Improved inference for a boundary parameter

The limiting distributions of statistics used to test hypotheses about parameters on the boundary of their domains may provide very poor approximations to the finite-sample behaviour of these statistics, even for very large samples. We review theoretical work on this problem, describe hard and soft boundaries and iceberg estimators, and give examples highlighting how the limiting results greatly underestimate the probability that the parameter lies on its boundary even in very large samples. We propose and evaluate some simple remedies for this difficulty based on normal approximation for the profile score function, and then outline how higher order approximations yield excellent results in a range of hard and soft boundary examples. We use the approach to develop an accurate test for the need for a spline component in a linear mixed model

Requirements for a Dashboard to Support Quality Improvement Teams in Pain Management

Pain management is often considered lower priority than many other aspects of health management in hospitals. However, there is potential for Quality Improvement (QI) teams to improve pain management by visualising and exploring pain data sets. Although dashboards are already used by QI teams in hospitals, there is limited evidence of teams accessing visualisations to support their decision making. This study aims to identify the needs of the QI team in a UK Critical Care Unit (CCU) and develop dashboards that visualise longitudinal data on the efficacy of patient pain management to assist the team in making informed decisions to improve pain management within the CCU. This research is based on an analysis of transcripts of interviews with healthcare professionals with a variety of roles in the CCU and their evaluation of probes. We identified two key uses of pain data: direct patient care (focusing on individual patient data) and QI (aggregating data across the CCU and over time); in this paper, we focus on the QI role. We have identified how CCU staff currently interpret information and determine what supplementary information can better inform their decision making and support sensemaking. From these, a set of data visualisations has been proposed, for integration with the hospital electronic health record. These visualisations are being iteratively refined in collaboration with CCU staff and technical staff responsible for maintaining the electronic health record. The paper presents user requirements for QI in pain management and a set of visualisations, including the design rationale behind the various methods proposed for visualising and exploring pain data using dashboards

Separable spatio-temporal kriging for fast virtual sensing

Environmental monitoring is a task that requires to surrogate system-wide information with limited sensor readings. Under the proximity principle, an environmental monitoring system can be based on the virtual sensing logic and then rely on distance-based prediction methods, such as $k$-nearest-neighbors, inverse distance weighted regression and spatio-temporal kriging. The last one is cumbersome with large datasets, but we show that a suitable separability assumption reduces its computational cost to an extent broader than considered insofar. Only spatial interpolation needs to be performed in a centralized way, while forecasting can be delegated to each sensor. This simplification is mostly related to the fact that two separate models are involved, one in time and one in the space domain. Any of the two models can be replaced without re-estimating the other under a composite likelihood approach. Moreover, the use of convenient spatial and temporal models eases up computation. We show that this perspective on kriging allows to perform virtual sensing even in the case of tall datasets.Comment: Submitted to Applied Stochastic Models in Business and Industry on September 30, 202

MTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs. \ua9 2013 Society for Endocrinology

Correlations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab

The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59\ub112 years, range 26-83; mean disease duration 11\ub15 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6\ub1 1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4\ub11.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of >3.2, an erythrocyte sedimentation rate (ESR) of >30 mm/hour, and CRP levels of >1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-a; and IL-6. TCZ and anti- TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of 10 \u3bcg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of 10 \u3bcg/mL showed the following differences: DAS28: 3.09\ub11.32 vs 2.78\ub11.32, P=0.0005; ESR: 27\ub114.8 vs 14\ub112 mm/hour, P=0.0001; CRP: 1.47\ub11.05 vs 0.65\ub10.80 mg/dL, P=0.0086; TNF-a: 10.2\ub11.2 vs 9.9\ub11.1 pg/mL, P=0.999; IL-6: 3.65\ub14.75 vs 3.62\ub14.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2\ub193.7 vs 86.7\ub190.3 IU/mL, P=0.94; RF IgM: 72.4\ub162.7 vs 68.3\ub161.6 IU/mL, P=0.754; RF IgA: 41.7\ub136.4 vs 47.8\ub142.1 U/mL, P=0.449; and RF IgG: 46.4\ub146.1 vs 59.3\ub158.2 U/mL, P=0.212. These findings show that the occurrence of anti-drug antibodies against TCZ is very rare and that there are statistically significant correlations between TCZ levels of >10 \u3bcg/mL and ESR, CRP levels, and DAS28

The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by zika virus

The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water sup-plies of NE compared to other regions of Brazil. Experimentally, we described that STX dou-bled the quantity of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.Fil: Pedrosa, Carolina da S. G.. D’Or Institute for Research and Education; BrasilFil: Souza, Leticia R. Q.. D’Or Institute for Research and Education; BrasilFil: Gomes, Tiago A.. Universidade Federal do Rio de Janeiro; Brasil. Instituto Oswaldo Cruz; BrasilFil: de Lima, Caroline V. F.. D’Or Institute for Research and Education; BrasilFil: Ledur, Pitia F.. D’Or Institute for Research and Education; BrasilFil: Karmirian, Karina. D’Or Institute for Research and Education; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Barbeito Andrés, Jimena. Universidade Federal do Rio de Janeiro; Brasil. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Costa, Marcelo do N.. Universidade Federal do Rio de Janeiro; BrasilFil: Higa, Luiza M.. Universidade Federal do Rio de Janeiro; BrasilFil: Rossi, Átila D.. Universidade Federal do Rio de Janeiro; BrasilFil: Bellio, Maria. Universidade Federal do Rio de Janeiro; BrasilFil: Tanuri, Amilcar. Universidade Federal do Rio de Janeiro; BrasilFil: Prata Barbosa, Arnaldo. D’Or Institute for Research and Education; BrasilFil: Tovar Moll, Fernanda. D’Or Institute for Research and Education; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Garcez, Patricia P.. Universidade Federal do Rio de Janeiro; BrasilFil: Lara, Flavio A.. Instituto Oswaldo Cruz; BrasilFil: Molica, Renato J. R.. Universidad Federal Rural Pernambuco; BrasilFil: Rehen, Stevens K.. D’Or Institute for Research and Education; Brasil. Universidade Federal do Rio de Janeiro; Brasi

Congenital Zika syndrome is associated with maternal protein malnutrition

Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS.Fil: Barbeito Andrés, Jimena. Universidade Federal do Rio de Janeiro; Brasil. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Pezzuto, Paula. Universidade Federal do Rio de Janeiro; BrasilFil: Higa, Luiza. Universidade Federal do Rio de Janeiro; BrasilFil: Dias, André Alves. Universidade Federal do Rio de Janeiro; BrasilFil: Vasconcelos, Janaina. Universidade Federal do Pará; BrasilFil: Santos, T. M. P.. Universidade Federal do Rio de Janeiro; BrasilFil: Ferreira, Jéssica. Universidade Federal do Rio de Janeiro; BrasilFil: Ferreira, R. O.. Universidade Federal do Rio de Janeiro; BrasilFil: Dutra, F. F.. Universidade Federal do Rio de Janeiro; BrasilFil: Rossi, A. D.. Universidade Federal do Rio de Janeiro; BrasilFil: Barbosa, R. V.. Universidade Federal Do Rio de Janeiro. Centro Nacional de Biologia Estrutural E Bioimagem.; BrasilFil: Amorim, C. K. N.. Evandro Chagas Institute; BrasilFil: de Souza, M. P. C.. Evandro Chagas Institute; BrasilFil: Chimelli, L.. Instituto Estadual do Cérebro Paulo Niemeyer ; BrasilFil: Aguiar, R. S.. Universidade Federal do Rio de Janeiro; BrasilFil: Gonzalez, Paula Natalia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Lara, F. A.. Oswaldo Cruz Institute; BrasilFil: Castro, M.C.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Molnár, Z.. University of Oxford; Reino UnidoFil: Lopes, R. T.. Universidade Federal do Rio de Janeiro; BrasilFil: Bozza, M. T.. Universidade Federal do Rio de Janeiro; BrasilFil: Vianez, J. L. S. G.. Evandro Chagas Institute; BrasilFil: Barbeito, Claudio Gustavo. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Cuervo, P.. Oswaldo Cruz Institute; BrasilFil: Bellio, M.. Universidade Federal do Rio de Janeiro; BrasilFil: Tanuri, A.. Universidade Federal do Rio de Janeiro; BrasilFil: Garcez, P. P.. Universidade Federal do Rio de Janeiro; Brasi