Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children with Autoimmune Cytopenia

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients

Development of a dynamic energy-partitioning model for enteric methane emissions and milk production in goats using energy balance data from indirect calorimetry studies

[EN] The main objective of this study was to develop a dynamic energy balance model for dairy goats to describe and quantify energy partitioning between energy used for work (milk) and that lost to the environment. Increasing worldwide concerns regarding livestock contribution to global warming underscore the importance of improving energy efficiency utilization in dairy goats by reducing energy losses in feces, urine and methane (CH4). A dynamic model of CH(4)emissions from experimental energy balance data in goats is proposed and parameterized (n= 48 individual animal observations). The model includes DM intake, NDF and lipid content of the diet as explanatory variables for CH(4)emissions. An additional data set (n= 122 individual animals) from eight energy balance experiments was used to evaluate the model. The model adequately (root MS prediction error,RMSPE) represented energy in milk (E-milk;RMSPE = 5.6%), heat production (HP;RMSPE = 4.3%) and CH(4)emissions (E-CH4; RMSPE = 11.9%). Residual analysis indicated that most of the prediction errors were due to unexplained variations with small mean and slope bias. Some mean bias was detected for HP (1.12%) and E-CH4(1.27%) but was around zero for E-milk (0.14%). The slope bias was zero for HP (0.01%) and close to zero for E-milk (0.10%) and E-CH4(0.22%). Random bias was >98% for E-CH4, HP and E-milk, indicating non-systematic errors and that mechanisms in the model are properly represented. As predicted energy increased, the model tended to underpredict E-CH(4)and E-milk. The model is a first step toward a mechanistic description of nutrient use by goats and is useful as a research tool for investigating energy partitioning during lactation. The model described in this study could be used as a tool for making enteric CH(4)emission inventories for goats.This study was supported by LOW CARBON FEED Project reference LIFE2016/CCM/ES/000088.Fernández Martínez, CJ.; Hernando, I.; Moreno-Latorre, E.; Loor, J. (2020). Development of a dynamic energy-partitioning model for enteric methane emissions and milk production in goats using energy balance data from indirect calorimetry studies. Animal. 14:s382-s395. https://doi.org/10.1017/S1751731120001470Ss382s39514Agricultural and Food Research Council (AFRC) 1997. The nutrition of goats. Nutrition Abstract and Reviews (Series B) 67, 776–861.Aguilera, J. F., Prieto, C., & FonollÁ, J. (1990). Protein and energy metabolism of lactating Granadina goats. British Journal of Nutrition, 63(2), 165-175. doi:10.1079/bjn19900104Bannink, A., France, J., Lopez, S., Gerrits, W. J. J., Kebreab, E., Tamminga, S., & Dijkstra, J. (2008). Modelling the implications of feeding strategy on rumen fermentation and functioning of the rumen wall. Animal Feed Science and Technology, 143(1-4), 3-26. doi:10.1016/j.anifeedsci.2007.05.002Bava, L., Rapetti, L., Crovetto, G. M., Tamburini, A., Sandrucci, A., Galassi, G., & Succi, G. (2001). Effects of a Nonforage Diet on Milk Production, Energy, and Nitrogen Metabolism in Dairy Goats throughout Lactation. Journal of Dairy Science, 84(11), 2450-2459. doi:10.3168/jds.s0022-0302(01)74695-4Beauchemin K, McAllister T and McGinn S 2009. Dietary mitigation of enteric CH4 from cattle. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources 4, 035.Blaxter, K. L., & Clapperton, J. L. (1965). Prediction of the amount of methane produced by ruminants. British Journal of Nutrition, 19(1), 511-522. doi:10.1079/bjn19650046Brouwer E 1965. Report of sub-committee on constants and factors. In Proceeding of the 3th EAAP Symposium on Energy Metabolism (ed. KL Blaxter ), pp. 441–443. Academic Press, London, UK.Criscioni, P., Marti, J. V., Pérez-Baena, I., Palomares, J. L., Larsen, T., & Fernández, C. (2016). Replacement of alfalfa hay ( Medicago sativa ) with maralfalfa hay ( Pennisetum sp.) in diets of lactating dairy goats. Animal Feed Science and Technology, 219, 1-12. doi:10.1016/j.anifeedsci.2016.05.020Ellis, J. L., Kebreab, E., Odongo, N. E., McBride, B. W., Okine, E. K., & France, J. (2007). Prediction of Methane Production from Dairy and Beef Cattle. Journal of Dairy Science, 90(7), 3456-3466. doi:10.3168/jds.2006-675Statistical data base Food and Agriculture Organization (FAOSTAT) 2018. FAO Statistical data base Food and Agriculture Organization of the United Nations, Rome, Italy. Retrieved on 25 June 2018 from http://faostat.fao.org/FERNÁNDEZ, C., LÓPEZ, M. C., & LACHICA, M. (2015). Low-cost mobile open-circuit hood system for measuring gas exchange in small ruminants: from manual to automatic recording. The Journal of Agricultural Science, 153(7), 1302-1309. doi:10.1017/s0021859615000416Fernández, C., Martí, J. V., Pérez-Baena, I., Palomares, J. L., Ibáñez, C., & Segarra, J. V. (2018). Effect of lemon leaves on energy and C–N balances, methane emission, and milk performance in Murciano-Granadina dairy goats. Journal of Animal Science, 96(4), 1508-1518. doi:10.1093/jas/sky028Fernández, C. (2018). Dynamic model development of enteric methane emission from goats based on energy balance measured in indirect open circuit respiration calorimeter. Global Ecology and Conservation, 15, e00439. doi:10.1016/j.gecco.2018.e00439Fernández, C., Pérez-Baena, I., Marti, J. V., Palomares, J. L., Jorro-Ripoll, J., & Segarra, J. V. (2019). Use of orange leaves as a replacement for alfalfa in energy and nitrogen partitioning, methane emissions and milk performance of murciano-granadina goats. Animal Feed Science and Technology, 247, 103-111. doi:10.1016/j.anifeedsci.2018.11.008Fernández, C., Gomis-Tena, J., Hernández, A., & Saiz, J. (2019). An Open-Circuit Indirect Calorimetry Head Hood System for Measuring Methane Emission and Energy Metabolism in Small Ruminants. Animals, 9(6), 380. doi:10.3390/ani9060380Grainger, C., & Beauchemin, K. A. (2011). Can enteric methane emissions from ruminants be lowered without lowering their production? Animal Feed Science and Technology, 166-167, 308-320. doi:10.1016/j.anifeedsci.2011.04.021Howarth, R. (2015). Methane emissions and climatic warming risk from hydraulic fracturing and shale gas development: implications for policy. Energy and Emission Control Technologies, 45. doi:10.2147/eect.s61539Hristov, A. N., Kebreab, E., Niu, M., Oh, J., Bannink, A., Bayat, A. R., … Yu, Z. (2018). Symposium review: Uncertainties in enteric methane inventories, measurement techniques, and prediction models. Journal of Dairy Science, 101(7), 6655-6674. doi:10.3168/jds.2017-13536Ibáñez, C., López, M. C., Criscioni, P., & Fernández, C. (2015). Effect of replacing dietary corn with beet pulp on energy partitioning, substrate oxidation and methane production in lactating dairy goats. Animal Production Science, 55(1), 56. doi:10.1071/an13119Institute Nationale Recherche Agronomique (INRA) 2017. Feeding system for ruminants. Wageningen Academic Publishers, Wageningen, the Netherlands.Jørgensen, S. E. (2015). New method to calculate the work energy of information and organisms. Ecological Modelling, 295, 18-20. doi:10.1016/j.ecolmodel.2014.09.001Kebreab, E., Johnson, K. A., Archibeque, S. L., Pape, D., & Wirth, T. (2008). Model for estimating enteric methane emissions from United States dairy and feedlot cattle1. Journal of Animal Science, 86(10), 2738-2748. doi:10.2527/jas.2008-0960Knapp, J. R., Laur, G. L., Vadas, P. A., Weiss, W. P., & Tricarico, J. M. (2014). Invited review: Enteric methane in dairy cattle production: Quantifying the opportunities and impact of reducing emissions. Journal of Dairy Science, 97(6), 3231-3261. doi:10.3168/jds.2013-7234Lin, L. I.-K. (1989). A Concordance Correlation Coefficient to Evaluate Reproducibility. Biometrics, 45(1), 255. doi:10.2307/2532051López, M. C., Estellés, F., Moya, V. J., & Fernández, C. (2014). Use of dry citrus pulp or soybean hulls as a replacement for corn grain in energy and nitrogen partitioning, methane emissions, and milk performance in lactating Murciano-Granadina goats. Journal of Dairy Science, 97(12), 7821-7832. doi:10.3168/jds.2014-8424López, M. C., & Fernández, C. (2013). Energy partitioning and substrate oxidation by Murciano-Granadina goats during mid lactation fed soy hulls and corn gluten feed blend as a replacement for corn grain. Journal of Dairy Science, 96(7), 4542-4552. doi:10.3168/jds.2012-6473Martí JV, Pérez-Baena I and Fernández C 2012. Replacement of barley grain with lemon pulp on energy partitioning in lactating goats. Unpublished.Merino, P., Ramirez-Fanlo, E., Arriaga, H., del Hierro, O., Artetxe, A., & Viguria, M. (2011). Regional inventory of methane and nitrous oxide emission from ruminant livestock in the Basque Country. Animal Feed Science and Technology, 166-167, 628-640. doi:10.1016/j.anifeedsci.2011.04.081Mills, J. A. N., Kebreab, E., Yates, C. M., Crompton, L. A., Cammell, S. B., Dhanoa, M. S., … France, J. (2003). Alternative approaches to predicting methane emissions from dairy cows1. Journal of Animal Science, 81(12), 3141-3150. doi:10.2527/2003.81123141xMoorby, J. M., Fleming, H. R., Theobald, V. J., & Fraser, M. D. (2015). Can live weight be used as a proxy for enteric methane emissions from pasture-fed sheep? Scientific Reports, 5(1). doi:10.1038/srep17915Niu, M., Kebreab, E., Hristov, A. N., Oh, J., Arndt, C., Bannink, A., … Yu, Z. (2018). Prediction of enteric methane production, yield, and intensity in dairy cattle using an intercontinental database. Global Change Biology, 24(8), 3368-3389. doi:10.1111/gcb.14094Patra, A. K., & Lalhriatpuii, M. (2016). Development of statistical models for prediction of enteric methane emission from goats using nutrient composition and intake variables. Agriculture, Ecosystems & Environment, 215, 89-99. doi:10.1016/j.agee.2015.09.018Pérez-Baena I, Martí JV and Fernández C 2012. Effect of replace barley grain with beet pulp in lactating goats diet; energy balance and milk performance. Unpublished.R Core Team 2016. R: A language and environment for statistical computing. Version 1.1.447. R Foundation for Statistical Computing, Vienna, Austria. Retrieved from https://www.R-project.org/Ramin, M., & Huhtanen, P. (2013). Development of equations for predicting methane emissions from ruminants. Journal of Dairy Science, 96(4), 2476-2493. doi:10.3168/jds.2012-6095Tovar-Luna, I., Puchala, R., Sahlu, T., Freetly, H. C., & Goetsch, A. L. (2010). Effects of stage of lactation and dietary concentrate level on energy utilization by Alpine dairy goats. Journal of Dairy Science, 93(10), 4818-4828. doi:10.3168/jds.2010-3315United Nations Framework Convention on Climate Change 2015. UN Climate Change Newsroom. Historic Paris agreement on climate change. 195 nations set path to keep temperature rise well below 2 degrees Celsius. Retrieved on 1 July 2018 from http://newsroom.unfccc.int/unfccc-newsroom/finale-cop21/Yan, T., Porter, M. G., & Mayne, C. S. (2009). Prediction of methane emission from beef cattle using data measured in indirect open-circuit respiration calorimeters. Animal, 3(10), 1455-1462. doi:10.1017/s175173110900473

Protecting the environment through insect farming as a means to produce protein for use as livestock, poultry, and aquaculture feed

Securing protein for the approximate 10 billion humans expected to inhabit our planet by 2050 is a major priority for the global community. Evidence has accrued over the past 30 years that strongly supports and justifies the sustainable use of insects as a means to produce protein products as feed for pets, livestock, poultry, and aquacultured species. Researchers and entrepreneurs affiliated with universities and industries, respectively, from 18 nations distributed across North and South America, Europe, Asia, Africa and Australia contributed to the development of this article, which is an indication of the global interest on this topic. A brief overview of insects as feed for the aquaculture industry along with a review of the black soldier fly, Hermetia illucens (Diptera: Stratiomyidae), as a model for such systems is provided

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-κB

Background:Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs.Methods:To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-kappaB (NF-kappaB) inactivation in the chemosensitising effect of monoHER.Results:MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-kappaB activation.Conclusion:These results suggest that reduction of doxorubicin-induced NF-kappaB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells

Social cognition in people with schizophrenia: A cluster-analytic approach

Background The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. Method A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. Results We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI &lt;10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. Conclusions If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person

White Matter Development in Early Puberty: A Longitudinal Volumetric and Diffusion Tensor Imaging Twin Study

White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ∼85%), surface area (∼85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = –0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p&nbsp;= 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p&nbsp;= 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Advancing a Conceptual Model of Evidence-Based Practice Implementation in Public Service Sectors

Implementation science is a quickly growing discipline. Lessons learned from business and medical settings are being applied but it is unclear how well they translate to settings with different historical origins and customs (e.g., public mental health, social service, alcohol/drug sectors). The purpose of this paper is to propose a multi-level, four phase model of the implementation process (i.e., Exploration, Adoption/Preparation, Implementation, Sustainment), derived from extant literature, and apply it to public sector services. We highlight features of the model likely to be particularly important in each phase, while considering the outer and inner contexts (i.e., levels) of public sector service systems