it is less frequently associated with microangiopathy and patients more frequently suffer complications of cirrhosis. DM increases the mortality of cirrhotic patients. Treatment of the diabetes is complex due to liver damage and hepatotoxicity of oral hypoglycemic drugs. This manuscript will review evidence that exists in relation to: type 2 DM alone or as part of the metabolic syndrome in the development of liver disease; factors involved in the genesis of hepatogenous diabetes; the impact of DM on the clinical outcome of liver disease; the management of DM in cirrhotic patients and the role of DM as a risk factor for the occurrence and exacerbation of hepatocellular carcinoma.


Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease.
Incidental cardiac irradiation during treatment of thoracic neoplasms has increased risks for subsequent acute myocardial infarction or sudden cardiac death. Identifying patients who have a high risk for a coronary event may decrease morbidity and mortality. The objective of this study was to evaluate whether stress imaging can identify severe, unsuspected coronary stenoses in patients who had prior mediastinal irradiation for Hodgkin's disease. We enrolled 294 outpatients observed at a tertiary care cancer treatment center after mediastinal irradiation doses 35 Gy for Hodgkin's disease who had no known ischemic cardiac disease. Patients underwent stress echocardiography and radionuclide perfusion imaging at one stress session. Coronary angiography was performed at the discretion of the physician. Among the 294 participants, 63 (21.4%) had abnormal ventricular images at rest, suggesting prior myocardial injury. During stress testing, 42 patients (14%) developed perfusion defects (n = 26), impaired wall motion (n = 8), or both abnormalities (n = 8). Coronary angiography showed stenosis 50% in 22 patients (55%), less than 50% in nine patients (22.5%), and no stenosis in nine patients (22.5%). Screening led to bypass graft surgery in seven patients. Twenty-three patients developed coronary events during a median of 6.5 years of follow-up, with 10 acute myocardial infarctions (two fatal). Stress-induced signs of ischemia and significant coronary artery disease are highly prevalent after mediastinal irradiation in young patients. Stress testing identifies asymptomatic individuals at high risk for acute myocardial infarction or sudden cardiac death.


Skein-like inclusions in the anterior horn cells in motor neuron disease.
Skein-like inclusions (SLIs) in the anterior horn cells of patients with motor neuron diseases, including familial amyotrophic lateral sclerosis with posterior column degeneration, sporadic lower motor neuron disease and classical amyotrophic lateral sclerosis, were investigated morphologically with hematoxylin and eosin preparations, immunostaining for ubiquitin and immunoelectron microscopy. The SLIs were thready linear or tubular structures which immunostained with antiubiquitin antibodies. They were detected on hematoxylin and eosin preparations as eosinophilic thread-like structures often surrounded by pale areas. SLIs were occasionally present as networks of threads or tubules. Sometimes, they were aggregated and formed larger pale inclusions. Ultrastructurally, the SLIs were bundles of filaments which appeared thicker than neurofilaments. The SLIs tended to have central hollow spaces which were devoid of filaments. When the SLIs were clustered, fuzzy thick filaments were randomly and loosely arranged among the individual SLIs. The SLIs were histologically and ultrastructurally distinct from other inclusions such as Bunina bodies and hyaline inclusions. This unique morphology of SLIs may provide a novel perspective on the degenerative processes of the anterior horn cells in MND.


Open versus laparoscopic (assisted) ileo pouch anal anastomosis for ulcerative colitis and familial adenomatous polyposis.
Restorative proctocolectomy with ileo pouch anal anastomosis (IPAA) is the main surgical treatment for patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). With the advancements of minimal-invasive surgery this demanding operation is increasingly being performed laparoscopically. Therefore, the presumed benefits of the laparoscopic approach need to be systematically evaluated. To compare the beneficial and harmful effects of laparoscopic versus open IPAA for patients with UC and FAP. We searched The Cochrane IBD/FBD Group Specialized Trial Register (April 2007), The Cochrane Library (Issue 1, 2007), MEDLINE (1990 to April 2007), EMBASE (1990 to April 2007), ISI Web of Knowledge (1990 to April 2007) and the web casts of the American Society of Colon and Rectal Surgeons (ASCRS) (up to 2006) for all trials comparing open versus laparoscopic IPAA. All trials in patients with UC or FAP comparing any kind of laparoscopic IPAA versus open IPAA. No language limitations were applied. Two authors independently performed selection of trials and data extraction. The methodological quality of all included trials was evaluated to assess bias risk. Analysis of RCTs and non-RCTs was performed separately. Analyses were based on the intention-to-treat principle. Authors were requested additional information in case of missing data. Sensitivity and subgroup analyses were performed if appropriate. Eleven trials included 607 patients of whom 253 (41%) in the laparoscopic IPAA group. Only one of the included trials was a randomised controlled trial. There were no significant differences in mortality or complications between the two groups. Reoperation and readmission rates were not significantly different. Operative time was significantly longer in the laparoscopic group both in the RCT and meta-analysis of non-RCTs (weighted mean difference (WMD) 91 minutes; 95% Confidence Interval (CI) 53 to 130). There were no significant differences between the two groups regarding postoperative recovery parameters. Total incision length was significantly shorter in the laparoscopic group, while two trials evaluating cosmesis found significantly higher cosmesis scores in the laparoscopic group. Other long-term outcomes were poorly reported. The laparoscopic IPAA is a feasible and safe procedure. Short-term advantages of the laparoscopic approach seem to be limited and their clinical significance is arguable. Large high-quality trials focusing on differences regarding specific postoperative complications, cosmesis, quality of life and costs are needed.


Towards the next frontier for simulation-based training: full-hospital simulation across the entire patient pathway.
To evaluate the efficacy of an entire hospital simulation in imparting skills to expert healthcare providers, encompassing both retention and transfer to clinical practice. Studies demonstrating the effectiveness of simulation do not concentrate upon expert multidisciplinary teams. Moreover, their focus is confined to a single clinical setting, thereby not considering the complex interactions across multiple hospital departments. A total of 288 participants (Attending surgeons, anesthesiologists, physicians, and nurses) completed this largest simulation study to date, set in the UK Defence Medical Services' Hospital Simulator and the conflict zone in Afghanistan. The simulator termed "Hospital Exercise" (HOSPEX) is a fully immersive live-in simulation experience that covers the entire environment of a military hospital with all departments. Participants undertook a 3-day training program within HOSPEX before deployment to war zones. Primary outcome measures were assessed with IMPAcT (the Imperial Military Personnel Assessment Tool). IMPAcT measures crisis management, trauma care, hospital environment, operational readiness, and transfer of skills to civilian practice. Reliability, skills learning, and retention in the conflict zone were assessed statistically. Reliability in skills assessment was excellent (Cronbach α: nontechnical skills = 0.87-0.94; environment/patient skills = 0.83-0.95). Pre/post-HOSPEX comparisons revealed significant improvements in decision making (M = 4.98, SD = 1.20 to M = 5.39, SD = 0.91; P = 0.03), situational awareness (M = 5.44, SD = 1.04 to M = 5.74, SD = 0.92; P = 0.01), trauma care (M = 5.53, SD = 1.23 to M = 5.85, SD = 1.09; P = 0.05), and knowledge of hospital environment (M = 5.19, SD = 1.17 to M = 5.42, SD = 0.97; P = 0.04). No skills decayed over time when assessed several months later in the real conflict zone. All skills transferred to civilian clinical practice. This is the first study to describe the value of a full-hospital simulation across the entire patient pathway. Such macrosimulations may be the way forward for integrating the complex training needs of expert clinicians and testing organizational "fitness for purpose" of entire hospitals.


Bayesian reassessment of the epigenetic architecture of complex traits.
Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% CI 71.70-79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3-51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed >1.5 times larger associations with >95% posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal.


Early allograft dysfunction after liver transplantation: an intermediate outcome measure for targeted improvements.
The term early allograft dysfunction (EAD) identifies liver transplant (LT) allografts with initial poor function and portends poor allograft and patient survival. Aims of this study are to use EAD as an intermediate outcome measure in a large single center cohort and identify donor, recipient and peri-operative risk factors. In 1950 consecutive primary LT, donor, recipient and peri-operative data were collected. EAD was defined by the presence of one or more of the following: total bilirubin ≥ 10 mg/dL (171 μmol/L) or, INR ≥ 1.6 on day 7, and ALT/AST > 2,000 IU/L within the first 7 days. The incidence of EAD was 26.5%. 1-, 3-, and 5-year allograft and patient survival for patients who developed EAD were significantly inferior to those who did not (P < 0.01 at all time points). Multivariate analysis demonstrated associations in the development of EAD with recipient pre-operative ventilator status, donation after cardiac death allografts, donor age, allograft size, degree of steatosis, operative time and intra-operative transfusion requirements (all P < 0.01). Patients with EAD had a significantly longer hospitalization at 20.9 ± 38.9 days (median: 9; range: 4-446) compared with 10.7 ± 13.5 days (median: 7; range: 3-231) in patients with no EAD (P < 0.01). This is the largest single center experience demonstrating incidence of EAD and identifying factors associated with development of EAD. EAD is a useful intermediate outcome measure for allograft and patient survival. Balancing recipient pretransplant conditions, donor risk factors and intra-operative conditions are necessary for avoiding EAD.


Bordetella parapertussis outbreak in Southeastern Minnesota and the United States, 2014.
Whooping cough is traditionally ascribed to Bordetella pertussis; however, Bordetella parapertussis can cause a similar clinical syndrome. This study describes an outbreak of B. parapertussis in Southeastern Minnesota and the United States (US) in 2014. This was a retrospective analysis of Mayo Clinic and Mayo Medical Laboratories patients who tested positive for B. parapertussis from 2012 to 2014. The medical records of Mayo Clinic patients who tested positive in 2014 were reviewed for demographic information, presenting symptoms, disease course, and vaccination history. In Southeast Minnesota, 81% of the 31 patients who tested positive for B. parapertussis in 2014 were found to be positive from October through December. Their mean age was 5.9 years. Five reported "exposure to pertussis." Two pairs of siblings were affected. Patients reported having had symptoms for an average of 2.6 weeks before nasopharyngeal specimen collection for B. parapertussis testing. Cough was the primary symptom reported. Forty percent reported posttussive vomiting, 40% coryza, 32% apnea/sleep disturbance, and 12% sore throat. All were current with pertussis vaccination. Based on the review of national data, an outbreak occurred nationally in the Northeast and Midwest US over the same time period. In 2014, there was an outbreak of B. parapertussis in Southeastern Minnesota and likely other parts of the US. The presenting illness was similar to that of B. pertussis. All patients were vaccinated against pertussis, suggesting that pertussis vaccination is ineffective against B. parapertussis.


Informing urban climate planning with high resolution data: the Hestia fossil fuel CO2 emissions for Baltimore, Maryland.
Cities contribute more than 70% of global anthropogenic carbon dioxide (CO2) emissions and are leading the effort to reduce greenhouse gas (GHG) emissions through sustainable planning and development. However, urban greenhouse gas mitigation often relies on self-reported emissions estimates that may be incomplete and unverifiable via atmospheric monitoring of GHGs. We present the Hestia Scope 1 fossil fuel CO2 (FFCO2) emissions for the city of Baltimore, Maryland-a gridded annual and hourly emissions data product for 2010 through 2015 (Hestia-Baltimore v1.6). We also compare the Hestia-Baltimore emissions to overlapping Scope 1 FFCO2 emissions in Baltimore's self-reported inventory for 2014. The Hestia-Baltimore emissions in 2014 totaled 1487.3 kt C (95% confidence interval of 1158.9-1944.9 kt C), with the largest emissions coming from onroad (34.2% of total city emissions), commercial (19.9%), residential (19.0%), and industrial (11.8%) sectors. Scope 1 electricity production and marine shipping were each generally less than 10% of the city's total emissions. Baltimore's self-reported Scope 1 FFCO2 emissions included onroad, natural gas consumption in buildings, and some electricity generating facilities within city limits. The self-reported Scope 1 FFCO2 total of 1182.6 kt C was similar to the sum of matching emission sectors and fuels in Hestia-Baltimore v1.6. However, 20.5% of Hestia-Baltimore's emissions were in sectors and fuels that were not included in the self-reported inventory. Petroleum use in buildings were omitted and all Scope 1 emissions from industrial point sources, marine shipping, nonroad vehicles, rail, and aircraft were categorically excluded. The omission of petroleum combustion in buildings and categorical exclusions of several sectors resulted in an underestimate of total Scope 1 FFCO2 emissions in Baltimore's self-reported inventory. Accurate Scope 1 FFCO2 emissions, along with Scope 2 and 3 emissions, are needed to inform effective urban policymaking for system-wide GHG mitigation. We emphasize the need for comprehensive Scope 1 emissions estimates for emissions verification and measuring progress towards Scope 1 GHG mitigation goals using atmospheric monitoring.


Comprehensive review and compilation of pretreatments for mesophilic and thermophilic anaerobic digestion.
Organic matter hydrolysis prior to anaerobic digestion has been shown to improve biogas production (30-50%) and reduce solids (20-60%) by ultrasound, chemical, conventional heating, and microwave pretreatments. Numerous studies have been performed to determine the extent of digestion improvement but few focus on financial feasibility of these processes. A comprehensive model was created using Microsoft Excel and its Visual Basic Assistant to evaluate pretreatment permutations for conventional wastewater treatment plants. The four above-mentioned processes were evaluated for energetic and financial demands. Well-established energy equations and wastewater characteristics, both average and high, were used. Average and high flows were 460 and 750×10(3) m3/d, respectively. Net costs per influent flow for ultrasound, chemical, conventional heating, and microwave were 0.0166, 0.0217, 0.0124, 0.0119 $/m3 and 0.0264, 0.0357, 0.0187, and 0.0162 $/m3 for average and high conditions, respectively. The average cost increase from results excluding pretreatment use for all processes was 0.003 and 0.0055 $/m3 for average and high conditions, respectively. No matter the permutation, pretreatments requiring more energy to achieve required hydrolysis levels were costlier. If energetic recoveries are substantial, dewaterability is positively affected, and solids meet environmental constraints to be handled and disposed at lower costs, pretreatments can be viable.


On the moving-obstacle path-planning algorithm of Shih, Lee, and Gruver.
We analyze a motion planning algorithm proposed by Shih, Lee, and Gruver (1990). In particular, we discuss the case of motion planning among moving obstacles, for which an algorithm is presented by Shih, Lee, and Gruver (1990). The algorithm is claimed to always yield a collision-free path when one exists. We provide a specific counter-example to this claim, examine the possibility of repairing the algorithm, and discuss the computational complexity of a corrected algorithm.


Randomized controlled trial demonstrates nutritional management is superior to metronidazole for treatment of acute colitis in dogs.
To describe the outcome of dietary management of canine noninfectious acute colitis with or without concurrent oral administration of metronidazole using a randomized controlled clinical trial. 59 client-owned dogs with noninfectious acute colitis. Dogs with acute noninfectious colitis were enrolled in a 30-day diet trial after exclusion of parasitic infectious etiologies (fecal centrifugation floatation, Giardia/Cryptosporidium antigen testing) and systemic disease (CBC, biochemistry, urinalysis). Dogs were randomized into 3 placebo-controlled groups: group 1, easily digestible diet + placebo tablet; group 2, easily digestible diet + metronidazole tablet; and group 3, psyllium-enhanced easily digestible diet + placebo tablet. Dogs were evaluated serially using fecal scoring for time to remission, average fecal score, relapse after remission, and dysbiosis index. Median remission time was significantly different among the 3 groups (P < .01) with median times of 5 days (range, 4 to 10) for group 1, 8.5 days (range, 7 to 12) for group 2, and 5 days (range, 3 to 6) for group 3. Metronidazole addition affected the fecal dysbiosis index negatively at days 7 to 10. No adverse effects or complications were noted throughout the study. For canine noninfectious acute colitis, dietary management with an easily digestible diet with or without psyllium enhancement proved a superior management strategy compared to metronidazole. The omission of metronidazole reduced the adverse impact significantly on intestinal microbiota. Longitudinal clinical trials are necessary to compare the long-term response, stability, and complications associated with dietary management alone versus combined dietary and antimicrobial therapy for canine acute colitis.


Pre-B cells and other possible precursor lymphoid cell lines derived from patients with X-linked agammaglobulinemia.
A group of unique Epstein-Barr virus-containing cell lines was derived from the bone marrow of three patients with X-linked agammaglobulinemia. Efforts to obtain cell lines from the peripheral blood of these patients were uniformly unsuccessful. Immunofluorescence analyses as well as biosynthetic studies with [(35)S]methionine indicated unusual patterns of Ig synthesis in many of these bone marrow derived lines. Seven of the lines were of particular interest in that two produced no Ig of any type; two others showed no Ig by fluorescence but small amounts by [(35)S]methionine labeling; one expressed only cytoplasmic mu chains without any evidence of light chain synthesis, and two produced primarily mu chains with only slight amounts of light chains. One of the lines without membrane or cytoplasmic Ig studied in detail grew like a typical lymphoid line and was carried in intermittent culture over a period of 2 yr without Ig expression. One line grew quite differently and resembled the round cell type described previously, which has been obtained from a variety of sources. The cell line with cytoplasmic mu chains and no light-chain expression had the characteristic properties of pre-B cells. Three normal type Ig-producing cell lines also were obtained from the patients. The accumulated evidence obtained in the present study indicates that these unusual cell lines represent normal precursor cells of the B-cell lineage; these grew out in these cases because of the virtual absence of mature B cells that ordinarily overgrow the culture system. However, the possibility that in certain instances they reflect abnormal Ig synthesis characteristic of the disease has not been ruled out.


Genome-wide identification of multifunctional laccase gene family in cotton (Gossypium spp.); expression and biochemical analysis during fiber development.
The single-celled cotton fibers, produced from seed coat epidermal cells are the largest natural source of textile fibers. The economic value of cotton fiber lies in its length and quality. The multifunctional laccase enzymes play important roles in cell elongation, lignification and pigmentation in plants and could play crucial role in cotton fiber quality. Genome-wide analysis of cultivated allotetraploid (G. hirsutum) and its progenitor diploid (G. arboreum and G. raimondii) cotton species identified 84, 44 and 46 laccase genes, respectively. Analysis of chromosomal location, phylogeny, conserved domain and physical properties showed highly conserved nature of laccases across three cotton species. Gene expression, enzymatic activity and biochemical analysis of developing cotton fibers was performed using G. arboreum species. Of the total 44, 40 laccases showed expression during different stages of fiber development. The higher enzymatic activity of laccases correlated with higher lignin content at 25 DPA (Days Post Anthesis). Further, analysis of cotton fiber phenolic compounds showed an overall decrease at 25 DPA indicating possible incorporation of these substrates into lignin polymer during secondary cell wall biosynthesis. Overall data indicate significant roles of laccases in cotton fiber development, and presents an excellent opportunity for manipulation of fiber development and quality.


Molecular networking based LC/MS reveals novel biotransformation products of green coffee by ex vivo cultures of the human gut microbiome.
Unroasted green coffee bean is an increasingly popular beverage and weight loss supplement that contains higher levels of chlorogenic acid derivatives and lower alkaloid levels than roasted beans. Nonetheless, how the gut microbiome metabolizes green coffee constituents has not been studied. To identify possible biotransformation products of green coffee extract by the human gut microbiome, and the potential implications of this process on its biological effects or fate inside the body. Molecular networking via the GNPS platform was employed for the visualization of green coffee metabolite profiles acquired using LC-tandem mass spectrometry post-incubation with an ex vivo culture of the human gut microbiome. 36 Metabolites were annotated including four unreported alkyl cinnamate esters in green coffee along with six novel biotransformation products. Our finding reveals new biotransformation products of cinnamate esters by the gut microbiome mediated via oxidative reactions such as dehydrogenation and hydroxylation, along with methylation, decarboxylation, and deglycosylation. These findings reveal potential interactions between the gut microbiome and green coffee constituents, and paves the way towards studying the effects of these interactions on both microbiome and the human host.


Hemoglobin potentiates central nervous system damage.
Iron and iron compounds--including mammalian hemoglobins--catalyze hydroxyl radical production and lipid peroxidation. To determine whether hemoglobin-mediated lipid peroxidation might be important in hemorrhagic injuries to the central nervous system (CNS), we studied the effects of purified hemoglobin on CNS homogenates and injected hemoglobin into the spinal cords of anesthetized cats. Hemoglobin markedly inhibits Na/K ATPase activity in CNS homogenates and spinal cords of living cats. Hemoglobin also catalyzes substantial peroxidation of CNS lipids. Importantly, the potent iron chelator, desferrioxamine, blocks these adverse effects of hemoglobin, both in vitro and in vivo. Because desferrioxamine is not known to interact with heme iron, these results indicate that free iron, derived from hemoglobin, is the proximate toxic species. Overall, our data suggest that hemoglobin, released from red cells after trauma, can promote tissue injury through iron-dependent mechanisms. Suppression of this damage by desferrioxamine suggests a rational therapeutic approach to management of trauma-induced CNS injury.


Time to Colonoscopy after Positive Fecal Blood Test in Four U.S. Health Care Systems.
To reduce colorectal cancer mortality, positive fecal blood tests must be followed by colonoscopy. We identified 62,384 individuals ages 50 to 89 years with a positive fecal blood test between January 1, 2011 and December 31, 2012 in four health care systems within the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. We estimated the probability of follow-up colonoscopy and 95% confidence intervals (CI) using the Kaplan-Meier method. Overall differences in cumulative incidence of follow-up across health care systems were assessed with the log-rank test. HRs and 95% CIs were estimated from multivariate Cox proportional hazards models. Most patients who received a colonoscopy did so within 6 months of their positive fecal blood test, although follow-up rates varied across health care systems (P <0.001). Median days to colonoscopy ranged from 41 (95% CI, 40-41) to 174 (95% CI, 123-343); percent followed-up by 12 months ranged from 58.1% (95% CI, 51.6%-63.7%) to 83.8% (95% CI, 83.4%-84.3%) and differences across health care systems were also observed at 1, 2, 3, and 6 months. Increasing age and comorbidity score were associated with lower follow-up rates. Individual characteristics and health care system were associated with colonoscopy after positive fecal blood tests. Patterns were consistent across health care systems, but proportions of patients receiving follow-up varied. These findings suggest that there is room to improve follow-up of positive colorectal cancer screening tests. Understanding the timing of colonoscopy after positive fecal blood tests and characteristics associated with lack of follow-up may inform future efforts to improve follow-up.


Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency.
A detailed understanding of the mechanisms that establish or maintain the latent reservoir of HIV will guide approaches to eliminate persistent infection. We used a cell line and primary cell models of HIV latency to investigate viral RNA (vRNA) expression and the role of the host transcriptome using single-cell approaches. Single-cell vRNA quantitation identified distinct populations of cells expressing various levels of vRNA, including completely silent populations. Strikingly, single-cell RNA-seq of latently infected primary cells demonstrated that HIV downregulation occurred in diverse transcriptomic environments but was significantly associated with expression of a specific set of cellular genes. In particular, latency was more frequent in cells expressing a transcriptional signature that included markers of naive and central memory T cells. These data reveal that expression of HIV proviruses within the latent reservoir are influenced by the host cell transcriptional program. Therapeutic modulation of these programs may reverse or enforce HIV latency.


An ounce of prevention is worth a pound of cure: improving communication to reduce mortality during bioterrorism responses.
To identify communication needs and evaluate the effectiveness of alternative communication strategies for bioterrorism responses. We provide a framework for evaluating communication needs during a bioterrorism response. Then, using a simulation model of a hypothetical response to anthrax bioterrorism in a large metropolitan area, we evaluate the costs and benefits of alternative strategies for communication during a response. Expected mortality increases significantly with increases in the time for attack detection and announcement; decreases in the rate at which exposed individuals seek and receive prophylaxis; increases in the number of unexposed people seeking prophylaxis; and increases in workload imbalances at dispensing centers. Thus, the timeliness, accuracy, and precision of communications about the mechanisms of exposure and instructions for obtaining prophylaxis and treatment are critical. Investment in strategies that improve adherence to prophylaxis is likely to be highly cost effective, even if the improvement in adherence is modest, and even if such strategies reduce the prophylaxis dispensing rate. Communication during the response to a bioterror attack must involve the right information delivered at the appropriate time in an effective manner from trusted sources. Because the response system for bioterror communication is only fully operationalized once an attack has occurred, tabletop planning and simulation exercises, and other up-front investments in the design of an effective communication strategy, are critical for effective response planning.


A modular cell-type focused inflammatory process network model for non-diseased pulmonary tissue.
Exposure to environmental stressors such as cigarette smoke (CS) elicits a variety of biological responses in humans, including the induction of inflammatory responses. These responses are especially pronounced in the lung, where pulmonary cells sit at the interface between the body's internal and external environments. We combined a literature survey with a computational analysis of multiple transcriptomic data sets to construct a computable causal network model (the Inflammatory Process Network (IPN)) of the main pulmonary inflammatory processes. The IPN model predicted decreased epithelial cell barrier defenses and increased mucus hypersecretion in human bronchial epithelial cells, and an attenuated pro-inflammatory (M1) profile in alveolar macrophages following exposure to CS, consistent with prior results. The IPN provides a comprehensive framework of experimentally supported pathways related to CS-induced pulmonary inflammation. The IPN is freely available to the scientific community as a resource with broad applicability to study the pathogenesis of pulmonary disease.


A phylogenetic analysis by multilocus enzyme electrophoresis and multiprimer random amplified polymorphic DNA fingerprinting of the Leishmania genome project Friedlin reference strain.
We have assessed the phylogenetic status of the Leishmania genome project Friedlin reference strain by MLEE and multiprimer RAPD including a set of 9 stocks representative of the main Leishmania species and of the whole genetic diversity of the Leishmania genus. To our knowledge, the detailed genetic characterization of the Friedlin strain has never been published before. As previously recorded (Tibayrenc et al. 1993), MLEE and RAPD data gave congruent phylogenetic results. The Friedlin reference strain was definitely attributed to Leishmania (Leishmania) major Yakimoff et Schokhor, 1914. Five specific RAPD patterns made it possible to distinguish between the Friedlin strain and the 2 other L. (L.) major stocks included in the study. Various specific MLEE and RAPD characters permitted to distinguish between the Leishmania species included in the study. All these characters are usable to detect accidental laboratory mix-ups involving the Friedlin reference strain. In confirmation with previous studies involving a more limited set of genetic markers, the general genetic diversity of the Leishmania genus proved to be considerable. It must be made clear that only one strain cannot be considered as representative of the whole genetic variability of the genus Leishmania. In the future, it is therefore advisable to complement the results obtained in the framework of the Leishmania genome project with data from other strains that should be selected on a criterion of important genetic differences with the Friedlin strain.


Estimation of a multi-fascicle model from single B-value data with a population-informed prior.
Diffusion tensor imaging cannot represent heterogeneous fascicle orientations in one voxel. Various models propose to overcome this limitation. Among them, multi-fascicle models are of great interest to characterize and compare white matter properties. However, existing methods fail to estimate their parameters from conventional diffusion sequences with the desired accuracy. In this paper, we provide a geometric explanation to this problem. We demonstrate that there is a manifold of indistinguishable multi-fascicle models for single-shell data, and that the manifolds for different b-values intersect tangentially at the true underlying model making the estimation very sensitive to noise. To regularize it, we propose to learn a prior over the model parameters from data acquired at several b-values in an external population of subjects. We show that this population-informed prior enables for the first time accurate estimation of multi-fascicle models from single-shell data as commonly acquired in clinical context. The approach is validated on synthetic and in vivo data of healthy subjects and patients with autism. We apply it in population studies of the white matter microstructure in autism spectrum disorder. This approach enables novel investigations from large existing DWI datasets in normal development and in disease.