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The Herberton Mineral Field in Northeast Australia hosts world class magmatic-hydrothermal Sn–W polymetallic deposits that are enriched in In. The Baal Gammon and Isabel deposits from the Herberton Mineral Field contains early tin, as cassiterite, overprinted by sulfide mineralization as chalcopyrite, sphalerite, galena, pyrrhotite, and stannite. We investigated the distribution of In in the sulfide ores from these two deposits, calculated the temperature of formation via sphalerite-stannite geothermometer, and deduced the physicochemical conditions favorable for enriching In in this mineralizing environment. The Baal Gammon deposit is dominated by chalcopyrite, with In contained in chalcopyrite, sphalerite, and stannite. The average In concentrations measured by EPMA in chalcopyrite, sphalerite, and stannite are 0.10, 0.68, and 0.92 wt%, respectively. Chalcopyrite, pyrrhotite, and sphalerite textures indicate that In incorporation occurred during exsolution from an intermediate solid solution of cubanite composition. The Isabel deposit is dominated by sphalerite associated with galena and contains only minor amounts of chalcopyrite. The average concentration of In in sphalerite from the Isabel deposit is 0.11 wt%. The stannite-sphalerite geothermometer indicates mineralization temperatures of ~ 290 °C at the Baal Gammon deposit, and ~ 307 °C at the Isabel deposit. At these temperatures, the physicochemical modeling suggests that stable In chlorine complexes occur in acidic conditions (pH

Background A recent meta-analysis of 48 studies, showed an equal prevalence of AP (16%) among the following etiologies; systemic disease, alcohol, medication, genetics, gallstones and infection in North American hospitalized and ambulatory pediatric patients. However, data on the epidemiology of severe pediatric acute pancreatitis (AP) in Canada are lacking. Purpose We aim to evaluate the clinical presentation, etiologies, comorbidities and outcome of pediatric patients with AP admitted to a tertiary hospital in Quebec, Canada. Method A retrospective observational cohort study (January 2014-December 2021) was performed at the CHU Sainte-Justine. Descriptive analyses were performed with SAS statistical softwar Result(s) Among the 214 patients included (110 (51%) males), 58 (27.1%) were already hospitalized at time of AP diagnosis (AP as secondary diagnosis) while 156 (72.9%) were admitted from the emergency room mainly with a presentation of abdominal pain (AP as primary diagnosis). Thirty-two patients (15.0%) were transferred to the ICU due to hemodynamic instability or respiratory failure. Comorbidities included cancer (38 patients (17.7%)), obesity (17 (7.9%)) and inflammatory bowel disease (15 (7.0%)). The three most commonly identified etiologies were medication (19.6%), biliary disease (16.3%) and infection (14,9%). Despite extensive investigations, 26.2% of cases were idiopathic. The main complications were, ascites (48 patients (22.4%)), necrotic pancreatitis (10 (4.6%)) and pancreatic pseudocyst (10 (4.6%)). The median duration of hospitalization for AP as a primary diagnosis was 4 days (interquartile range (IQR) 2-7) as compared to 22 (11-37) for AP as a secondary diagnosis. Conclusion(s) Approximately one third of hospitalized patients had an underlying condition requiring treatments that could cause AP, which explains the high prevalence of drug-induced AP in this report. The longest hospitalizations were associated with AP as secondary diagnosis. Ongoing work will identify factors associated with disease severity and outcome in particular in primary AP. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Background Few risk factors are associated with the risk of relapses of Crohn’s disease in children. Aims The aims of this retrospective cohort study were to describe the rate of relapses in children with Crohn’s disease, its evolution over the past decade and to determine risk factors associated with relapse. Methods Patients under 18 years old and diagnosed between 2009 and 2019 were included. Patients clinical, endoscopic, histological, and laboratory characteristics, as well as their treatments, where collected from their medical records and the prospective CHU Sainte-Justine inflammatory bowel disease registry. Survival analyses and Cox regression models were used to assess the impact of those risk factors on relapse. Results 639 patients were included. There was a decrease in the clinical relapse rate over the past decade: 70.9% of patients diagnosed between 2009 and 2014 experienced a relapse compared to 49.1% of patients diagnosed between 2015 and 2019 (p Conclusions Relapse risk was significantly associated with baseline clinical, endoscopic, histological and laboratory data and treatment strategies. These results could help better select treatment options for pediatric Crohn’s disease at induction and maintenance. Kaplan-Meier curve representing patients time to relapse according to the mean infliximab level in post-induction. Funding Agencies NoneFonds Recherche Santé Québec / Fondation du CHU Sainte-Justine

Background The natural evolution of Crohn’s disease is incompletely understood in the pediatric population. Data on factors influencing time-to-remission are very limited in the literature. Aims The aim of this retrospective cohort study was to describe the time to clinical remission in children with Crohn’s disease as well as changes over the past decade and to identify factors associated with time to clinical remission. Methods Patients under 18 years old diagnosed between 2009 and 2019 were included. All data were collected from the patients’ medical records and the CHU Sainte-Justine inflammatory bowel disease registry. Survival analyses and linear regression models were used to assess the impact of clinical, laboratory, endoscopic, histological and therapeutic factors on time to clinical remission. Results 654 patients were included in the study. There was no change in the time to clinical remission over the past decade. Female sex in adolescents (ajusted bêta regression coefficient (aβ)= 31.8 days, p= 0.02), upper digestive tract involvement (aβ= 46.4 days, p= 0.04), perianal disease (aβ= 32.2 days, p= 0.04), presence of active inflammation on biopsies (aβ= 46.7 days, p= 0.01) and oral 5-ASA exposure (aβ=56.6 days, p= 0.002) were all associated with longer time to clinical remission. However, antibiotic exposure (aβ= -29.3 days, p=0.04), increased eosinophils on biopsies (aβ= -29.6 days, p=0.008) and combination of exclusive enteral nutrition and TNF- alpha inhibitors as induction therapy (aβ= -36.8, p=0.04) were associated with shorter time to clinical remission. Conclusions Time to clinical remission did not improve during the decade and was associated with baseline clinical and histological data and treatment strategies. Combination of enteral nutrition and TNF-alpha inhibitors was associated with faster clinical remission. Kaplan-Meier curve representing the time to clinical remission of patients according to the first induction treatment administered. Funding Agencies NoneFonds Recherche Santé Québec / Fondation du CHU Sainte-Justine

Background Crohn’s disease (CD) triggers are incompletely understood and the incidence of the disease has been increasing. Aims The aims of this study were to describe the trends in the clinical, endoscopic, histological, and laboratory characteristics of pediatric CD during the last decade and to describe the seasonal variation of disease presentation at diagnosis. Methods Patients under 18 years old and diagnosed between 2009 and 2019 were included. Patients clinical, endoscopic, histological, and laboratory data were collected from the medical records. Data were analyzed for the cohort as a whole and according to diagnostic periods (2009–2014 and 2015–2019) and seasons. Results 654 patients were included in the study. The total number of incident CD cases significantly increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR: 2.30, p There were fewer CD diagnosis during winter. The highest vitamin D levels in patients occurred in summer and fall, but the majority of patients had, regardless of the season of diagnosis, severe vitamin D deficiency (the median vitamin D level was 60.0 nmol/L in summer and fall compared to 47.0 nmol/L in winter-spring, p=0.003). Vitamin D levels at diagnosis are inversely correlated with PCDAI (Pearson correlation coefficient = -0.19, p=0.03) and SES-CD (-0.20, p=0.04). Patients diagnosed in fall had lower PCDAI and SES-CD scores, less failure to thrive, less digestive symptoms and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall (27.3% of patients diagnosed in summer and fall versus 18.2% of cases in winter and spring, p=0.01). Conclusions The disease phenotype has changed over the years and there are important seasonal trends in the frequency and severety of the disease suggesting possible disease triggers. Our findings provide interesting avenues for future research, such as identifying the clinical significance of granulomas, vitamin D deficiency and microbiota on pediatric CD activity. PCDAI at diagnosis according to the season. Funding Agencies NoneFonds Recherche Santé Québec / Fondation du CHU Sainte-Justine

Background Foreign Body Ingestions (FBI), sometimes associated with severe complications, are a common reason for emergency unit visits in children. In Quebec, since March 2020, the restrictions in response to the COVID-19 pandemic have increased the time children spend at home. We hypothesized that this could contribute to a rise in FBI incidence and severity. Aims The primary objective of our study was to evaluate the incidence as well as the clinical presentation of FBI cases seen at CHU Sainte-Justine Children’s Hospital in Montreal (CHUSJ) during the COVID-19 pandemic as compared to the two previous years. Our secondary objectives were to estimate the rate of severe FBI (involving hospitalisations and/or complications) and to evaluate the nature of the foreign bodies that were ingested. Methods All children referred to or who presented at CHUSJ for FBI between March 2018 and February 2020 (pre-pandemic) as well as between March 2020 and February 2021 (pandemic) were included (n=690). Cases of food impaction were excluded (n=78). Incidence of FBI was calculated by dividing the number of FBI cases by the total number of emergency department visits per period. Differences between the two groups were analyzed by Student T test or Chi-square test. Results Between March 2018 and February 2021, 612 patients (median age 3.5 years (1.6–5.9); 54% male) were eligible. The mean monthly number of FBI cases (min-max) in 2020–2021 was 18.6 (9–28), significantly higher than the year 2018 [16.6 (8–22)] and the year 2019 [15.5 (9–24)]; p=0.04. The incidence rate of FBI doubled during the pandemic as compared to the prepandemic group: respectively 57.5/10,000 emergency department visits and 23.2/10,000 visits (p=0.002). Almost one fourth of the cohort was hospitalized. The hospitalization rate (>1 day) was similar between the 2 periods: 8.8% before the pandemic and 7.1% during the pandemic. Digestive endoscopy was performed in 21.5% of cases, a rate similar before and during the pandemic. A total of 3.3% of the children developed complications related to FBI. This rate remained stable between the two periods. The most frequently ingested objects were coins (25.0%), toys (10.8%), button batteries (10.6%), magnets (6.2%), and jewellery (6.2%). There was no significant difference in the nature of FB ingested between the 2 periods although the number of magnet ingestions increased during the pandemic (18 per year vs 10 per year). Conclusions The incidence of FBI increased significantly during the pandemic in comparison with the two previous years. The high hospitalization and complications rates, although stable during the pandemic, underline the significant impact of pediatric FBI. Funding Agencies None

Background Crohn’s disease (CD) triggers are incompletely understood and the incidence of the disease has been increasing. The aims of this study were to describe the trends in the clinical, endoscopic, histological, and laboratory characteristics of pediatric CD during the last decade and to describe the seasonal variation of disease presentation at diagnosis. Methods Patients under 18 years old and diagnosed between 2009 and 2019 were included. Patients clinical, endoscopic, histological, and laboratory data were collected from the medical records. Data were analyzed for the cohort as a whole and according to diagnostic periods (2009–2014 and 2015–2019) and seasons. Results 654 patients were included in the study. The total number of incident CD cases significantly increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR: 2.30, p There were fewer CD diagnosis during winter. The highest vitamin D levels in patients occurred in summer and fall, but the majority of patients had, regardless of the season of diagnosis, severe vitamin D deficiency (the median vitamin D level was 60.0 nmol/L in summer and fall compared to 47.0 nmol/L in winter-spring, p=0.003). Vitamin D levels at diagnosis are inversely correlated with PCDAI (Pearson correlation coefficient = -0.19, p=0.03) and SES-CD (-0.20, p=0.04). Patients diagnosed in fall had lower PCDAI and SES-CD scores, less failure to thrive, less digestive symptoms and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall (27.3% of patients diagnosed in summer and fall versus 18.2% of cases in winter and spring, p=0.01). Figure 1:PCDAI at diagnosis according to the season. Figure 2:Proportion of patients with L1-L2-L3 disease locations by the Paris classification according to the season of diagnosis. Conclusion The disease phenotype has changed over the years and there are important seasonal trends in the frequency and severety of the disease suggesting possible disease triggers. Our findings provide interesting avenues for future research, such as identifying the clinical significance of granulomas, vitamin D deficiency and microbiota on pediatric CD activity.

A ruptured abdominal aortic aneurysm (rAAA) is a life-threatening condition, with high mortality rates. The Shock Index (SI) is an easy tool and a useful predictor of hemodynamic instability in trauma patients. We aimed to assess the predictive and prognostic value of the SI for patients with a suspected rAAA in the prehospital and hospital setting.This was a retrospective, observational, single-center study. Patients18 years old who visited the emergency department with a suspected rAAA between January 2009 and December 2018 were included. Prehospital and hospital SI were calculated and analyzed for its predictive value on the presence of a rAAA, need for packed cells (PCs) and mortality.A total of 313 patients met the inclusion criteria, of which 71 patients (22.6%) presented with a rAAA. Prehospital and hospital SI were significantly increased in the rAAA group. A SI ≥ 1.0 was estimated as an optimal cutoff point for the presence of a rAAA (AUROC 0.74, 95% CI 0.67-0.82;The prehospital and hospital SI were significantly elevated in the rAAA group. As such, the SI showed promising results as a predictive and prognostic tool, with SI ≥ 1.0 as cutoff point.

Background The natural evolution of Crohn’s disease is incompletely understood in the pediatric population. Data on factors influencing time-to-remission are very limited in the literature. The aim of this retrospective cohort study was to describe the time to clinical remission in children with Crohn’s disease as well as changes over the past decade and to identify factors associated with time to clinical remission. Methods Patients under 18 years old diagnosed between 2009 and 2019 were included. All data were collected from the patients’ medical records and the CHU Sainte-Justine inflammatory bowel disease registry. Survival analyses and linear regression models were used to assess the impact of clinical, laboratory, endoscopic, histological and therapeutic factors on time to clinical remission. Results 654 patients were included in the study. There was no change in the time to clinical remission over the past decade. Female sex in adolescents (ajusted bêta regression coefficient (aβ)= 31.8 days, p= 0.02), upper digestive tract involvement (aβ= 46.4 days, p= 0.04), perianal disease (aβ= 32.2 days, p= 0.04), presence of active inflammation on biopsies (aβ= 46.7 days, p= 0.01) and oral 5-ASA exposure (aβ=56.6 days, p= 0.002) were all associated with longer time to clinical remission. However, antibiotic exposure (aβ= -29.3 days, p=0.04), increased eosinophils on biopsies (aβ= -29.6 days, p=0.008) and combination of exclusive enteral nutrition and TNF- alpha inhibitors as induction therapy (aβ= -36.8, p=0.04) were associated with shorter time to clinical remission. Figure 1: Kaplan-Meier curve representing time to clinical remission in patients 13 years old and older by sex. Figure 2: Kaplan-Meier curve representing the time to clinical remission of patients according to the first induction treatment administered. Conclusion Time to clinical remission did not improve during the decade and was associated with baseline clinical and histological data and treatment strategies. Combination of enteral nutrition and TNF-alpha inhibitors was associated with faster clinical remission.

Background Few risk factors are associated with the risk of relapses of Crohn’s disease in children. The aims of this retrospective cohort study were to describe the rate of relapses in children with Crohn’s disease, its evolution over the past decade and to determine risk factors associated with relapse. Methods Patients under 18 years old and diagnosed between 2009 and 2019 were included. Patients clinical, endoscopic, histological, and laboratory characteristics, as well as their treatments, where collected from their medical records and the prospective CHU Sainte-Justine inflammatory bowel disease registry. Survival analyses and Cox regression models were used to assess the impact of those risk factors on relapse. Results 639 patients were included. There was a decrease in the clinical relapse rate over the past decade: 70.9% of patients diagnosed between 2009 and 2014 experienced a relapse compared to 49.1% of patients diagnosed between 2015 and 2019 (p Figure 1: Kaplan-Meier curve representing patients time to relapse according to the first maintenance treatment administered. Conclusion Relapse risk was significantly associated with baseline clinical, endoscopic, histological and laboratory data and treatment strategies. These results could help better select treatment options for pediatric Crohn’s disease at induction and maintenance. Figure 2: Kaplan-Meier curve representing patients time to relapse according to the mean infliximab level in post-induction.

The structural geology and tectonic setting of hydrothermal gold deposits are paramount in understanding their genesis, and for their exploration. Strong structural control on mineralization is one of the defining features of these deposits, and arises because the permeabilities of crustal rocks are too low to allow the formation of hydrothermal deposits on realistic time scales unless rocks are deformed. Deformation zones and networks of deformation zones are the fundamental structures that control mineralization. Systematically analyzing deposit geometry, kinematics and dynamics leads to the most thorough comprehension of a deposit. Geometrical analysis relates ore body shape to controlling structures, and networks of deformation zones can be analyzed using topology to understand their connectivity and mineralizing potential. Kinematic analysis determines the location of permeability creation and mineralization. New views of shear zone kinematics allow for variable ratios of pure to simple shear, which change likely directions of mineralization. Multiple orientations of mineralized deformation zones may form simultaneously and symmetrically about the principal strain axes. Dynamic analysis is necessary for a mechanical understanding of deformation, fluid flow and mineralization, and can be achieved through numerical modeling. The relationship between deformation (kinematics) and stress (dynamics) constitutes the rheology: rheological contrasts are critical for the localization of many deposits. Numerous gold deposits, especially the largest, have evidence for multiple mineralizing events that may be separated by tens to hundreds of millions of years. In these cases, reactivation of structures is common, and a range of orientations of pre-existing structures are predicted to be reactivated, given that they are weaker than intact rock. Physical and chemical processes of mineralization can be integrated using a nonequilibrium thermodynamics approach. Hydrothermal gold deposits form in contractional, strike-slip and extensional tectonic settings. However there may be great variation in the spatial scale over which the tectonic setting applies, and tectonic settings may also change on rapid time scales, so that it is inadvisable to infer local tectonics from deposit-scale patterns, and visa versa. It is essential to place mineralizing events within a complete geological history in order to distinguish pre- and post- mineralizing structures from syn-mineralization deformation features.

We describe a framework for designing the sequences of multiple nucleic acid strands intended to hybridize in solution via a prescribed reaction pathway. Sequence design is formulated as a multistate optimization problem using a set of target test tubes to represent reactant, intermediate, and product states of the system, as well as to model crosstalk between components. Each target test tube contains a set of desired "on-target" complexes, each with a target secondary structure and target concentration, and a set of undesired "off-target" complexes, each with vanishing target concentration. Optimization of the equilibrium ensemble properties of the target test tubes implements both a positive design paradigm, explicitly designing for on-pathway elementary steps, and a negative design paradigm, explicitly designing against off-pathway crosstalk. Sequence design is performed subject to diverse user-specified sequence constraints including composition constraints, complementarity constraints, pattern prevention constraints, and biological constraints. Constrained multistate sequence design facilitates nucleic acid reaction pathway engineering for diverse applications in molecular programming and synthetic biology. Design jobs can be run online via the NUPACK web application.

Significance The complex and often highly dynamic 3D structures of RNA molecules are central to their diverse cellular functions. Molecular dynamics (MD) simulations have played a major role in characterizing the structure and dynamics of proteins, but the physical models (“force fields”) used for simulating nucleic acids are substantially less accurate overall than those used in protein simulations, creating a major challenge for MD studies of RNA. Here, we report an RNA force field capable of describing the structural and thermodynamic properties of RNA molecules with accuracy comparable to state-of-the-art protein force fields. This force field should facilitate the use of MD simulation as a tool for the study of biologically significant RNA molecules and protein–RNA complexes., Molecular dynamics (MD) simulation has become a powerful tool for characterizing at an atomic level of detail the conformational changes undergone by proteins. The application of such simulations to RNA structures, however, has proven more challenging, due in large part to the fact that the physical models (“force fields”) available for MD simulations of RNA molecules are substantially less accurate in many respects than those currently available for proteins. Here, we introduce an extensive revision of a widely used RNA force field in which the parameters have been modified, based on quantum mechanical calculations and existing experimental information, to more accurately reflect the fundamental forces that stabilize RNA structures. We evaluate these revised parameters through long-timescale MD simulations of a set of RNA molecules that covers a wide range of structural complexity, including single-stranded RNAs, RNA duplexes, RNA hairpins, and riboswitches. The structural and thermodynamic properties measured in these simulations exhibited dramatically improved agreement with experimentally determined values. Based on the comparisons we performed, this RNA force field appears to achieve a level of accuracy comparable to that of state-of-the-art protein force fields, thus significantly advancing the utility of MD simulation as a tool for elucidating the structural dynamics and function of RNA molecules and RNA-containing biological assemblies.

BACKGROUND Tattooed persons examined with magnetic resonance imaging (MRI) can develop burning sensation suggested in the literature to be thermal burn from the procedure. MRI-induced thermal effect and magnetic behavior of known tattoo pigments were examined ex vivo. MATERIALS AND METHODS Magnetic resonance imaging effects on 3 commonly used commercial ink stock products marketed for cosmetic tattooing was studied. A main study tested 22 formulations based on 11 pigment raw materials, for example, one line of 11 called pastes and another called dispersions. Samples were spread in petri dishes and tested with a 0.97 T neodymium solid magnet to observe visual magnetic behavior. Before MRI, the surface temperature of the ink was measured using an infrared probe. Samples were placed in a clinical 3T scanner. Two scans were performed, that is, one in the isocenter and one 30 cm away from the center. After scanning, the surface temperature was measured again. Chemical analysis of samples was performed by mass spectroscopy. RESULTS Mean temperature increase measured in the isocenter ranged between 0.14 and 0.26°C (P

The evaluation of electrostatic energy for a set of point charges in a periodic lattice is a computationally expensive part of molecular dynamics simulations (and other applications) because of the long-range nature of the Coulomb interaction. A standard approach is to decompose the Coulomb potential into a near part, typically evaluated by direct summation up to a cutoff radius, and a far part, typically evaluated in Fourier space. In practice, all decomposition approaches involve approximations---such as cutting off the near-part direct sum---but it may be possible to find new decompositions with improved tradeoffs between accuracy and performance. Here we present the $\textit{u-series}$, a new decomposition of the Coulomb potential that is more accurate than the standard (Ewald) decomposition for a given amount of computational effort, and achieves the same accuracy as the Ewald decomposition with approximately half the computational effort. These improvements, which we demonstrate numerically using a lipid membrane system, arise because the $\textit{u}$-series is smooth on the entire real axis and exact up to the cutoff radius. Additional performance improvements over the Ewald decomposition may be possible in certain situations because the far part of the $\textit{u}$-series is a sum of Gaussians, and can thus be evaluated using algorithms that require a separable convolution kernel; we describe one such algorithm that reduces communication latency at the expense of communication bandwidth and computation, a tradeoff that may be advantageous on modern massively parallel supercomputers.

Molecular simulations aim to sample all of the thermodynamically important states; when the sampling is inadequate, inaccuracy follows. A widely used technique to enhance sampling in simulations is Hamiltonian exchange. This technique introduces auxiliary Hamiltonians under which sampling is computationally efficient and attempts to exchange the molecular states among the auxiliary and the original Hamiltonians. The effectiveness of Hamiltonian exchange depends in part on the probability that the trial exchanges can be accepted, which involves good choices of auxiliary Hamiltonians and a good method of generating the trial exchanges. In this paper, we investigate nonequilibrium simulations as trial exchange generators and develop a theoretical model for the efficiency of Hamiltonian exchange and an algorithm to better configure such simulations. We show that properly configured nonequilibrium simulations can modestly increase the overall efficiency of Hamiltonian exchange.

Thirty-six novel human leukocyte antigen (HLA) alleles are described in this article: A*9225N, A*9234, A*030106, A*0337, A*2317, A*2480, A*3023; B*070206, B*0759, B*0761, B*0765, B*150106, B*1827, B*352002, B*3585, B*3943, B*4082, B*5151; Cw*0342, Cw*0343, Cw*0344, Cw*0428, Cw*0430, Cw*0433, Cw*050104, Cw*0519, Cw*060203, Cw*070109, Cw*070202, Cw*0750, Cw*0815, Cw*120306, Cw*1409; DRB1*0336, DRB1*0473 and DRB1*1382.

Contexte L’ustekinumab est un anticorps monoclonal dirige contre la sous-unite p40 de l’interleukine-12/23. Il a ete montre superieur au placebo dans l’induction de la reponse et le maintien de la remission chez les patients adultes atteints de maladie de Crohn moderee a severe, mais pas encore etudie en pediatrie. Buts de l’etude Decrire la securite et l’efficacite de l’ustekinumab chez les enfants atteints de maladie de Crohn refractaire. Methodes Nous rapportons six patients (4 garcons) qui ont recu de l’ustekinumab dans notre centre entre fevrier et octobre 2014 pour maladie de Crohn refractaire aux anti-TNF. Resultats L’âge median au debut de l’ustekinumab etait de 16,4 ans (10,7–18,2) et la duree mediane de la maladie etait de 3,6 ans (1,0–8,4). La localisation de la maladie distale selon la classification de Paris etait L1 chez 1 patient, L3 chez 4 et pas atteinte colique chez 1 ; la localisation haute etait : L4a chez 2 patients et L4b chez 2. Le phenotype etait non penetrant non stenosant dans 5 cas et stenosant dans 1. Aucun patient n’avait de maladie perianale. Tous les patients avaient echoue ou etaient intolerants aux immunomodulateurs (5 patients a l’azathioprine, 6 au methotrexate). Tous avaient eu un echec d’infliximab (2 avaient interrompu pour perte de reponse, 2 pour allergies ou evenements indesirables et 2 pour les deux raisons). Cinq patients avaient echoue a l’adalimumab, et un n’en avait pas recu. Un patient avait eu deux resections intestinales avec stricturoplasties. A l’initiation de l’ustekinumab, quatre patients etaient sous prednisone et 3 sous methotrexate. L’ustekinumab etait administree par voie sous-cutanee a la dose de 45 mg (si le poids ≤ 45 kg) par semaine ou 90 mg (si le poids > 45 kg) par semaine, pendant trois semaines pendant le traitement d’induction. Apres le traitement d’induction, 3 patients ont eu une reponse clinique, 1 etait en remission clinique et 2 n’ont pas eu de reponse. Cinq patients ont continue le traitement d’entretien de 45 mg toutes les 8 semaines ou 90 mg toutes les 8 semaines en fonction de la posologie recue lors de l’induction. Une augmentation de la dose etait necessaire dans deux cas. Au total, les patients ont recu une mediane de 6,5 doses (3–9) d’ustekinumab. La reponse au traitement d’entretien a ete evaluee apres une periode mediane de 5,1 mois (3,7 a 7,1) : 1 patient etait en remission clinique, 2 avaient une reponse clinique et 2 n’ont eu aucune reponse, dont l’un a necessite une colectomie subtotale avec ileostomie. Aucun evenement indesirable n’a ete note. Conclusions L’ustekinumab est bien tolere chez les patients pediatriques. Plus de donnees sont necessaires pour confirmer l’efficacite montree chez l’adulte.

Previous studies have shown that popping volume of popcorn is affected by water content, and that popping volume increases with an increase in water content up to an optimal value, and then the volume decreases with any additional moisture. The aim of this study was to explore the mechanism responsible for the peak in popping volume as a function of water content. Popcorn was equilibrated to various water contents from 6.7 to 16.5 g/100 g d.b. over salt solutions (aw0.33–0.82), and popped by an air popper. Maximal popping volume occurred at a water content of 15.5 g/100 g d.b. (aw=0.745 at room temperature) while the popping temperature dropped with increasing water content. Thermal analysis of the popcorn by DSC showed no significant effect of the moisture on the melting temperature orTg of the unpopped endosperm. However, the decrease of the pericarp melting temperature correlated with an increased water content. The results suggest that elevated water contents cause a rubbery collapse of the pericarp at lower temperature. The temperature of this melting event decreases by ∼7 °C over the 6–16.5 g/100 g moisture range. Thus, as the water content increases, the pressure in the kernel at the popping moment is lower, causing less expansion and lower final popped volume.

Aerodynamic measurements of latent (λE) and sensible heat (H) exchange were made in an intensively managed peat pasture during 2 consecutive years; the fetch was approximately 1.5 km. The surface conductance (gs) was calculated from the Penman-Monteith equation. The analysis focused on 2 successive aspects of gs: gs as a function of environment (primarily vapour pressure deficit (D)) and the energy balance as a function of gs. The effect of D on gs consisted of 2 components: the range of D over which gs was reduced (beyond inflection point Di) and the reducing effect per unit D. As average D increased, so did inflection point Di and the range of D over which gs was reduced; the reducing effect per unit D decreased. gs was a strong mediator in the energy balance. λE increased with D upto the inflection point Di, beyond which gs increasingly offset the positive effect of D. As gs impaired λE, the surface to air temperature difference (Δ T) and consequently H increased. With increasing gs, λE and H added up to progressively lower values, suggesting an increasing soil heat flux. Hysteresis in the diurnal patterns of the energy balance showed that the positive effect of D on λE remained stronger than the consequent negative effect of gs. λE was higher after than before noon, whereas ΔT and H were lower.

Intergovernmental Panel on Climate Change (IPCC) estimates indicate that potential changes in seasonal rainfall and temperature patterns in central North America and the African Sahel will have a greater impact on biological response (such as plant production and biogeochemical cycling) and feedback to climate than changes in the overall amount of annual rainfall. Simulation of grassland and dryland ecosystem responses to climate and CO2 changes demonstrates the sensitivity of plant productivity and soil C storage to projected changes in precipitation, temperature and atmospheric CO2. Using three different land cover projections, changes in C levels in the grassland and dryland regions from 1800 to 1990 were estimated to be -13.2, -25.5 and -14.7 Pg, i.e., a net source of C due to land cover removal resulting from cropland conversion. Projections into the future based on a double-CO2 climate including climate-driven shifts in biome areas by the year 2040 resulted in a net sink of +5.6, +27.4 and +26.8 Pg, respectively, based upon sustainable grassland management. The increase in C storage resulted mainly from an increase in area for the warm grassland sub-biome, together with increased soil organic matter. Preliminary modeling estimates of soil C losses due to 50 yr of regressive land management in these grassland and dryland ecoregions result in a 11 Pg loss relative to current conditions, and a potential loss of 37 Pg during a 50 yr period relative to sustainable land-use practices, an average source of 0.7 Pg C yr-1. Estimates of the cost of a 20 yr rehabilitation program are 5 to 8 x 109 US$ yr-1, for a C sequestering cost of approximately 10 US$ per tC.

Cancer cells are characterized by genetic mutations that deregulate cell proliferation and suppress cell death. To arrest the uncontrolled replication of malignant cells, conventional chemotherapies systemically disrupt cell division, causing diverse and often severe side effects as a result of collateral damage to normal cells. Seeking to address this shortcoming, we pursue therapeutic regulation that is conditional, activating selectively in cancer cells. This functionality is achieved using small conditional RNAs that interact and change conformation to mechanically transduce between detection of a cancer mutation and activation of a therapeutic pathway. Here, we describe small conditional RNAs that undergo hybridization chain reactions (HCR) to induce cell death via an innate immune response if and only if a cognate mRNA cancer marker is detected within a cell. The sequences of the small conditional RNAs can be designed to accept different mRNA markers as inputs to HCR transduction, providing a programmable framework for selective killing of diverse cancer cells. In cultured human cancer cells (glioblastoma, prostate carcinoma, Ewing’s sarcoma), HCR transduction mediates cell death with striking efficacy and selectivity, yielding a 20- to 100-fold reduction in population for cells containing a cognate marker, and no measurable reduction otherwise. Our results indicate that programmable mechanical transduction with small conditional RNAs represents a fundamental principle for exploring therapeutic conditional regulation in living cells.

The Nucleic Acid Package (NUPACK) is a growing software suite for the analysis and design of nucleic acid systems. The NUPACK web server (http://www.nupack.org) currently enables: •Analysis: thermodynamic analysis of dilute solutions of interacting nucleic acid strands. •Design: sequence design for complexes of nucleic acid strands intended to adopt a target secondary structure at equilibrium. •Utilities: evaluation, display, and annotation of equilibrium properties of a complex of nucleic acid strands. NUPACK algorithms are formulated in terms of nucleic acid secondary structure. In most cases, pseudoknots are excluded from the structural ensemble.

New Rb/Sr biotite dates for the Tia Granodiorite of 264 ± 2.6 Ma and 262 ± 2.6 Ma are considerably younger than the 290 ± 4 Ma Rb/Sr whole rock dates from the Hillgrove Plutonic Suite (including the Tia Granodiorite). The whole rock dates mark the approximate emplacement age of the plutons. The Tia Granodiorite exhibits two distinct biotite fabrics both of which formed during west over east movements on a ductile shear zone directly east of the pluton. Structural analysis suggests that the earliest fabric, formed synchronous with emplacement of the granodiorite in the hanging wall of the ductile shear zone. The later fabric probably formed during a major faulting event that juxtaposed this area against unmetamorphosed Permian strata of the Manning Basin to the west and the Yarrowitch Block to the east.

The presence of polyphase shear zones transected by several suites of dolerite dykes in Archaean basement of the Vestfold Hills, East Antarctica, allows a detailed reconstruction of the local structural evolution. Archaean and early Proterozoic deformation at granulite facies conditions was followed by two phases of dolerite intrusion and mylonite generation in strike-slip zones at amphibolite facies conditions. A subsequent middle Proterozoic phase of brittle normal faulting led to the development of pseudotachylite, predating intrusion of the major swarm of dolerite dykes around 1250 Ma. During the later stages and following this event, pseudotachylite veins were reactivated as ductile, mylonitic thrusts under prograde conditions, culminating in amphibolite facies metamorphism around 1000–1100 Ma. This is possibly part of a large-scale tectonic event during which the Vestfold block was overthrust from the south. In a final phase of strike-slip deformation, several pulses of pseudotachylite-generating brittle faulting alternated with ductile reactivation of pseudotachylite.

Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, MD, {Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile, {Centre for Diarrheal Disease and Nutrition Research, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India, §Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Melbourne, Australia, jjDivision of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Hopital Sainte-Justine, University of Montreal, Montreal, Canada, Departments of Pediatrics, Leiden University Medical Center and Free University Medical Center, Amsterdam, the Netherlands, {{Pediatric Gastroenterology and Nutrition Unit, Ntra Sra de Candelaria Universitary Hospital School of Medicine

We present a synthetic molecular motor capable of autonomous nanoscale transport in solution. Inspired by bacterial pathogens such as Rickettsia rickettsii, which locomote by inducing the polymerization of the protein actin at their surfaces to form 'comet tails', the motor operates by polymerizing a double-helical DNA tail2. DNA strands are propelled processively at the living end of the growing polymers, demonstrating autonomous locomotion powered by the free energy of DNA hybridization.

Tower CO2 flux measurements from 20 European grasslands in the EUROGRASSFLUX data set covering a wide range of environmental and management conditions were analyzed with respect to their ecophysiological characteristics and CO2 exchange (gross primary production, P g, and ecosystem respiration, R e) using light-response function analysis. Photosynthetically active radiation (Q ) and top-soil temperature (T s) were identified as key factors controlling CO2 exchange between grasslands and the atmosphere at the 30-min scale. A nonrectangular hyperbolic light-response model P (Q ) and modified nonrectangular hyperbolic light–temperature-response model P (Q , T s) proved to be flexible tools for modeling CO2 exchange in the light. At night, it was not possible to establish robust instantaneous relationships between CO2 evolution rate r n and environmental drivers, though under certain conditions, a significant relationship rn=r0 ekTTsrn=r0 ekTTs was found using observation windows 7–14 days wide. Principal light-response parameters—apparent quantum yield, saturated gross photosynthesis, daytime ecosystem respiration, and gross ecological light-use efficiency, ɛ = Pg/Q, display patterns of seasonal dynamics which can be formalized and used for modeling. Maximums of these parameters were found in intensively managed grasslands of Atlantic climate. Extensively used semi-natural grasslands of southern and central Europe have much lower production, respiration, and light-use efficiency, while temperate and mountain grasslands of central Europe ranged between these two extremes. Parameters from light–temperature-response analysis of tower data are in agreement with values obtained using closed chambers and free-air CO2 enrichment. Correlations between light-response and productivity parameters provides the possibility to use the easier to measure parameters to estimate the parameters that are more difficult to measure. Gross primary production (Pg) of European grasslands ranges from 1700 g CO2 m−2 year−1 in dry semi-natural pastures to 6900 g CO2 m−2 year−1 in intensively managed Atlantic grasslands. Ecosystem respiration (Re) is in the range 1800 2400 g CO2 m−2 year−1) to significant release (Tower CO2 flux measurements from 20 European grasslands in the EUROGRASSFLUX data set covering a wide range of environmental and management conditions were analyzed with respect to their ecophysiological characteristics and CO2 exchange (gross primary production, P-g, and ecosystem respiration, R-e) using light-response function analysis. Photosynthetically active radiation (Q) and top-soil temperature (T-s) were identified as key factors controlling CO2 exchange between grasslands and the atmosphere at the 30-min scale. A nonrectangular hyperbolic light-response model P(Q) and modified nonrectangular hyperbolic light-temperature-response model P(Q, T-s) proved to be flexible tools for modeling CO2 exchange in the light. At night, it was not possible to establish robust instantaneous relationships between CO2 evolution rate r(n) and environmental drivers, though under certain conditions, a significant relationship r(n) = r(0) e(kTTs) was found using observation windows 7-14 days wide. Principal light-response parameters-apparent quantum yield, saturated gross photosynthesis, daytime ecosystem respiration, and gross ecological light-use efficiency, epsilon = P-g/Q, display patterns of seasonal dynamics which can be formalized and used for modeling. Maximums of these parameters were found in intensively managed grasslands of Atlantic climate. Extensively used semi-natural grasslands of southern and central Europe have much lower production, respiration, and light-use efficiency, while temperate and mountain grasslands of central Europe ranged between these two extremes. Parameters from light-temperature-response analysis of tower data are in agreement with values obtained using closed chambers and free-air CO, enrichment. Correlations between light-response and productivity parameters provides the possibility to use the easier to measure parameters to estimate the parameters that are more difficult to measure. Gross primary production (P,) of European grasslands ranges from 1700 g CO2 m(-2) year(-1) in dry semi-natural pastures to 6900 g CO2 m(-2) year(-1) in intensively managed Atlantic grasslands. Ecosystem respiration (R-e) is in the range 1800 2400 g CO2 m(-2) year(-1)) to significant release (

Over the past decade, specialist services for stroke patients have been introduced, and evidence suggests that they are both effective and efficient. 1–5 In many European countries, these services consist of stroke units in hospitals, rehabilitation facilities and community care organizations. In such networks, health professionals and organizations must coordinate their work to ensure that patients receive appropriate timely care, in appropriate settings. However, the pathway from stroke onset to hospital treatment is often far from seamless. Many stroke patients are admitted too late for appropriate treatment, or not at all. With the increasing effectiveness of acute stroke unit care and of thrombolysis, it is vital that this situation changes. If patients with an acute ischaemic stroke receive thrombolytic therapy within 3 h, they have an increased chance of recovery with a good outcome. 6 We therefore need to identify and use tools and strategies for creating an effective and efficient continuum of care for acute stroke patients. 7,,8 In this paper, we summarize the evidence in favour of a beneficial effect of intravenous thrombolysis, explore the barriers for the delivery of this treatment, suggest ways to overcome these barriers, and discuss an approach to measuring improvements in the organization of stroke care. The NINDS-rtPA trial is the only phase III trial of thrombolysis for acute ischaemic stroke that showed an unequivocal positive result. 9 In this study, patients were treated with intravenous alteplase within 3 h from onset of symptoms. Other trials showed no comparable results, partly because of difficulties with the design and choice of outcome parameters, and perhaps also because of a longer (6 h) time window, and higher doses of thrombolytic agent. 10 Wardlaw and colleagues 10 included all published randomized controlled trials of thrombolysis in a Cochrane review. They concluded that thrombolytic therapy, administered up to …

We introduce the concept of hybridization chain reaction (HCR), in which stable DNA monomers assemble only upon exposure to a target DNA fragment. In the simplest version of this process, two stable species of DNA hairpins coexist in solution until the introduction of initiator strands triggers a cascade of hybridization events that yields nicked double helices analogous to alternating copolymers. The average molecular weight of the HCR products varies inversely with initiator concentration. Amplification of more diverse recognition events can be achieved by coupling HCR to aptamer triggers. This functionality allows DNA to act as an amplifying transducer for biosensing applications.

Given a nucleic acid sequence, a recent algorithm allows the calculation of the partition function over secondary structure space including a class of physically relevant pseudoknots. Here, we present a method for computing base-pairing probabilities starting from the output of this partition function algorithm. The approach relies on the calculation of recursion probabilities that are computed by backtracking through the partition function algorithm, applying a particular transformation at each step. This transformation is applicable to any partition function algorithm that follows the same basic dynamic programming paradigm. Base-pairing probabilities are useful for analyzing the equilibrium ensemble properties of natural and engineered nucleic acids, as demonstrated for a human telomerase RNA and a synthetic DNA nanostructure.

The design of DNA and RNA sequences is critical for many endeavors, from DNA nanotechnology, to PCR-based applications, to DNA hybridization arrays. Results in the literature rely on a wide variety of design criteria adapted to the particular requirements of each application. Using an extensively studied thermodynamic model, we perform a detailed study of several criteria for designing sequences intended to adopt a target secondary structure. We conclude that superior design methods should explicitly implement both a positive design paradigm (optimize affinity for the target structure) and a negative design paradigm (optimize specificity for the target structure). The commonly used approaches of sequence symmetry minimization and minimum free-energy satisfaction primarily implement negative design and can be strengthened by introducing a positive design component. Surprisingly, our findings hold for a wide range of secondary structures and are robust to modest perturbation of the thermodynamic parameters used for evaluating sequence quality, suggesting the feasibility and ongoing utility of a unified approach to nucleic acid design as parameter sets are refined further. Finally, we observe that designing for thermodynamic stability does not determine folding kinetics, emphasizing the opportunity for extending design criteria to target kinetic features of the energy landscape.

Nucleic acid secondary structure models usually exclude pseudoknots due to the difficulty of treating these nonnested structures efficiently in structure prediction and partition function algorithms. Here, the standard secondary structure energy model is extended to include the most physically relevant pseudoknots. We describe an O(N(5)) dynamic programming algorithm, where N is the length of the strand, for computing the partition function and minimum energy structure over this class of secondary structures. Hence, it is possible to determine the probability of sampling the lowest energy structure, or any other structure of particular interest. This capability motivates the use of the partition function for the design of DNA or RNA molecules for bioengineering applications.

To compare the safety and efficacy of bimatoprost and latanoprost in patients with primary open-angle glaucoma or ocular hypertension.This was a 30-day, multicenter, double-masked, randomized, clinical trial. Patients (n = 64) diagnosed with primary open-angle glaucoma or ocular hypertension were randomly assigned to receive bimatoprost 0.03%, latanoprost 0.005%, or vehicle topically in both eyes once daily, in the evening, for 29 days. The primary endpoint was the reduction in IOP from baseline on day 14 and day 29. Secondary outcome measures included eye examinations and safety parameters.Bimatoprost and latanoprost significantly lowered IOP from baseline (p.001). Bimatoprost lowered IOP more than latanoprost at every timepoint measured (bimatoprost: 25-34% reduction, 5.9-8.9 mm Hg; latanoprost: 20-31% reduction, 4.4-7.9 mm Hg), although the between-group differences did not reach statistical significance. Over the 12-hour course of IOP measurements on day 29, bimatoprost provided better diurnal IOP control than latanoprost (p =.0378, area under the curve of diurnal IOP reductions, 1-way ANOVA with pairwise t-test). Both treatment regimens were safe and well tolerated, with no significant between-group differences in reports of specific adverse events. The most common side effect was conjunctival hyperemia, which was similarly apparent in the bimatoprost and latanoprost treatment groups.At the end of this 30-day trial, once-daily bimatoprost 0.03% provided better diurnal IOP control than latanoprost and was safe and well tolerated in patients with ocular hypertension and glaucoma.

We investigate the decay of metastable states with broken CP-symmetry which have recently been proposed by Kharzeev, Pisarski and Tytgat to form in hot hadronic matter. We consider the efficiency of the amplification of the $\eta'$-field via parametric resonance, taking the backreaction into account. For times of the order $t\approx 10 fm$, we find a particle density of about $0.7/fm^3$ and a correlation length of $\xi_{max}\approx 2.5 fm$. The corresponding momentum spectra show a non-thermal behaviour., Comment: 11 pages latex file with 4 gif - figures. Uses elsart.cls (included)