Analytical characterization and formulation assessment of model secretory- immunoglobulin-A (sIgAs) for their potential use as low cost, orally delivered sIgAs

Enterotoxigenic Escherichia coli (ETEC) is a major cause of bacterial diarrheal disease in developing countries, especially among children and infants. ETEC is estimated to cause 280-400 million diarrheal episodes per year in children \u3c5 years of age, resulting in 300,000 to 500,000 deaths.1 Despite the need for a vaccine, there are currently no licensed vaccines against ETEC. Alternatively, passive immunization by oral delivery of pathogen-specific immunoglobulins is another promising approach to provide “instant” protection against ETEC. The potential advantages of oral delivery are reduced cost, simplicity of administration and localized treatment within the GI tract. Secretory IgA (sIgA) is of particular interest because it is naturally found in the mucosal surfaces within the GI tract, relatively more resistant to proteolysis by digestive enzymes (vs. IgGs), and can protect against enteric bacteria by directly neutralizing virulence factors.2 One major challenge of this approach is the instability of protein molecules during oral delivery (in the digestive tract) as well as during long-term storage (in various formulations). In this study, two proteins, sIgA1 and sIgA2 against heat labile toxin (LT, one of the major virulence factors of ETEC), were used as model sIgA molecules for developing analytical techniques and assessing stability (physicochemical as well as in vitro binding) under various conditions. A combination of biochemical and biophysical methods were employed to comprehensively characterize the sIgA1 and sIgA2 model proteins including primary structure, post translational modifications (i.e., N-linked glycans), size, apparent solubility, higher order structure and conformational stability as well as in vitro antigen binding. Using these characterization and stability indicating methods, we are monitoring the stability of these two model sIgAs both in an in vitro digestion model (to mimic in vivo degradation conditions), and during accelerated stability studies (to assess storage stability). Our goal is to use the information gained by these aforementioned methods and stability studies to design stable, low-cost liquid formulations for oral delivery of sIgAs in the developing world. Please click Additional Files below to see the full abstract

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Effect of the Growth Assessment Protocol on the DEtection of Small for GestatioNal age fetus: process evaluation from the DESiGN cluster randomised trial

BACKGROUND: Reducing the rate of stillbirth is an international priority. At least half of babies stillborn in high-income countries are small for gestational-age (SGA). The Growth Assessment Protocol (GAP), a complex antenatal intervention that aims to increase the rate of antenatal detection of SGA, was evaluated in the DESiGN type 2 hybrid effectiveness-implementation cluster randomised trial (n = 13 clusters). In this paper, we present the trial process evaluation. METHODS: A mixed-methods process evaluation was conducted. Clinical leads and frontline healthcare professionals were interviewed to inform understanding of context (implementing and standard care sites) and GAP implementation (implementing sites). Thematic analysis of interview text used the context and implementation of complex interventions framework to understand acceptability, feasibility, and the impact of context. A review of implementing cluster clinical guidelines, training and maternity records was conducted to assess fidelity, dose and reach. RESULTS: Interviews were conducted with 28 clinical leads and 27 frontline healthcare professionals across 11 sites. Staff at implementing sites generally found GAP to be acceptable but raised issues of feasibility, caused by conflicting demands on resource, and variable beliefs among clinical leaders regarding the intervention value. GAP was implemented with variable fidelity (concordance of local guidelines to GAP was high at two sites, moderate at two and low at one site), all sites achieved the target to train > 75% staff using face-to-face methods, but only one site trained > 75% staff using e-learning methods; a median of 84% (range 78–87%) of women were correctly risk stratified at the five implementing sites. Most sites achieved high scores for reach (median 94%, range 62–98% of women had a customised growth chart), but generally, low scores for dose (median 31%, range 8–53% of low-risk women and median 5%, range 0–17% of high-risk women) were monitored for SGA as recommended. CONCLUSIONS: Implementation of GAP was generally acceptable to staff but with issues of feasibility that are likely to have contributed to variation in implementation strength. Leadership and resourcing are fundamental to effective implementation of clinical service changes, even when such changes are well aligned to policy mandated service-change priorities. TRIAL REGISTRATION: Primary registry and trial identifying number: ISRCTN 67698474. Registered 02/11/16. https://doi.org/10.1186/ISRCTN67698474

Altered Responses to Homeostatic Cytokines in Patients with Idiopathic CD4 Lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4+ T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4+ T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4+ T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4+ T cells of some ICL patients, which correlated with a decreased expression of the IL-7R\uce\ub1 receptor chain (R = 0.74, p<0.005) and with lower CD4+ T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4+ T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = -0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4+ T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in \uce\ub3c cytokine responses. \uc2\ua9 2013 Bugault et al

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Analysis and implementation of high resolution precipitation data in urban drainage modelling

Urban SIS is a project that develops, demonstrates and puts into production a method to downscale climate and impact indicators to urban scale, realizing a set of Essential Climate Variables over three area of Europe, including Bologna; in particular the precipitation was estimated for 5 non-consecutives years at a spatial resolution of 1x1 km2 and a temporal resolution of 15 min. The database of the area of Bologna contains an amount of data in the order of 10 millions that was managed in this study with RStudio. An analysis of the high resolution precipitation data over the most critical flood prone area of Bologna was performed, selecting a set of critical rainfall events. In the selection were considered the intensities, the cumulated depth and an index of spatial rainfall variability, taken from a firstly in-depth research in the literature regarding the use and the application of high resolution precipitation data in urban drainage modelling. Thanks to HERA, that gently provided the model of the entire urban drainage network of Bologna and the license for the utilization of InfoWorks software, the high resolution precipitation data were implemented into the drainage system. A series of indicators were calculated, in order to quantify the critical surcharge and flooded states of the network. Using the Intensity-Duration-Frequency curves of the area of Bologna, two types of synthetic events were elaborated: one constant over the area and another one with a pyramidal structure, representing the effects of a pour down rainfall event. The comparison between the synthetic events and the selected ones from Urban SIS assesses the direct correlation between the evaluation of the intensity at 1 hour and the indicators of the critical states in the network; the index of spatial rainfall variability has proved to be irrelevant in most of the cases. This study has to be considered valid for the urban drainage system of the area of Bologna

Dichotomous thinking in borderline personality disorder

This study examined dichotomous thinking in borderline personality disorder (BPD). In particular, it sought to determine whether dichotomous thinking is characteristic of individuals with BPD, and whether it is unidimensional—all-good or all-bad, and thus synonymous with splitting, or multidimensional—characterized by a mix of positive and negative attributes. The other objectives of the study were to determine whether dichotomous thinking in BPD is correlated with (1) self-injury, and (2) borderline severity. 16 individuals with BPD, 16 individuals with other personality disorders (OPD), and 16 normal controls (NPD) were presented with 6 brief film clips depicting interpersonal situations of varying emotional intensity. 2 of the clips depicted themes thought to be specific to borderline pathology: rejection, abuse, and a relationship crisis. 4 clips depicted themes that were not specific to BPD, and included emotionally positive and neutral themes. After viewing the clips, subjects were asked to rate the characters using visual analogue scales with bipolar trait descriptions. Borderline severity and personality diagnoses were assessed using the PDQ. Frequency of self-injury was assessed using the Self-Injury Interview (McKay, Greiner, Greisberg, Napolitano & D\u27Andrea, 2000). The BPD group exhibited significantly more dichotomous thinking than the NPD group; differences between the BPD and OPD group were not significant. Dichotomous thinking in the BPD was predominantly multidimensional, rather than unidimensional. It was not limited to borderline-specific stimuli, but occurred in emotionally positive and neutral circumstances as well. Dichotomous thinking was correlated with the total number of borderline traits endorsed, but was not correlated with frequency of self-injury. Analyzed at the aggregate level, none of the 3 subjects groups exhibited splitting or purely unidimensional evaluations. However, visual inspection of the data revealed limited instances of splitting within each group. Splitting by the BPD and OPD groups was more frequent than splitting within the NPD group. Additionally, splitting for the BPD and OPD groups, unlike the NPD group, occurred most frequently in response to positive stimuli. Notably, splitting accounted for a very small proportion of the total ratings made by individuals in the BPD group, and 37% of the BPD group did not split

The effectiveness of learning strategies for the development of Emotional Intelligence in undergraduate nursing students: A systematic review protocol

Aim: This protocol proposes a systematic review to identify and disclose learning strategies and evaluation tools to improve Emotional Intelligence (EI) in undergraduate nursing students. Background: EI improves the ability to manage emotions and their consequences. Management of emotions is fundamental in nursing both at inter- and intra-professional levels, and with the patients and their family carers. Design: Systematic review protocol of effectiveness based on the Joanna Briggs Institute (JBI) guidelines. Review methods: All articles based on educational programmes and/or activities to develop EI in nursing curricula will be included in the review. It will analyse the principle EI attributes and outcomes such as burnout, intention to leave and problem-solving skills. Based on the review question, seven databases will be searched: MEDLINE, The Cochrane Library, SCOPUS, CINAHL, EMBASE, PsycINFO and ERIC. Also, grey literature (Google Scholar and Open Gray) will be searched. Since no similar systematic reviews are present in the literature, no time limits will be set. To establish the quality of studies JBI tools will be used. When appropriate, we will meta-analyse prevalence and incidence estimates or we will meta-synthesize themes and findings. Expected results: This systematic review is expected to provide an overview of educational and training methods, pedagogical strategies and evaluation tools to address EI in nursing and provide high-quality care to patients and their families. Results of the review will support nursing educators and leaders in implementing teaching and learning strategies to improve the Emotional Intelligence of undergraduate nursing students. Conclusions: Mastering emotions is fundamental for nurses. Implementing education courses based on EI according to the best training methods and pedagogical strategies could become key for nursing curricula. Moreover, after the review, it will be possible to identify the best training methods and pedagogical strategies for implementing continuing professional development (CPD) courses in EI in the courses of following graduation