SU-E-T-24: Development and Implementation of an Automated Algorithm to Determine Radiation Isocenter, Radiation vs. Light Field Coincidence, and Analyze Strip Tests.
The aim of this study was to develop a phantom and analysis software that could be used to quickly and accurately determine the location of radiation isocenter using the Electronic Portal Imaging Device (EPID). The phantom could then be used as a static reference point for performing other tests including: radiation vs. light field coincidence, MLC and Jaw strip tests, and Varian Optical Guidance Platform (OGP) calibration. The solution proposed uses a collimator setting of 10×10 cm to acquire EPID images of the new phantom constructed from LEGO® blocks. Images from a number of gantry and collimator angles are analyzed by the software to determine the position of the jaws and center of the phantom in each image. The distance between a chosen jaw and the phantom center is then compared to the same distance measured after a 180 degree collimator rotation to determine if the phantom is centered in the dimension being investigated. The accuracy of the algorithm's measurements were verified by independent measurement to be approximately equal to the detector's pitch. Light versus radiation field as well as MLC and Jaw strip tests are performed using measurements based on the phantom center once located at the radiation isocenter. Reproducibility tests show that the algorithm's results were objectively repeatable. Additionally, the phantom and software are completely independent of linac vendor and this study presents results from two major linac manufacturers. An OGP calibration array was also integrated into the phantom to allow calibration of the OGP while the phantom is positioned at radiation isocenter to reduce setup uncertainty contained in the calibration. This solution offers a quick, objective method to perform isocenter localization as well as laser alignment, OGP calibration, and other tests on a monthly basis.


Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density.
Many patients with Crohn's disease (CD) have low bone mineral density (BMD) that may not be solely attributable to glucocorticoid use. We hypothesised that low BMD in patients with CD is associated with elevated circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D). We further hypothesised that this was secondary to increased synthesis of 1,25(OH)(2)D by inflammatory cells in the intestine. The aim of this study was to examine the relationship between 1,25(OH)(2)D levels and BMD in patients with CD. An IRB approved retrospective review of medical records from patients with CD (n = 138) or ulcerative colitis (UC, n = 29). Measurements of vitamin D metabolites and immunoreactive parathyroid hormone (iPTH) were carried out. BMD results were available for 88 CD and 20 UC patients. Immunohistochemistry or real time reverse transcription-polymerase chain reaction (RT-PCR) for the enzyme 1alpha-hydroxylase was performed on colonic biopsies from patients with CD (14) or UC (12) and normal colons (4). Inappropriately high levels of serum 1,25(OH)(2)D (>60 pg/ml) were observed in 42% of patients with CD compared with only 7% in UC, despite no differences in mean iPTH. Serum 1,25(OH)(2)D levels were higher in CD (57 pg/ml) versus UC (41 pg/ml) (p = 0.0001). In patients with CD, there was a negative correlation between 1,25(OH)(2)D levels and lumbar BMD (r = -0.301, p = 0.005) independent of therapeutic glucocorticoid use. 1,25(OH)(2)D levels also correlated with CD activity. Lastly, immunohistochemistry and RT-PCR demonstrated increased expression of intestinal 1alpha-hydroxylase in patients with CD. These data demonstrate that elevated 1,25(OH)(2)D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.


Pupil dilation signals uncertainty and surprise in a learning gambling task.
Pupil dilation under constant illumination is a physiological marker where modulation is related to several cognitive functions involved in daily decision making. There is evidence for a role of pupil dilation change during decision-making tasks associated with uncertainty, reward-prediction errors and surprise. However, while some work suggests that pupil dilation is mainly modulated by reward predictions, others point out that this marker is related to uncertainty signaling and surprise. Supporting the latter hypothesis, the neural substrate of this marker is related to noradrenaline (NA) activity which has been also related to uncertainty signaling. In this work we aimed to test whether pupil dilation is a marker for uncertainty and surprise in a learning task. We recorded pupil dilation responses in 10 participants performing the Iowa Gambling Task (IGT), a decision-making task that requires learning and constant monitoring of outcomes' feedback, which are important variables within the traditional study of human decision making. Results showed that pupil dilation changes were modulated by learned uncertainty and surprise regardless of feedback magnitudes. Interestingly, greater pupil dilation changes were found during positive feedback (PF) presentation when there was lower uncertainty about a future negative feedback (NF); and by surprise during NF presentation. These results support the hypothesis that pupil dilation is a marker of learned uncertainty, and may be used as a marker of NA activity facing unfamiliar situations in humans.


Class II antigens on retinal vascular endothelium, pericytes, macrophages, and lymphocytes of the rat.
Class II histocompatibility complex antigens on the retinal vascular endothelium may allow these cells to function as antigen-presenting cells to circulating T cells. The present study investigated induction of class II antigens in vitro to characterize the response under controlled conditions. Retinal vascular endothelium from Lewis and Brown Norway rats (high versus low responders in experimental autoimmune uveitis) were exposed in vitro to recombinant rat gamma interferon, interleukin-1, interleukin-2, or Concanavalin-A spleen supernatant. Retinal pericytes, macrophages and lymphocytes were studied in comparison. A newly adapted ELISA technique was used to assay levels of antigen expression. Class II antigens (I-A OX6, I-E OX17, polymorphic I-A OX3), class I antigens (OX18), macrophage marker (OX42), macrophage and T helper cell marker (W3/25), and T suppressor/cytotoxic cell marker (OX8) were studied. Results showed that retinal vascular endothelium normally expresses very little class II antigen. However, high levels of I-A and I-E were induced by interferon or spleen supernatant. The levels of class II antigen approached that of the traditional antigen-presenting cell (macrophage) and were much higher than levels for pericytes and lymphocytes. The same doses of interferon showed larger increases in the Lewis rat compared to Brown Norway. No effect was seen with interleukin-1 or -2. Therefore, retinal vascular endothelium may be induced by gamma interferon to express class II antigens with degree of induction greater than or equal to the macrophage, and higher levels of induction were seen in the high responder strain.(ABSTRACT TRUNCATED AT 250 WORDS)


Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair.
Cardiac cell therapy for older patients who experience a myocardial infarction may require highly regenerative cells from young, healthy (allogeneic) donors. Bone marrow mesenchymal stem cells (MSCs) are currently under clinical investigation because they can induce cardiac repair and may also be immunoprivileged (suitable for allogeneic applications). However, it is unclear whether allogeneic MSCs retain their immunoprivilege or functional efficacy late after myocardial implantation. We evaluated the effects of MSC differentiation on the immune characteristics of cells in vitro and in vivo and monitored cardiac function for 6 months after post-myocardial infarction MSC therapy. In the in vitro experiments, inducing MSCs to acquire myogenic, endothelial, or smooth muscle characteristics (via 5-azacytidine or cytokine treatment) increased major histocompatibility complex-Ia and -II (immunogenic) expression and reduced major histocompatibility complex-Ib (immunosuppressive) expression, in association with increased cytotoxicity in coculture with allogeneic leukocytes. In the in vivo experiments, we implanted allogeneic or syngeneic MSCs into infarcted rat myocardia. We measured cell differentiation and survival (immunohistochemistry, real-time polymerase chain reaction) and cardiac function (echocardiography, pressure-volume catheter) for 6 months. MSCs (versus media) significantly improved ventricular function for at least 3 months after implantation. Allogeneic (but not syngeneic) cells were eliminated from the heart by 5 weeks after implantation, and their functional benefits were lost within 5 months. The long-term ability of allogeneic MSCs to preserve function in the infarcted heart is limited by a biphasic immune response whereby they transition from an immunoprivileged to an immunogenic state after differentiation, which is associated with an alteration in major histocompatibility complex-immune antigen profile.


Pilot Study of the Juvenile Dermatomyositis Consensus Treatment Plans: A CARRA Registry Study.
To determine the feasibility of comparing the Childhood Arthritis and Rheumatology ResearchAlliance (CARRA) consensus treatment plans (CTP) in treating moderate new-onset juvenile dermatomyositis (JDM) using the CARRA registry, and to establish appropriate analytic methods to control for confounding by indication and missing data. A pilot cohort of 39 patients with JDM from the CARRA registry was studied. Patients were assigned by the treating physician, considering patient/family preferences, to 1 of 3 CTP: methotrexate (MTX) and prednisone (MP); intravenous (IV) methylprednisolone, MTX, and prednisone (MMP); or IV methylprednisolone, MTX, prednisone, and IV immunoglobulin (MMPI). The primary outcome was the proportion of patients achieving moderate improvement at 6 months under each CTP. Statistical methods including multiple imputation and inverse probability of treatment weighting were used to handle missing data and confounding by indication. Patients received MP (n = 13), MMP (n = 18) and MMPI (n = 8). Patients in all CTP had significant improvement in disease activity. Of the 36 patients who remained in our pilot study at 6 months, 16 (44%) of them successfully achieved moderate improvement at 6 months (6/13, 46% for MP; 7/15, 47% for MMP; 3/8, 38% for MMPI). After correcting for confounding, there were no statistically significant pairwise differences between the CTP (P = 0.328-0.88). We gained valuable experience and insight from our pilot study that can be used to guide the design and analysis of comparative effectiveness studies using the CARRA registry CTP approach. Our analytical methods can be adopted for future comparative effectiveness studies and applied to other rare disease observational studies.


Investigation and modelling of high rate algal ponds utilising secondary effluent at Western Water, Bacchus Marsh Recycled Water Plant.
There is growing interest in the ability of high rate algal ponds (HRAP) to treat wastewater. This method reduces the costs of algal production while treating the wastewater quicker and more efficiently than standard lagoon practices. Two parallel HRAPs were used in this study to treat secondary effluent. Nitrogen levels were significantly reduced with a mean reduction of 71% for ammonia and 64% for total nitrogen. The use of the HRAPs significantly increased the algal biomass levels compared to the algal growth in the storage lagoons, with a mean increase of 274%. Beneficial use of algae can be used to reduce treatment costs; so being able to predict and optimise the amount of algal biomass produced in HRAPs is vital. However, most models are complicated and require specific, detailed information. In this study, a predictive microalgal growth model was developed for HRAP by adapting two previously established models: the Steele and Monod models. The model could predict algal growth based on temperatures and solar radiation and account for limiting ammonia concentrations in an elevated pH environment with natural variations in the algal community. This model used experimental data that would be readily available to any established HRAP study.


Signal regulatory protein alpha (SIRPalpha) cells in the adaptive response to ESAT-6/CFP-10 protein of tuberculous mycobacteria.
Early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) are co-secreted proteins of Mycobacterium tuberculosis complex mycobacteria (includes M. bovis, the zoonotic agent of bovine tuberculosis) involved in phagolysosome escape of the bacillus and, potentially, in the efficient induction of granulomas. Upon tuberculosis infection, multi-nucleate giant cells are elicited, likely as a response aimed at containing mycobacteria. In tissue culture models, signal regulatory protein (SIRP)alpha (also referred to as macrophage fusion receptor or CD172a) is essential for multi-nucleate giant cell formation. In the present study, ESAT-6/CFP-10 complex and SIRPalpha interactions were evaluated with samples obtained from calves experimentally infected with M. bovis. Peripheral blood CD172a(+) (SIRPalpha-expressing) cells from M. bovis-infected calves proliferated upon in vitro stimulation with ESAT-6/CFP-10 (either as a fusion protein or a peptide cocktail), but not with cells from animals receiving M. bovis strains lacking ESAT-6/CFP-10 (i.e, M. bovis BCG or M. bovis DeltaRD1). Sorted CD172a(+) cells from these cultures had a dendritic cell/macrophage morphology, bound fluorescently-tagged rESAT-6:CFP-10, bound and phagocytosed live M. bovis BCG, and co-expressed CD11c, DEC-205, CD44, MHC II, CD80/86 (a subset also co-expressed CD11b or CD8alpha). Intradermal administration of rESAT-6:CFP-10 into tuberculous calves elicited a delayed type hypersensitive response consisting of CD11c(+), CD172a(+), and CD3(+) cells, including CD172a-expressing multi-nucleated giant cells. These findings demonstrate the ability of ESAT-6/CFP-10 to specifically expand CD172a(+) cells, bind to CD172a(+) cells, and induce multi-nucleated giant cells expressing CD172a.


Gender differences in awareness and outcomes during acute traumatic brain injury recovery.
Recent literature on traumatic brain injury (TBI), though mixed when reporting outcomes, seems collectively to suggest possible gender advantage for women in postinjury recovery, especially in executive functions. Hormonal neuroprotection, through female reproductive hormones, is often proposed as an underlying factor in these results. We explored potential gender differences in an aspect of executive functions, self-awareness (SA), which is often impaired after TBI, limits patient effort in critical rehabilitation, and increases caregiver burden. Within a prospective survey, repeated-measures design, 121 patients with moderate or severe TBI undergoing acute rehabilitation in a Level 1 trauma center, a family member or caregiver informant, and a treating clinician were asked to complete the Patient Competency Rating Scale (PCRS) and the Frontal Systems Behavior Scale (FrSBe) at admission and discharge. Although overall, women and men with TBI showed generally similar levels of SA, women had significantly better awareness of their injury-related deficits at acute rehabilitation discharge, even when controlling for age, education, and injury severity. Mixed findings in this study mirror the pattern of results that dominate the published literature on gender and TBI. Gender differences in executive dysfunction may not be as large or robust as some researchers argue. In addition, complex interplays of socialization, gender-role expectations, naturally occurring male and female ability differences, and differences in access to postinjury rehabilitation are understudied potential moderators.


Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats.
In a previous study conducted at the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation (CMCRC/ERF), we demonstrated for the first time that aspartame (APM) is a multipotent carcinogenic agent when various doses are administered with feed to Sprague-Dawley rats from 8 weeks of age throughout the life span. The aim of this second study is to better quantify the carcinogenic risk of APM, beginning treatment during fetal life. We studied groups of 70-95 male and female Sprague-Dawley rats administered APM (2,000, 400, or 0 ppm) with feed from the 12th day of fetal life until natural death. Our results show a) a significant dose-related increase of malignant tumor-bearing animals in males (p < 0.01), particularly in the group treated with 2,000 ppm APM (p < 0.01); b) a significant increase in incidence of lymphomas/leukemias in males treated with 2,000 ppm (p < 0.05) and a significant dose-related increase in incidence of lymphomas/leukemias in females (p < 0.01), particularly in the 2,000-ppm group (p < 0.01); and c) a significant dose-related increase in incidence of mammary cancer in females (p < 0.05), particularly in the 2,000-ppm group (p < 0.05). The results of this carcinogenicity bioassay confirm and reinforce the first experimental demonstration of APM's multipotential carcinogenicity at a dose level close to the acceptable daily intake for humans. Furthermore, the study demonstrates that when life-span exposure to APM begins during fetal life, its carcinogenic effects are increased.


Universal Expositions, physics-chemistry and new occupational diseases: the case of Marie Sklodowska Curie and radium girls.
Radium discovery by Marie and Pierre Curies caused previously unknown diseases. Marie Sklodowska Curie (1867-1934) suffered from radiations effects, as did girls in the radium dial watches factories. Therapeutic effects of radium were soon discovered, its unhealthy effects were as yet unheard of. Analysis of Marie Sklodowska Curie (Marie) and radium girls occupational exposure, taking scientific debate on radium dangerous effects into account. analysis of occupational exposure and diseases of Marie and radium girls in major documents, including Curie archive letters. Marie had dermatitis, radiodermatitis, tinnitus, one abortion, cataracts, tubercolosis, aplastic anemia. She also was a victim of mobbing. Women employed in the New Jersey radium dial watches factories, often immigrants, died of jaw necrosis, sarcoma of femur, anemia, leukemia and other radium related diseases. Marie was first asked about radium adverse effects by the New Jersey Department of labour (1925), Lise Meitner (1928) and the American Society for Cancer Control (1929). In 1928 Alice Hamilton organized a radium conference in order to find a solution to the radium girls' new disease. In 1929, during her second visit to the United States of America (USA), Marie declared how only prevention could save "radium girls". In 1934 she died of aplastic anemia, just like many radium girls. That year International Labour Office listed the new disease as due to "radium, radioactive substances, X-rays"; it was followed in 1937 by five USA states. Unheard of knowledge, conflict of interest, scientific delay, incompetence and no prevention were yesterday, as they are today, the cause of many preventable women deaths.


Prehistorical and historical declines in Caribbean coral reef accretion rates driven by loss of parrotfish.
Caribbean coral reefs have transformed into algal-dominated habitats over recent decades, but the mechanisms of change are unresolved due to a lack of quantitative ecological data before large-scale human impacts. To understand the role of reduced herbivory in recent coral declines, we produce a high-resolution 3,000 year record of reef accretion rate and herbivore (parrotfish and urchin) abundance from the analysis of sediments and fish, coral and urchin subfossils within cores from Caribbean Panama. At each site, declines in accretion rates and parrotfish abundance were initiated in the prehistorical or historical period. Statistical tests of direct cause and effect relationships using convergent cross mapping reveal that accretion rates are driven by parrotfish abundance (but not vice versa) but are not affected by total urchin abundance. These results confirm the critical role of parrotfish in maintaining coral-dominated reef habitat and the urgent need for restoration of parrotfish populations to enable reef persistence.


Mobile lidar for simultaneous measurements of ozone, aerosols, and temperature in the stratosphere.
A Meteorological Research Institute Mark II mobile lidar was developed for simultaneous measurements of ozone, temperature, and aerosols in the stratosphere. The lidar consists of an XeCl laser, a Nd:YAG laser, and an 80-cm diam receiving telescope. The laser beams at three wavelengths (308, 355, and 532 nm) can be almost simultaneously transmitted. The purpose of this lidar is to study, for example, the aerosol impact on the ozone layer through radiative and photochemical processes, the aerosol impact on the Umkehr measurements after violent volcanic eruptions, and the interaction between temperature and ozone. The performance of the lidar system and some data about ozone, aerosols, and temperature are described.


Thermoresponsive substrates used for the expansion of human mesenchymal stem cells and the preservation of immunophenotype.
The facile regeneration of undifferentiated human mesenchymal stem cells (hMSCs) from thermoresponsive surfaces facilitates the collection of stem cells avoiding the use of animal derived cell detachment agents commonly used in cell culture. This communication proposes a procedure to fabricate coatings from commercially available pNIPAm which is both affordable and a significant simplification on alternative approaches used elsewhere. Solvent casting was used to produce films in the micrometer range and successful cell adhesion and proliferation was highly dependent on the thickness of the coating produced with 1 μm thick coatings supporting cells to confluence. 3T3 cell sheets and hMSCs were successfully detached from the cast coatings upon temperature reduction. Furthermore, results indicate that the hMSCs remained undifferentiated as the surface receptor profile of hMSCs was not altered when cells were detached in this manner.


Ethane diffusion in mixed linker zeolitic imidazolate framework-7-8 by pulsed field gradient NMR in combination with single crystal IR microscopy.
Pulsed field gradient (PFG) NMR was used in combination with single crystal IR microscopy (IRM) to study diffusion of ethane inside crystals of a mixed linker zeolitic imidazolate framework (ZIF) of the type ZIF-7-8 under comparable experimental conditions. These crystals contain 2-methylimidazolate (ZIF-8 linker) and benzimidazolate (ZIF-7 linker). It was observed that the PFG NMR attenuation curves measured for ethane in ZIF-7-8 exhibit deviations from the monoexponential behaviour, thereby indicating that the ethane self-diffusivity in different crystals of a crystal bed can be different. Measurements of the ethane uptake curves performed by IRM under the same conditions in different ZIF-7-8 crystals of the bed yield different transport diffusivities thus confirming that the rate of ethane diffusion is different in different ZIF-7-8 crystals. The IRM observation that the fractions of ZIF-8 and ZIF-7 linkers are different in different ZIF-7-8 crystals allowed attributing the observed heterogeneity in diffusivities to the heterogeneity in the linker fraction. The quantitative comparison of the average ethane self-diffusivities measured by PFG NMR in ZIF-7-8 with the corresponding data on corrected diffusivities from IRM measurements revealed a good agreement between the results obtained by the two techniques. In agreement with the expectation of smaller aperture sizes in ZIF-7-8 than in ZIF-8, the average ethane self-diffusivities in ZIF-7-8 were found to be significantly lower than the corresponding self-diffusivities in ZIF-8.


A phosphorylation switch turns a positive regulator of phototropism into an inhibitor of the process.
Phototropins are light-activated protein kinases, which contribute to photosynthesis optimization both through enhancement of photon absorption when light is limiting and avoidance responses in high light. This duality is in part endowed by the presence of phototropins with different photosensitivity (phot1 and phot2). Here we show that phot1, which senses low light to promote positive phototropism (growth towards the light), also limits the response in high light. This response depends in part on phot1-mediated phosphorylation of Phytochrome Kinase Substrate 4 (PKS4). This light-regulated phosphorylation switch changes PKS4 from a phototropism enhancer in low light to a factor limiting the process in high light. In such conditions phot1 and PKS4 phosphorylation prevent phototropic responses to shallow light gradients and limit phototropism in a natural high light environment. Hence, by modifying PKS4 activity in high light the phot1-PKS4 regulon enables appropriate physiological adaptations over a range of light intensities.


Structure and function of the fallopian tubes following exposure to diethylstilbestrol (DES) during gestation.
The association between the use of diethylstilbestrol (DES) and vaginal and cervical adenocarcinoma and adenosis in the progeny was first reported by Herbst et al. in 1971. This progeny will reach a peak as far as reproduction is concerned in this decade. It is estimated that 2 million women may be involved to varying degrees. Changes in uterine and cervical contour and structure have been detailed. Thus DES exposure and anatomic changes in the Müllerian system have been documented. In this report 16 women in the reproductive age group who were exposed to DES in utero and presented with infertility are discussed. On workup for infertility they were found to have unique tubal morphologic features consisting of a foreshortened, convoluted tube with "withered" fimbria with a pinpoint os at laparoscopy. The diagnosis could not be made at the time of hysterosalpingogram. Three patients had surgery in an attempt to correct this condition; and in all cases the surgery was unsuccessful. No statistical data is offered as to epidemiologic factors or incidence rates, but the suspected increase in infertility and ectopic pregnancy rates in patients with DES exposure may corroborate these findings.


Developmental dissociation of excitability and secretory ability in Aplysia bag cell neurons.
1. Despite the considerable progress made in understanding the role of electrical activity in triggering secretion, the developmental relationships between excitability and secretion are not well understood. The well-characterized bag cell neurons of Aplysia provide an advantageous system in which to investigate developmental interactions of these two key properties of neurons. 2. A prolonged afterdischarge triggers egg laying hormone (ELH) secretion in mature bag cell neurons. To investigate secretion in the developmental framework of excitability, we first examined whether immature neurons, which are incapable of the mature form of excitability (afterdischarge), contain ELH and whether this hormone is packaged in vesicles. We used immunoelectron microscopy to compare vesicular localization of ELH and to compare the size and density of ELH-containing vesicles in neurons from adult and juvenile Aplysia. This comparison revealed that immature neurons contain ELH in vesicles in the size range of secretory vesicles. However, they lack a class of large vesicles (> 250 nm in diameter) that is characteristic of mature neurons. 3. To investigate whether the ELH contained in immature bag cell neurons could be secreted in response to electrical activity, we used the potassium channel blocker tetraethylammonium (TEA) combined with nerve stimulation to depolarize neurons from both juvenile animals (ovotestes do not contain eggs) and from adult Aplysia (ovotestes contain eggs). Using radioimmunoassay, we have found that the duration and amount of ELH secreted from bag cell neurons from juvenile Aplysia in response to TEA does not depend on whether or not the cells can be induced to afterdischarge, and the amount and duration of ELH secreted from bag cell neurons of juvenile Aplysia (whether or not they afterdischarged) differed from those secreted by adult neurons. However, by normalizing for body size, we found that the final estimated hemolymph concentration of ELH would be similar in juvenile and adult animals. 4. We investigated the potential functional significance of secretion of bag cell hormones in juvenile Aplysia by attempting to bypass the bag cell neurons and directly activate downstream elements with extract from adult bag cell neurons (BCE), known to contain ELH and other peptides. We found that juvenile Aplysia exhibit at least one component of egg-laying behavior, cessation of locomotion, in response to BCE during a developmental period (as measured by weight) in which they normally would possess neurons incapable of afterdischarge. Thus developmental regulation of excitability in the bag cell neurons may prevent inappropriate hormone release and subsequent premature expression of reproductive behaviors.


Milk production and composition, ovarian function, and prostaglandin secretion of dairy cows fed omega-3 fats.
Four multiparous Holstein cows were used in a 4 x 4 Latin square experiment to study the effects of fat sources rich in omega-3 fatty acids on milk production and composition, follicular development, and prostaglandin secretion. All cows were fed a total mixed diet containing 60% grass silage and 40% concentrate. The four treatments were concentrates based either on Megalac, formaldehyde-treated whole linseed, a mixture (50:50, oil basis) of fish oil and formaldehyde-treated whole linseed, or no fat source in the concentrate but with 500 g per day of linseed oil being infused into the duodenum. Feed intakes and milk yield were similar among treatments. In general, the lowest digestibility was observed for the formaldehyde-treated whole linseed treatment. Feeding fish oil decreased milk fat and protein percentages. Alpha-linolenic acid increased from 1.0 to 13.9% of milk fatty acids with linseed oil infusion. This confirms the high potential to incorporate alpha-linolenic acid into milk, and suggests that the formaldehyde treatment had little effect to limit biohydrogenation in the rumen. Increasing the supply of alpha-linolenic acid to these cows did not result in an increase in the concentration of eicosapentaenoic acid in milk. Levels of 13,14-dihydro-15-keto-PGF2alpha in plasma were higher for cows receiving formaldehyde-treated linseed and fish oil. Increases in this metabolite in response to oxytocin challenge, tended to be lower for cows given linseed either as sole oil supplement in the diet or as a duodenal infusion of linseed oil. Follicle dynamics were similar among treatments. Larger corpora lutea (CL) were found with cows that received high levels of omega-3 fatty acids through the diet as formaldehyde-treated linseed or as a mixture of formaldehyde-treated linseed and fish oil, although CL were smaller when cows were infused with linseed oil into the duodenum. These results suggest that the improvement in gestation rate that was observed when feeding increased levels of alpha-linolenic acid in earlier work may partly result from lower levels of production of the dienoic prostaglandin PGF2alpha.


Drosophila Sal and Salr are transcriptional repressors.
The SALL (Spalt-like) family of zinc-finger transcription factors is conserved in metazoans. In Drosophila Sal (Spalt) and Salr (Spalt-related) control the expression of genes involved in wing and central nervous system development, including cell adhesion and cytoskeletal proteins. In humans, SALL mutations associate with congenital disorders such as the Townes-Brocks and Okihiro syndromes. Human and Drosophila SALL proteins are modified by SUMO (small ubiquitin-related modifier), which influences their subnuclear localization. In the present study, we have analysed the transcriptional activity of Drosophila Sall proteins in cultured cells. We show that both Sal and Salr act as transcriptional repressors in Drosophila cells where they repress transcription through an AT-rich sequence. Furthermore, using the UAS/Gal4 heterologous system, Drosophila Sal and Salr repress transcription in human cells. Under our experimental conditions, only in the case of Salr is the repression activity dependent on the HDAC (histone deacetylase) complex. This complex might interact with the C-terminal zinc fingers of Salr. We describe the differential subcellular localizations of Sal and Salr fragments and identify their repression domains. Surprisingly, both repressors also contain transcription activation domains. In addition, under our experimental conditions SUMOylation has differential effects on Sal and Salr repressor activity. Phylogenetic comparison between nematodes, insects and vertebrates identifies conserved peptide sequences that are presumably critical for SALL protein function.


The Fas death factor.
Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.


Knowledge Generation Model for Visual Analytics.
Visual analytics enables us to analyze huge information spaces in order to support complex decision making and data exploration. Humans play a central role in generating knowledge from the snippets of evidence emerging from visual data analysis. Although prior research provides frameworks that generalize this process, their scope is often narrowly focused so they do not encompass different perspectives at different levels. This paper proposes a knowledge generation model for visual analytics that ties together these diverse frameworks, yet retains previously developed models (e.g., KDD process) to describe individual segments of the overall visual analytic processes. To test its utility, a real world visual analytics system is compared against the model, demonstrating that the knowledge generation process model provides a useful guideline when developing and evaluating such systems. The model is used to effectively compare different data analysis systems. Furthermore, the model provides a common language and description of visual analytic processes, which can be used for communication between researchers. At the end, our model reflects areas of research that future researchers can embark on.


Practical Use of Robot Manipulators as Intelligent Manufacturing Systems.
This paper presents features and advanced settings for a robot manipulator controller in a fully interconnected intelligent manufacturing system. Every system is made up of different agents. As also occurs in the Internet of Things and smart cities, the big issue here is to ensure not only that implementation is key, but also that there is better common understanding among the main players. The commitment of all agents is still required to translate that understanding into practice in Industry 4.0. Mutual interactions such as machine-to-machine and man-to-machine are solved in real time with cyber physical capabilities. This paper explores intelligent manufacturing through the context of industrial robot manipulators within a Smart Factory. An online communication algorithm with proven intelligent manufacturing abilities is proposed to solve real-time interactions. The algorithm is developed to manage and control all robot parameters in real-time. The proposed tool in conjunction with the intelligent manufacturing core incorporates data from the robot manipulators into the industrial big data to manage the factory. The novelty is a communication tool that implements the Industry 4.0 standards to allow communications among the required entities in the complete system. It is achieved by the developed tool and implemented in a real robot and simulation.


Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines.
Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus.


Percolation thresholds of two-dimensional continuum systems of rectangles.
The present paper introduces an efficient Monte Carlo algorithm for continuum percolation composed of randomly oriented rectangles. By conducting extensive simulations, we report high-precision percolation thresholds for a variety of homogeneous systems with different rectangle aspect ratios. This paper verifies and extends the excluded area theory. It is confirmed that percolation thresholds are dominated by the average excluded areas for both homogeneous and heterogeneous rectangle systems (except for some special heterogeneous systems where the rectangle lengths differ too much from one another). In terms of the excluded areas, generalized formulas are proposed to effectively predict precise percolation thresholds for all these rectangle systems. This paper is, therefore, helpful for both practical applications and theoretical studies concerning relevant systems.


Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis.
Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.


Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.
To evaluate the effectiveness and cost-effectiveness of two complementary interventions, using familial breast cancer as a model condition. The primary care intervention consisted of providing computerised referral guidelines and related education to GPs. The nurse counsellor intervention evaluated genetic nurses as substitutes for specialist geneticists in the initial assessment and management of referred patients. The computerised referral guidelines study was a pragmatic, cluster randomised controlled trial (RCT) with general practices randomised to intervention or control groups. The nurse counsellor intervention was tested in two concurrent RCTs conducted in separate UK health service locations, using predetermined definitions of equivalence. The computerised referral guidelines trial took place in general practices in Scotland from November 2000 to June 2001. The nurse counsellor intervention took place in a regional genetics clinic in Scotland, and in two health authorities in Wales served by a single genetics service during 2001. The computerised referral guidelines study involved GPs and referred patients. Both nurse counsellor intervention trials included women referred for the first time, aged 18 years or over and whose main concern was family history of breast cancer. The software system was developed with GPs, presenting cancer genetic referral guidelines in a checklist approach. Intervention GPs were invited to postgraduate update education sessions, and both intervention and control practices received paper-based guidelines. The intervention period was November 2000 to June 2001. For the nurse counsellor trial, trial 1 ran outpatient sessions with the same appointment length as the standard service offered by geneticists, but the nurse counsellor saw new patients at the first appointment and referred back to the GP or on to a clinical geneticist according to locally developed protocol, under the supervision of a consultant geneticist. The control intervention was the current service, which comprised an initial and a follow-up appointment with a clinical geneticist. In trial 2, a nurse counsellor ran outpatient sessions with the same appointment length as the new consultant-based cancer genetics service and new patients were seen at the first appointment and referred as in trial 1. The control intervention was a new service, and comprised collection of family history by telephone followed by a consultation with a clinical assistant or a specialist registrar, supervised by a consultant. The intervention was implemented between 1998 and 2001. In the software system trial, the primary outcome was GPs' confidence in their management of patients with concerns about family history of breast cancer. For the nurse counsellor trial, the primary outcome was patient anxiety, measured using standard scales. In the software system trial, 57 practices (230 GPs) were randomised to the intervention group and 29 (116 GPs) to the control group. No statistically significant differences were detected in GPs' confidence or any other outcomes. Fewer than half of the intervention GPs were aware of the software, and only 22 reported using it in practice. The estimated total cost was GBP3.12 per CD-ROM distributed (2001 prices). For the two arms of the nurse counsellor trial, 289 patients (193 intervention, 96 control) and 297 patients (197 intervention and 100 control) consented, were randomised, returned a baseline questionnaire and attended the clinic for trials 1 and 2 respectively. The analysis in both cases suggested equivalence in all anxiety scores, and no statistically significant differences were detected in other outcomes in either trial. A cost-minimisation analysis suggested that the cost per counselling episode was GBP10.23 lower in intervention arm than in the control arm and GBP10.89 higher in the intervention arm than in the control arm (2001 prices) for trials 1 and 2, respectively. Taking the trials together, the costs were sensitive to the grades of doctors and the time spent in consultant supervision of the nurse counsellor, but they were only slightly affected by the grade of nurse counsellor, the selected discount rate and the lifespan of equipment. Computer-based systems in the primary care intervention cannot be recommended for widespread use without further evaluation and testing in real practice settings. Genetic nurse counsellors may be a cost-effective alternative to assessment by doctors. This trial does not provide definitive evidence that the general policy of employing genetics nurse counsellors is sound, as it was based on only three individuals. Future evaluations of computer-based decision support systems for primary care must first address their efficacy under ideal conditions, identify barriers to the use of such systems in practice, and provide evidence of the impact of the policy of such systems in routine practice. The nurse counsellor trial should be replicated in other settings to provide reassurance of the generalisability of the intervention and other models of nurse-based assessment, such as in outreach clinics, should be developed and evaluated. The design of future evaluations of professional substitution should also address issues such as the effect of different levels of training and experience of nurse counsellors, and learning effects.


Non-response to psychotherapy for borderline personality disorder: A systematic review.
This is the first systematic review to investigate non-response to psychotherapy for borderline personality disorder. Psychotherapy is the recommended treatment for borderline personality disorder. While systematic reviews have demonstrated the effectiveness of psychotherapy for borderline personality disorder, effect sizes remain small and influenced by bias. Furthermore, the proportion of people who do not respond to treatment is seldom reported or analysed. To obtain an informed estimate of the proportion of people who do not respond to psychotherapy for borderline personality disorder. Systematic searches of five databases, PubMed, Web of Science, Scopus, PsycINFO and the Cochrane Library, occurred in November 2020. Inclusion criteria: participants diagnosed with borderline personality disorder, treated with psychotherapy and data reporting either (a) the proportion of the sample that experienced 'reliable change' or (b) the percentage of sample that no longer met criteria for borderline personality disorder at conclusion of therapy. Exclusion criteria: studies published prior to 1980 or not in English. Of the 19,517 studies identified, 28 met inclusion criteria. Twenty-eight studies were included in the review comprising a total of 2436 participants. Average treatment duration was 11 months using well-known evidence-based approaches. Approximately half did not respond to treatment; M = 48.80% (SD = 22.77). Data regarding within sample variability and non-response are seldom reported. Methods of reporting data on dosage and comorbidities were highly divergent which precluded the ability to conduct predictive analyses. Other limitations include lack of sensitivity analysis, and studies published in English only. Results of this review suggest that a large proportion of people are not responding to psychotherapy for borderline personality disorder and that factors relating to non-response are both elusive and inconsistently reported. Novel, tailored or enhanced interventions are needed to improve outcomes for individuals not responding to current established treatments.


Symptom cluster experience profiles in adult survivors of childhood cancers.
Although aggressive medical treatment protocols have led to 80% five-year survival rates for most childhood cancer patients, many long-term survivors experience multiple troubling symptoms. Using data from 100 adult survivors of childhood cancers (ACC-survivors), we used latent variable mixture modeling to generate unique subgroups of survivors based on their experiences with a cluster of eight symptoms: lack of energy, worry, pain, difficulty sleeping, feeling irritable, feeling nervous, difficulty concentrating, and feeling sad (as measured by the Memorial Symptom Assessment Scale). We also examined factors that were likely to predict subgroup membership (chronic health conditions [CHCs], health-promoting lifestyle, and demographic variables) and determined the extent to which satisfaction with quality of life (QoL) varied across the subgroups. The final mixture model included three subgroups of ACC-survivors: high symptoms (HS; n=21), moderate symptoms (MS; n=45), and low symptoms (LS; n=34). ACC-survivors who reported at least one CHC were six times as likely to be classified in the HS subgroup as compared with the LS subgroup. Mean health-promoting lifestyle scores were lowest in the HS subgroup and highest in the LS subgroup. Differences in QoL among the subgroups were statistically significant, thus validating that the subgroups were characterized uniquely for identifying those symptoms with highest life impact. To our knowledge, we are the first to identify distinct subgroups of ACC-survivors differentiated by symptom cluster experience profiles. The findings warrant additional research to confirm the subgroup-specific symptom cluster experience profiles in larger studies of ACC-survivors.


Asthma in adults.
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild-to-moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for chronic asthma? What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 99 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review, we present information relating to the effectiveness and safety of the following interventions. For acute asthma: beta(2) agonists (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, and short-acting intravenous); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium-oxygen mixture (heliox); magnesium sulphate (intravenous and adding isotonic nebulised magnesium to inhaled beta(2) agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care. For chronic asthma: beta(2) agonists (adding long-acting inhaled beta(2) agonists when asthma is poorly controlled by inhaled corticosteroids, or short-acting inhaled beta(2) agonists as needed for symptom relief); inhaled corticosteroids (low dose and increasing dose); leukotriene antagonists (with or without inhaled corticosteroids); and theophylline (when poorly controlled by inhaled corticosteroids).


Increased fetuin-A concentrations in impaired glucose tolerance with or without nonalcoholic fatty liver disease, but not impaired fasting glucose.
Fetuin-A, a liver-derived glycoprotein that impairs insulin signaling, is associated with nonalcoholic fatty liver disease (NAFLD), diabetes, and the risk of cardiovascular diseases. Both prediabetes and NAFLD are associated with increased cardiovascular risk, and their concurrence significantly impairs hepatic and adipose tissue insulin sensitivity. Our objective was to investigate the relationship between serum fetuin-A levels and prediabetes in subjects with or without NAFLD. This was a cross-sectional case-control study. A total of 510 age- and sex-matched subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) with or without NAFLD were recruited. Each subject was assessed by abdominal ultrasound to diagnose NAFLD. Serum fetuin-A concentrations were compared between groups. The association with clinico-metabolic parameters was examined. The presence of NAFLD significantly increases fetuin-A levels in subjects with NGT and prediabetes. As compared with NGT, IGT, but not IFG, significantly increases fetuin-A levels in subjects with or without NAFLD. Serum fetuin-A concentrations were positively related to postload 2-h glucose, body mass index, triglyceride, and homeostasis model assessment of insulin resistance but negatively associated with age, high-density lipoprotein cholesterol, and adiponectin. In multiple regression analysis, age, IGT vs. NGT, and IGT with NAFLD vs. NGT were independently associated with fetuin-A levels after adjustment for cardiovascular risk factors and adiponectin. IGT with or without NAFLD was independently associated with fetuin-A levels after adjustment for cardiometabolic risk factors. The elevated fetuin-A levels could have a clinical implication in the increased cardiovascular risk and insulin resistance associated with NAFLD and IGT.


MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias.
The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.


Future coastal population growth and exposure to sea-level rise and coastal flooding--a global assessment.
Coastal zones are exposed to a range of coastal hazards including sea-level rise with its related effects. At the same time, they are more densely populated than the hinterland and exhibit higher rates of population growth and urbanisation. As this trend is expected to continue into the future, we investigate how coastal populations will be affected by such impacts at global and regional scales by the years 2030 and 2060. Starting from baseline population estimates for the year 2000, we assess future population change in the low-elevation coastal zone and trends in exposure to 100-year coastal floods based on four different sea-level and socio-economic scenarios. Our method accounts for differential growth of coastal areas against the land-locked hinterland and for trends of urbanisation and expansive urban growth, as currently observed, but does not explicitly consider possible displacement or out-migration due to factors such as sea-level rise. We combine spatially explicit estimates of the baseline population with demographic data in order to derive scenario-driven projections of coastal population development. Our scenarios show that the number of people living in the low-elevation coastal zone, as well as the number of people exposed to flooding from 1-in-100 year storm surge events, is highest in Asia. China, India, Bangladesh, Indonesia and Viet Nam are estimated to have the highest total coastal population exposure in the baseline year and this ranking is expected to remain largely unchanged in the future. However, Africa is expected to experience the highest rates of population growth and urbanisation in the coastal zone, particularly in Egypt and sub-Saharan countries in Western and Eastern Africa. The results highlight countries and regions with a high degree of exposure to coastal flooding and help identifying regions where policies and adaptive planning for building resilient coastal communities are not only desirable but essential. Furthermore, we identify needs for further research and scope for improvement in this kind of scenario-based exposure analysis.


Bamboo leaf-assisted formation of carbon/nitrogen co-doped anatase TiO2 modified with silver and graphitic carbon nitride: novel and green synthesis and cooperative photocatalytic activity.
We report a novel synthesis approach employing bamboo leaves as sources of both the C/N dopant and reductant to the formation of C/N co-doped TiO2 modified with Ag and g-C3N4 (Ag/CN-TiO2@g-C3N4). In this case, the ternary composite has a hierarchical structure and a large surface area, which increases the contact area of reactants. Degradation of rhodamine B (RhB) and hydrogen generation were carried out to evaluate the photocatalytic activity of as-prepared samples under visible light irradiation. It is found that with respect to single and binary catalysts, the Ag/CN-TiO2@g-C3N4 ternary composite shows the highest photocatalytic activity (degradation of RhB, H2 evolution from water splitting) as a result of the fast generation, separation and transportation of the photogenerated carriers, which was evidenced by photoluminescence measurements and free radical/hole scavenging experiments. At last, a possible photocatalytic mechanism under visible light irradiation was proposed. The novel and green synergistic approach presented here could provide a facile yet effective method for designing other visible light active non-metal co-doped TiO2 based photocatalysts with enhanced activity and high chemical stability.


Does urbanicity modify the relationship between a polygenic risk score for depression and mental health symptoms? Cross-sectional evidence from the observational HUNT Study in Norway.
Research suggests that genetic predisposition for common mental disorders may be moderated by the environment. This study examines whether a polygenic risk score (PRS) for depression is moderated by the level of residential area urbanicity using five symptoms of poor mental health as outcomes. The study sample consisted of 41 198 participants from the 2006-2008 wave of the Norwegian HUNT study. We created a weighted PRS for depression based on 99 variants identified in a recent genome -wide association study. Participants were classified into urban or rural place of residence based on wards that correspond to neighbourhoods. Mixed effects logistic regression models with participants nested in 477 neighbourhoods were specified. A SD increase in PRS for depression was associated with a small but statistically significant increase in the odds of anxiety, comorbid anxiety and depression and mental distress. Associations for depression were weaker and not statistically significant. Compared with urban residents, rural resident had higher odds for reporting poor mental health. Genetic propensity for depression was higher for residents of urban than rural areas, suggesting gene-environment correlation. There was no sign of effect modification between genetic propensity and urbanicity for depression, anxiety, comorbid anxiety and depression, or mental distress. The PRS predicted small but significant odds of anxiety, comorbid anxiety and depression and mental distress, but we found no support for a differential effect of genetic propensity in urban and rural neighbourhoods for any of the outcomes.


Ammonia Transport.
This review reviews the ammonium/methylammonium transport (Amt) proteins of Escherichia coli and Salmonella enterica serovar Typhimurium. The Amt proteins and their homologs, the methylammonium/ammonium permease proteins of Saccharomyces cerevisiae, constitute a distinct class of membrane-associated ammonia transporters. Members of the Amt family are found in archaea, bacteria, fungi, plants, and invertebrate animals. In E. coli and serovar Typhimurium, the Amt proteins are essential to maintain maximal growth at low concentrations of ammonia, the preferred nitrogen source. Soupene and coworkers showed that a mutant of E. coli with only the low-affinity glutamate dehydrogenase pathway for assimilation of ammonia, which therefore grows slowly at low ammonia concentrations, is not relieved of its growth defect by overexpression of AmtB. A recent study on an Amt protein from tomato concluded that it was a specific transporter for NH4+. A trimeric stoichiometry for AmtB is supported by the observation of a direct interaction between AmtB and the trimeric signal-transduction protein GlnK. In E. coli, GlnK has been observed to associate with the membrane in an AmtB-dependent fashion. Both GlnK and GlnB are sensors of nitrogen status. Their interaction with AmtB suggests a role for AmtB in nitrogen regulation. In summary, AmtB is a membrane-associated ammonia transporter that is important for growth at external concentrations of the uncharged species (NH3) below about 50 nM. The preponderance of evidence suggests that AmtB specifically transports the charged species (NH4+) and that this transport is passive and, hence, bidirectional.


Optical properties of Bismuth-doped silica core photonic crystal fiber.
Optical properties of a Bismuth-doped pure silica sol-gel core photonic crystal fiber (PCF) were investigated. We report on the absorption, CW luminescence and time resolved luminescence spectra at different excitation wavelengths at room temperature. Complex structure of the energy levels of Bismuth-connected centers in pure silica glass is put in evidence.


Costing a Maternity Leave Cash Transfer to Support Breastfeeding Among Informally Employed Mexican Women.
Investing in maternity protection for working women is an important social equity mechanism. Addressing the maternity leave needs of women employed in the informal sector economy should be a priority as more than half of women in Latin America, South Asia, and sub-Saharan Africa are employed in this sector. To develop a costing methodology framework to assess the financial feasibility, at the national level, of implementing a maternity cash transfer for informally employed women. A World Bank costing methodology was adapted for estimating the financial need to establish a maternity cash transfer benefit. The methodology estimates the cash transfer's unitary cost, the incremental coverage of the policy in terms of time, the weighted population to be covered, and the administrative costs. The 6-step methodology uses employment and sociodemographic data that are available in many countries through employment and demographic surveys and the population census. The methodology was tested with data for Mexico assuming different cash transfer unitary costs and the benefit's time coverage. The methodological framework estimated that the annual financial needs of setting up a maternity cash transfer for informally working women in Mexico ranges between US$87 million and US$280 million. A pragmatic methodology for assessing the costs of maternity cash transfer for informally employed women was developed. In the case of Mexico, the maternity cash transfer for women in the informal sector is financially feasible.


Modelling the urban water cycle as an integrated part of the city: a review.
In contrast to common perceptions, the urban water infrastructure system is a complex and dynamic system that is constantly evolving and adapting to changes in the urban environment, to sustain existing services and provide additional ones. Instead of simplifying urban water infrastructure to a static system that is decoupled from its urban context, new management strategies use the complexity of the system to their advantage by integrating centralised with decentralised solutions and explicitly embedding water systems into their urban form. However, to understand and test possible adaptation strategies, urban water modelling tools are required to support exploration of their effectiveness as the human-technology-environment system coevolves under different future scenarios. The urban water modelling community has taken first steps to developing these new modelling tools. This paper critically reviews the historical development of urban water modelling tools and provides a summary of the current state of integrated modelling approaches. It reflects on the challenges that arise through the current practice of coupling urban water management tools with urban development models and discusses a potential pathway towards a new generation of modelling tools.


Preconception nutrition intervention improved birth length and reduced stunting and wasting in newborns in South Asia: The Women First Randomized Controlled Trial.
South Asia has >50% of the global burden of low birth weight (LBW). The objective was to determine the extent to which maternal nutrition interventions commenced before conception or in the 1st trimester improved fetal growth in this region. This was a secondary analysis of combined newborn anthropometric data for the South Asian sites (India and Pakistan) in the Women First Preconception Maternal Nutrition Trial. Participants were 972 newborn of mothers who were poor, rural, unselected on basis of nutritional status, and had been randomized to receive a daily lipid-based micronutrient supplement commencing ≥3 months prior to conception (Arm 1), in the 1st trimester (Arm 2), or not at all (Arm 3). An additional protein-energy supplement was provided if BMI <20 kg/m2 or gestational weight gain was less than guidelines. Gestational age was established in the 1st trimester and newborn anthropometry obtained <48-hours post-delivery. Mean differences at birth between Arm 1 vs. 3 were length +5.3mm and weight +89g. Effect sizes (ES) and relative risks (RR) with 95% CI for Arm 1 vs. 3 were: length-for-age Z-score (LAZ) +0.29 (0.11-0.46, p = 0.0011); weight-for-age Z-score (WAZ) +0.22 (0.07-0.37, p = 0.0043); weight-to-length-ratio-for-age Z-score (WLRAZ) +0.27 (0.06-0.48, p = 0.0133); LAZ<-2, 0.56 (0.38-0.82, p = 0.0032); WAZ <-2, 0.68 (0.53-0.88, p = 0.0028); WLRAZ <-2, 0.76 (0.64-0.89, p = 0.0011); small-for-gestational-age (SGA), 0.74 (0.66-0.83, p<0.0001); low birth weight 0.81 (0.66-1.00, p = 0.0461). For Arm 2 vs. 3, LAZ, 0.21 (0.04-0.38); WAZ <-2, 0.70 (0.53-0.92); and SGA, 0.88 (0.79-0.97) were only marginally different. ES or RR did not differ for preterm birth for either Arm 1 vs. 3 or 2 vs. 3. In conclusion, point estimates for both continuous and binary anthropometric outcomes were consistently more favorable when maternal nutrition supplements were commenced ≥3 months prior to conception indicating benefits to fetal growth of improving women's nutrition in this population.


High-speed ultrawideband photonically enabled compressed sensing of sparse radio frequency signals.
We demonstrate a new architecture for high-speed compressed sensing using chirp processing with ultrafast laser pulses, presently applied to the measurement of sparse-frequency microwave signals. We spectrally encode highly chirped ultrafast laser pulses with pseudorandom bit sequences such that every laser pulse acquires a unique spectral pattern. The pulses are partially compressed in time, extending the effective sampling rate beyond the electronic limit, and then modulated with a sparse microwave signal. Finally the pulses are fully compressed and detected, effectively integrating the measurement. We achieve 100 usable features per pattern allowing for 100 points in the reconstructed microwave spectra and experimentally demonstrate reconstruction of two- and three-tone microwave signals spanning from 900 MHz to 14.76 GHz. These spectra are reconstructed by measuring the energy of only 23 to 38 consecutive laser pulses acquired in a single shot with a 500 MHz real-time oscilloscope.


Trihalomethanes in Drinking Water and Bladder Cancer Burden in the European Union.
Trihalomethanes (THMs) are widespread disinfection by-products (DBPs) in drinking water, and long-term exposure has been consistently associated with increased bladder cancer risk. We assessed THM levels in drinking water in the European Union as a marker of DBP exposure and estimated the attributable burden of bladder cancer. We collected recent annual mean THM levels in municipal drinking water in 28 European countries (EU28) from routine monitoring records. We estimated a linear exposure-response function for average residential THM levels and bladder cancer by pooling data from studies included in the largest international pooled analysis published to date in order to estimate odds ratios (ORs) for bladder cancer associated with the mean THM level in each country (relative to no exposure), population-attributable fraction (PAF), and number of attributable bladder cancer cases in different scenarios using incidence rates and population from the Global Burden of Disease study of 2016. We obtained 2005-2018 THM data from EU26, covering 75% of the population. Data coverage and accuracy were heterogeneous among countries. The estimated population-weighted mean THM level was 11.7μg/L [standard deviation (SD) of 11.2]. The estimated bladder cancer PAF was 4.9% [95% confidence interval (CI): 2.5, 7.1] overall (range: 0-23%), accounting for 6,561 (95% CI: 3,389, 9,537) bladder cancer cases per year. Denmark and the Netherlands had the lowest PAF (0.0% each), while Cyprus (23.2%), Malta (17.9%), and Ireland (17.2%) had the highest among EU26. In the scenario where no country would exceed the current EU mean, 2,868 (95% CI: 1,522, 4,060; 43%) annual attributable bladder cancer cases could potentially be avoided. Efforts have been made to reduce THM levels in the European Union. However, assuming a causal association, current levels in certain countries still could lead to a considerable burden of bladder cancer that could potentially be avoided by optimizing water treatment, disinfection, and distribution practices, among other possible measures. https://doi.org/10.1289/EHP4495.


Computational modeling of coupled blood-wall mass transport of LDL: effects of local wall shear stress.
The work herein represents a novel approach for the modeling of low-density lipoprotein (LDL) transport from the artery lumen into the arterial wall, taking into account the effects of local wall shear stress (WSS) on the endothelial cell layer and its pathways of volume and solute flux. We have simulated LDL transport in an axisymmetric representation of a stenosed coronary artery, where the endothelium is represented by a three-pore model that takes into account the contributions of the vesicular pathway, normal junctions, and leaky junctions also employing the local WSS to yield the overall volume and solute flux. The fraction of leaky junctions is calculated as a function of the local WSS based on published experimental data and is used in conjunction with the pore theory to determine the transport properties of this pathway. We have found elevated levels of solute flux at low shear stress regions because of the presence of a larger number of leaky junctions compared with high shear stress regions. Accordingly, we were able to observe high LDL concentrations in the arterial wall in these low shear stress regions despite increased filtration velocity, indicating that the increase in filtration velocity is not sufficient for the convective removal of LDL.


Regulation of neural crest cell fate by the retinoic acid and Pparg signalling pathways.
Although the regulation of osteoblast and adipocyte differentiation from mesenchymal stem cells has been studied for some time, very little is known about what regulates their appearance in discrete regions of the embryo. Here we show that, as in other vertebrates, zebrafish osteoblasts and adipocytes originate in part from cephalic neural crest (CNC) precursors. We investigated the roles that the retinoic acid (RA) and Peroxisome proliferator-activated receptor gamma (Pparg) pathways play in vivo and found that both pathways act on CNC to direct adipocyte differentiation at the expense of osteoblast formation. In addition, we identify two distinct roles for RA in the osteoblast lineage: an early role in blocking the recruitment of osteoblasts and a later role in mature osteoblasts to promote bone matrix synthesis. These findings might help to increase our understanding of skeletal and obesity-related diseases and aid in the development of stem cell-based regenerative therapies.


Decoding in the absence of a codon by tmRNA and SmpB in the ribosome.
In bacteria, ribosomes stalled at the end of truncated messages are rescued by transfer-messenger RNA (tmRNA), a bifunctional molecule that acts as both a transfer RNA (tRNA) and a messenger RNA (mRNA), and SmpB, a small protein that works in concert with tmRNA. Here, we present the crystal structure of a tmRNA fragment, SmpB and elongation factor Tu bound to the ribosome at 3.2 angstroms resolution. The structure shows how SmpB plays the role of both the anticodon loop of tRNA and portions of mRNA to facilitate decoding in the absence of an mRNA codon in the A site of the ribosome and explains why the tmRNA-SmpB system does not interfere with normal translation.


Elevated matrix metalloproteinase-9 in patients with systemic sclerosis.
Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of cancer, autoimmune disease, and various pathologic conditions characterized by excessive fibrosis. In this study, we investigated the expression of MMP-9 and its clinical significance in systemic sclerosis (SSc). The patients (n = 42) with SSc had higher concentrations of MMP-9 and of tissue inhibitor of metalloproteinase-1 (TIMP-1) and a higher ratio of MMP-9 to TIMP-1 in sera than healthy controls (n = 32). Serum MMP-9 concentrations were significantly higher in the diffuse type (n = 23) than the limited type of SSc (n = 19). Serum concentrations of MMP-9 correlated well with the degree of skin involvement, as determined by the Rodnan score and with serum concentrations of transforming growth factor beta. Moreover, dermal fibroblasts from patients with SSc produced more MMP-9 than those from healthy controls when they were stimulated with IL-1beta, tumor necrosis factor alpha, or transforming growth factor beta. Such an increase in MMP-9 production was partially blocked by treatment with cyclosporin A. In summary, the serum MMP-9 concentrations were elevated in SSc patients and correlated well with skin scores. The increased MMP-9 concentrations may be attributable to overproduction by dermal fibroblasts in SSc. These findings suggest that the enhanced production of MMP-9 may contribute to fibrogenic remodeling during the progression of skin sclerosis in SSc.


Genome sequence of the lignocellulose-bioconverting and xylose-fermenting yeast Pichia stipitis.
Xylose is a major constituent of plant lignocellulose, and its fermentation is important for the bioconversion of plant biomass to fuels and chemicals. Pichia stipitis is a well-studied, native xylose-fermenting yeast. The mechanism and regulation of xylose metabolism in P. stipitis have been characterized and genes from P. stipitis have been used to engineer xylose metabolism in Saccharomyces cerevisiae. We have sequenced and assembled the complete genome of P. stipitis. The sequence data have revealed unusual aspects of genome organization, numerous genes for bioconversion, a preliminary insight into regulation of central metabolic pathways and several examples of colocalized genes with related functions. The genome sequence provides insight into how P. stipitis regulates its redox balance while very efficiently fermenting xylose under microaerobic conditions.


Hereditary myopathy with lactic acidosis, succinate dehydrogenase and aconitase deficiency in northern Sweden: a genealogical study.
A hereditary myopathy with lactic acidosis during physical exercise, low physical work capacity, and paroxysmal myoglobinuria (HML), called "Myopathy with deficiency of succinate dehydrogenase and aconitase" (McKusick 255125) has been described in 19 members of nine families who lived in two geographically separate areas in northern Sweden. By using the unique Swedish historical archives, including Catechetical Meeting Records from a number of northern Swedish parishes, it has been possible to trace ancestors of the nine families including all known 19 cases back in time to some key couples, who lived up to 300 years ago (that is seven to ten generations). No common single couple or common links between families in the past was found in these registers as a support for a single or several mutations that had developed far back in time. The mode of inheritance in this family is most likely autosomal recessive. This material will be used for the chromosomal localisation of the gene.


Sperm size is negatively related to relative testis size in West African riverine cichlid fishes.
Fishes show a great diversity of mating systems and fertilization mechanisms. This diversity creates an enormous potential for sperm competition. Typically, monogamous species face a low risk of sperm competition and invest less into sperm, and thus show smaller relative testis mass compared to polygamous species with high sperm competition. In cichlids, sperm competition risk is very variable. In lacustrine East African cichlids, large sperm are interpreted as an adaptation to sperm competition, as in those species sperm length correlates with sperm swimming speed. The aim of the present study was to examine variation in sperm and testis traits of substrate breeding cichlids from West African river systems and its relationship to sperm competition. Therefore, sperm traits (total sperm size, flagellum-, midpiece-, and head size) and sperm number were related to the gonadosomatic index (GSI), an indicator of sperm competition, in eight species of two large informal tribes, the chromidotilapiines and the haplotilapiines. We found significant differences between species in all examined sperm traits, sperm number, and GSI with pronounced differences between chromidotilapiines and haplotilapiines. We used a generalized least-squares approach to control for non-independence of data. GSI was positively correlated with sperm number but negatively correlated with total sperm size (also negatively with the flagellum and head size but not significantly with midpiece size). Sperm number and sperm size were negatively correlated suggesting a trade-off between sperm size and quality. Our results suggest that large sperm can evolve in species with relatively low sperm expenditure and probably in absence of high sperm competition between males.


Primary care physicians' and psychiatrists' approaches to treating mild depression.
To measure how primary care physicians (PCPs) and psychiatrists treat mild depression. We surveyed a national sample of US PCPs and psychiatrists using a vignette of a 52-year-old man with depressive symptoms not meeting Major Depressive Episode criteria. Physicians were asked how likely they were to recommend an antidepressant counseling, combined medication, and counseling or to make a psychiatric referral. Response rate was 896/1427 PCPs and 312/487 for psychiatrists. Compared with PCPs, psychiatrists were more likely to recommend an antidepressant (70% vs. 56%), counseling (86% vs. 54%), or the combination of medication and counseling (61% vs. 30%). More psychiatrists (44%) than PCPs (15%) were 'very likely' to promote psychiatric referral. PCPs who frequently attended religious services were less likely (than infrequent attenders) to refer the patient to a psychiatrist (12% vs. 18%); and more likely to recommend increased involvement in meaningful relationships/activities (50% vs. 41%) and religious community (33% vs. 17%). Psychiatrists treat mild depression more aggressively than PCPs. Both are inclined to use antidepressants for patients with mild depression.


Experimental approach to the fundamental limit of the extinction coefficients of ultra-smooth and highly spherical gold nanoparticles.
The theoretical extinction coefficients of gold nanoparticles (AuNPs) have been mainly verified by the analytical solving of the Maxwell equation for an ideal sphere, which was firstly founded by Mie (generally referred to as Mie theory). However, in principle, it has not been directly feasible with experimental verification especially for relatively large AuNPs (i.e., >40 nm), as conventionally proposed synthetic methods have inevitably resulted in a polygonal shaped, non-ideal Au nanosphere. Here, mono-crystalline, ultra-smooth, and highly spherical AuNPs of 40-100 nm were prepared by the procedure reported in our recent work (ACS Nano, 2013, 7, 11064). The extinction coefficients of the ideally spherical AuNPs of 40-100 nm were empirically extracted using the Beer-Lambert law, and were then compared with the theoretical limits obtained by the analytical and numerical methods. The obtained extinction coefficients of the ideally spherical AuNPs herein agree much more closely with the theoretical limits, compared with those of the faceted or polygonal shaped AuNPs. In addition, in order to further elucidate the importance of being spherical, we systematically compared our ideally spherical AuNPs with the polygonal counterparts; effectively addressing the role of the surface morphology on the spectral responses in both theoretical and experimental manners.


Tool for estimating the risk of anthropogenic spread of Batrachochytrium denrobatidis between water bodies.
Batrachochytrium dendrobatidis (Bd) is a chytrid fungus, which has been associated with numerous amphibian mortality events around the world. It is hypothesized that Bd was inadvertently spread through human activities. We have developed a basic risk assessment tool to better understand the potential risk of transferring Bd between water bodies through field activities, and to target disinfection strategies which reduce the risk of spreading Bd. The questions in the risk assessment focus on the likelihood of Bd being present at sites, the likelihood of transferring the pathogen from one site to another, and the impact of transferring the pathogen. Identified risk factors include the presence of amphibians in the visited areas, the presence of Bd in one or more of the sites and in the surrounding area, the number of visitors to the sites, direct contact with amphibians, and the sharing of equipment between sites. The risk assessment tool can be found on the Internet at: (http://www.cefas.co.uk/4449.aspx).


Understanding the relationship between urban blue infrastructure and land surface temperature.
Urban heat island (UHI) effect has serious negative impacts on urban ecosystems and human well-being. Mitigation of UHI using nature-based solutions is highly desirable. It was well known that urban green infrastructure (UGI), i.e., urban vegetation, can effectively mitigate UHI effect. However, the potential of urban blue infrastructure (UBI), i.e., urban surface water, on UHI mitigation is not well understood, although its potential to lower UHI effect via evaporation is similar to the biophysical mechanism of evapotranspiration through vegetation. In this paper, we study the relationship between UBI and land surface temperature (LST) in Wuhan city in central China, using a normalized difference water index (NDWI), maximum local cool island intensity and the maximum cooling distance as indicators for the cooling effects of UBI, respectively. We found a significant negative linear relationship between mean LST and NDWI after NDWI passes a critical threshold value. NDWI is an effective biophysical parameter to delineate the spatial distribution of UBI. The cooling effects of UBI are influenced both by its size and shape. Water surface temperature decreased logarithmically with increasing UBI size, critical threshold values of UBI size corresponding to maximum cooling efficiency do exists. Maximum cooling distance and maximum local cool island intensity are also affected by the shape and size of UBI, and exhibit seasonal and spatial variations. These results provide insights for urban landscape planning regarding how to use UBI as a nature-based solution to improve urban thermal environment.


Wavelet analysis techniques in cavitating flows.
Cavitating and bubbly flows involve a host of physical phenomena and processes ranging from nucleation, surface and interfacial effects, mass transfer via diffusion and phase change to macroscopic flow physics involving bubble dynamics, turbulent flow interactions and two-phase compressible effects. The complex physics that result from these phenomena and their interactions make for flows that are difficult to investigate and analyse. From an experimental perspective, evolving sensing technology and data processing provide opportunities for gaining new insight and understanding of these complex flows, and the continuous wavelet transform (CWT) is a powerful tool to aid in their elucidation. Five case studies are presented involving many of these phenomena in which the CWT was key to data analysis and interpretation. A diverse set of experiments are presented involving a range of physical and temporal scales and experimental techniques. Bubble turbulent break-up is investigated using hydroacoustics, bubble dynamics and high-speed imaging; microbubbles are sized using light scattering and ultrasonic sensing, and large-scale coherent shedding driven by various mechanisms are analysed using simultaneous high-speed imaging and physical measurement techniques. The experimental set-up, aspect of cavitation being addressed, how the wavelets were applied, their advantages over other techniques and key findings are presented for each case study.This paper is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'.


Early onset bipolar disorder: possible linkage to chromosome 9q34.
Bipolar disorder (BD) is characterized by manic and depressive states that onset at various times in life. Research shows that early onset forms of BD are associated with a stronger genetic loading for the illness. We hypothesized that using age at onset to look at subsets of BD families in a genetic linkage analysis would prove useful in separating etiologically homogeneous BD sub-groups and subsequently identifying genetic susceptibility regions. We used the wave-I National Institute of Mental Health (NIMH) Genetics Initiative BD sample, which includes 540 individuals from 97 families with BD, in an ordered-subsets linkage analysis with age at onset of mania as the subset-identifying covariate. This analysis was performed using GENEHUNTER-PLUS followed by the ordered-subsets analysis program. This program generates empirical p-values for the subset with the largest LOD score to determine whether this value was significantly higher than the baseline LOD score using all families. Three chromosomal regions resulted in LOD scores above 2.0: 2.21 (6q25), 3.21 (9q34), and 2.16 (20q11). The largest increase in LOD score was observed on chromosome 9q34 between markers D9S290 and D9S915 in the subset of 58 families that had mania onset before age 20. Families with a minimal mania onset less than 20 years had a significantly greater number of psychiatric comorbidities (p = 0.02) and a marginal increase in depressive symptoms (p = 0.10). Further investigation into chromosomal region 9q34 is necessary to determine whether this region may harbor a gene specific to families with a minimal age at onset of less than 20.


Ubiquitin, SUMO, and NEDD8: Key Targets of Bacterial Pathogens.
Manipulation of host protein post-translational modifications (PTMs) is used by various pathogens to interfere with host cell functions. Among these modifications, ubiquitin (UBI) and ubiquitin-like proteins (UBLs) constitute key targets because they are regulators of pathways essential for the host cell. In particular, these PTM modifiers control pathways that have been described as crucial for infection such as pathogen entry, replication, propagation, or detection by the host. Although bacterial pathogens lack eucaryotic-like UBI or UBL systems, many of them produce proteins that specifically interfere with these host PTMs during infection. In this review we discuss the different mechanisms used by bacteria to interfere with host UBI and the two UBLs, SUMO and NEDD8.


Appropriateness of peripherally inserted central catheter use among general medical inpatients: an observational study using routinely collected data.
Peripherally inserted central catheters (PICC) are among the most commonly used medical devices in hospital. This study sought to determine the appropriateness of inpatient PICC use in general medicine at five academic hospitals in Toronto, Ontario, Canada, based on the Michigan Appropriateness Guide for Intravenous Catheters (MAGIC). This was a retrospective, cross-sectional study of general internal medicine patients discharged between 1 April 2010 and 31 March 2015 who received a PICC during hospitalisation. The primary outcomes were the proportions of appropriate and inappropriate inpatient PICC use based on MAGIC recommendations. Hospital administrative data and electronic clinical data were used to determine appropriateness of each PICC placement. Multivariable regression models were fit to explore patient predictors of inappropriate use. Among 3479 PICC placements, 1848 (53%, 95% CI 51% to 55%) were appropriate, 573 (16%, 95% CI 15% to 18%) were inappropriate and 1058 (30%, 95% CI 29% to 32%) were of uncertain appropriateness. The proportion of appropriate and inappropriate PICCs ranged from 44% to 61% (p<0.001) and 13% to 21% (p<0.001) across hospitals, respectively. The most common reasons for inappropriate PICC use were placement in patients with advanced chronic kidney disease (n=500, 14%) and use for fewer than 15 days in patients who are critically ill (n=53), which represented 14% of all PICC placements in the intensive care unit. Patients who were older, female, had a Charlson Comorbidity Index score greater than 0 and more severe illness based on the Laboratory-based Acute Physiology Score were more likely to receive an inappropriate PICC. Clinical practice recommendations can be operationalised into measurable domains to estimate the appropriateness of PICC insertions using routinely collected hospital data. Inappropriate PICC use was common and varied substantially across hospitals in this study, suggesting that there are important opportunities to improve care.


Managing DICOM images: Tips and tricks for the radiologist.
All modalities in radiology practice have become digital, and therefore deal with DICOM images. Image files that are compliant with part 10 of the DICOM standard are generally referred to as "DICOM format files" or simply "DICOM files" and are represented as ".dcm." DICOM differs from other image formats in that it groups information into data sets. A DICOM file consists of a header and image data sets packed into a single file. The information within the header is organized as a constant and standardized series of tags. By extracting data from these tags one can access important information regarding the patient demographics, study parameters, etc. In the interest of patient confidentiality, all information that can be used to identify the patient should be removed before DICOM images are transmitted over a network for educational or other purposes. In addition to the DICOM format, the radiologist routinely encounters images of several file formats such as JPEG, TIFF, GIF, and PNG. Each format has its own unique advantages and disadvantages, which must be taken into consideration when images are archived, used in teaching files, or submitted for publication. Knowledge about these formats and their attributes, such as image resolution, image compression, and image metadata, helps the radiologist in optimizing the archival, organization, and display of images. This article aims to increase the awareness among radiologists regarding DICOM and other image file formats encountered in clinical practice. It also suggests several tips and tricks that can be used by the radiologist so that the digital potential of these images can be fully utilized for maximization of workflow in the radiology practice.


The persistence of epiphyseal scars in the adult tibia.
Estimation of chronological age from skeletal material is dependent upon estimation of maturational stage observed. Following completion of epiphyseal fusion, a transverse radio-opaque line, termed "epiphyseal scar", may be observed in the region of the former growth plate. According to the literature, this line is likely to become obliterated shortly after completion of epiphyseal fusion. Consequently, presence of an epiphyseal scar has been interpreted as an indication of recent epiphyseal fusion; however, this has not been validated by quantitative research. A study was undertaken to determine persistence of the epiphyseal scars in a cross-sectional population of adults between 20 and 50 years of age. This study examined 1,216 radiographs of proximal and distal tibiae from both sexes and sides of the body. This study suggested that 98.05% of females and 97.74% of males retained some remnant of the epiphyseal scar at the proximal tibia whilst 92.72% of females and 92.95% of males retained some remnant of the epiphyseal scar at the distal tibia. General linear model (GLM) analysis determined that chronological age accounted for 2.7% and 7.6% of variation in persistence of the epiphyseal scar at the proximal and distal tibiae, respectively. This study suggests that obliteration of the epiphyseal scar is not as dependent on chronological age as previously thought. It is, therefore, recommended that this feature not be used as an indicator of chronological age during forensic age assessment.


Fast Sparse Level Sets on Graphics Hardware.
The level-set method is one of the most popular techniques for capturing and tracking deformable interfaces. Although level sets have demonstrated great potential in visualization and computer graphics applications, such as surface editing and physically based modeling, their use for interactive simulations has been limited due to the high computational demands involved. In this paper, we address this computational challenge by leveraging the increased computing power of graphics processors, to achieve fast simulations based on level sets. Our efficient, sparse GPU level-set method is substantially faster than other state-of-the-art, parallel approaches on both CPU and GPU hardware. We further investigate its performance through a method for surface reconstruction, based on GPU level sets. Our novel multiresolution method for surface reconstruction from unorganized point clouds compares favorably with recent, existing techniques and other parallel implementations. Finally, we point out that both level-set computations and rendering of level-set surfaces can be performed at interactive rates, even on large volumetric grids. Therefore, many applications based on level sets can benefit from our sparse level-set method.


Transcription from the P3 promoter of the Bacillus subtilis spx gene is induced in response to disulfide stress.
The spx gene of Bacillus subtilis encodes a global regulator that controls transcription initiation in response to oxidative stress by interaction with RNA polymerase (RNAP). It is located in a dicistronic operon with the yjbC gene. The spx gene DNA complements an spx null mutation with respect to disulfide stress resistance, suggesting that spx is transcribed from a promoter located in the intergenic region of yjbC and spx. Transcription of the yjbC-spx operon has been reported to be driven by four promoters, three (P(1), P(2), and P(B)) residing upstream of yjbC and one (P(M)) located in the intergenic region between yjbC and spx. Primer extension analysis uncovered a second intergenic promoter, P(3), from which transcription is elevated in cells treated with the thiol-specific oxidant diamide. P(3) is utilized by the sigma(A) form of RNA polymerase in vitro without the involvement of a transcriptional activator. Transcriptional induction from P(3) did not require an Spx-RNAP interaction and was observed in a deletion mutant lacking DNA upstream of position -40 of the P(3) promoter start site. Deletion mutants with endpoints 3' to the P(3) transcriptional start site (positions +5, +15, and +30) showed near-constitutive transcription at the induced level, indicating the presence of a negative control element downstream of the P(3) promoter sequence. Point mutations characterized by bgaB fusion expression and primer extension analyses uncovered evidence for a second cis-acting site in the P(3) promoter sequence itself. The data indicate that spx transcription is under negative transcriptional control that is reversed when disulfide stress is encountered.