Transplacental innate immune training via maternal microbial exposure: role of XBP1-ERN1 axis in dendritic cell precursor programming

We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease

Silent slips, trips and broken hips in the under 60s: a review of the literature

This critical review of the literature regarding the recovery experiences and healthcare needs of people under 60 following a fragility hip fracture seeks to identify the associated implications for nursing practice and inform care delivery. Forty papers were included following a structured database, citation and grey literature search and filtering of results in line with specified inclusion criteria. Hip fracture is a common, serious and complex injury and an important cause of morbidity, mortality and rising healthcare costs worldwide. This review indicates that although commonly associated with the elderly, incidence and impact in the under 60s has been under-explored. Current health policy, professional and social norms almost exclusively focus on the elderly, surgical interventions and short-term outcomes, rendering the under 60s an inadvertently marginalised, relatively 'silent' sub-set of the hip fracture population. Nurses must be aware, however, of the different recovery needs of this younger group. The limited evidence available indicates these include work related needs and long term physical and psychosocial limitations in this socially and economically active group. Priorities are identified for research to inform policy and practice. Meanwhile, nurses can address the needs of this group by listening to and involving them and their families as healthcare partners. [Abstract copyright: Copyright © 2018. Published by Elsevier Ltd.

Evasion by Stealth: Inefficient Immune Activation Underlies Poor T Cell Response and Severe Disease in SARS-CoV-Infected Mice

Severe Acute Respiratory Syndrome caused substantial morbidity and mortality during the 2002–2003 epidemic. Many of the features of the human disease are duplicated in BALB/c mice infected with a mouse-adapted version of the virus (MA15), which develop respiratory disease with high morbidity and mortality. Here, we show that severe disease is correlated with slow kinetics of virus clearance and delayed activation and transit of respiratory dendritic cells (rDC) to the draining lymph nodes (DLN) with a consequent deficient virus-specific T cell response. All of these defects are corrected when mice are treated with liposomes containing clodronate, which deplete alveolar macrophages (AM). Inhibitory AMs are believed to prevent the development of immune responses to environmental antigens and allergic responses by interacting with lung dendritic cells and T cells. The inhibitory effects of AM can also be nullified if mice or AMs are pretreated with poly I:C, which directly activate AMs and rDCs through toll-like receptors 3 (TLR3). Further, adoptive transfer of activated but not resting bone marrow–derived dendritic cells (BMDC) protect mice from lethal MA15 infection. These results may be relevant for SARS in humans, which is also characterized by prolonged virus persistence and delayed development of a SARS-CoV-specific immune response in individuals with severe disease

Digital PCR provides sensitive and absolute calibration for high throughput sequencing

<p>Abstract</p> <p>Background</p> <p>Next-generation DNA sequencing on the 454, Solexa, and SOLiD platforms requires absolute calibration of the number of molecules to be sequenced. This requirement has two unfavorable consequences. First, large amounts of sample-typically micrograms-are needed for library preparation, thereby limiting the scope of samples which can be sequenced. For many applications, including metagenomics and the sequencing of ancient, forensic, and clinical samples, the quantity of input DNA can be critically limiting. Second, each library requires a titration sequencing run, thereby increasing the cost and lowering the throughput of sequencing.</p> <p>Results</p> <p>We demonstrate the use of digital PCR to accurately quantify 454 and Solexa sequencing libraries, enabling the preparation of sequencing libraries from nanogram quantities of input material while eliminating costly and time-consuming titration runs of the sequencer. We successfully sequenced low-nanogram scale bacterial and mammalian DNA samples on the 454 FLX and Solexa DNA sequencing platforms. This study is the first to definitively demonstrate the successful sequencing of picogram quantities of input DNA on the 454 platform, reducing the sample requirement more than 1000-fold without pre-amplification and the associated bias and reduction in library depth.</p> <p>Conclusion</p> <p>The digital PCR assay allows absolute quantification of sequencing libraries, eliminates uncertainties associated with the construction and application of standard curves to PCR-based quantification, and with a coefficient of variation close to 10%, is sufficiently precise to enable direct sequencing without titration runs.</p

Outcomes of Cardiac Transplantation in Highly Sensitized Pediatric Patients

Despite aggressive immunosuppressive therapy, pediatric orthotopic heart transplant (OHT) candidates with elevated pre-transplant panel reactive antibody (PRA) carry an increased risk of rejection and early graft failure following transplantation. This study has aimed to more specifically evaluate the outcomes of transplant candidates stratified by PRA values. Records of pediatric patients listed for OHT between April 2004 and July 2008 were reviewed (n = 101). Survival analysis was performed comparing patients with PRA < 25 to those with PRA > 25, as well as patients with PRA < 80 and PRA > 80. Patients with PRA > 25 had decreased survival compared with those with PRA < 25 after listing (P = 0.004). There was an even greater difference in survival between patients with PRA > 80 and those with PRA < 80 (P = 0.002). Similar analyses for the patients who underwent successful transplantation showed no significant difference in post-transplant survival between patients with a pre-transplant PRA > 25 and those with PRA < 25 (P = 0.23). A difference approaching significance was noted for patients with PRA > 80 compared with PRA < 80 (P = 0.066). Patients with significantly elevated pre-transplant PRAs at the time of listing have a significantly worse outcome compared to those with moderately increased PRA values or non-sensitized patients. Further study is necessary to guide physician and family treatment decisions at the time of listing

Development and psychometric testing of the online Adolescent Diabetes Needs Assessment Tool (ADNAT)

Supplementary information published since the original article was published.This document is the Accepted Manuscript version of a published work that appeared in final form in World Biomedical Frontiers. To access the final edited and published work see http://biomedfrontiers.org/diabetes-obesity-2015-1-21/.World Biomedical Frontiers provides a platform for the exchange of the latest research progress, including strategic and emerging research areas such as diabetes. Their aim is to accelerate understanding of human health and improvetreatment of a variety of human diseases. Our article, published in the Journal of Advanced Nursing, was selected for their web based publication. It provides an abstract plus supplementary information on the research work associated with ADNAT

Increasing the Effectiveness of Vaginal Microbicides: A Biophysical Framework to Rethink Behavioral Acceptability

Microbicide candidates delivered via gel vehicles are intended to coat the vaginal epithelium after application. The coating process depends on intrinsic biophysical properties of the gel texture, which restricts the potential choices for an effective product: the gel first must be physically synthesizable, then acceptable to the user, and finally applied in a manner promoting timely adequate coating, so that the user adherence is optimized. We present a conceptual framework anchoring microbicide behavioral acceptability within the fulfillment of the product biophysical requirements.We conducted a semi-qualitative/quantitative study targeting women aged 18-55 in Northern California to assess user preferences for microbicide gel attributes. Attributes included: (i) the wait time between application and intercourse, (ii) the gel texture and (iii) the trade-off between wait time and gel texture. Wait times were assessed using a mathematical model determining coating rates depending upon the gel's physical attributes.71 women participated. Results suggest that women would independently prefer a gel spreading rapidly, in 2 to 15 minutes (P<0.0001), as well as one that is thick or slippery (P<0.02). Clearly, thick gels do not spread rapidly; hence the motivation to study the trade-off. When asked the same question 'constrained' by the biophysical reality, women indicated no significant preference for a particular gel thickness (and therefore waiting time) (P>0.10) for use with a steady partner, a preference for a watery gel spreading rapidly rather than one having intermediate properties for use with a casual partner (P = 0.024).Biophysical constraints alter women's preferences regarding acceptable microbicide attributes. Product developers should offer a range of formulations in order to address all preferences. We designed a conceptual framework to rethink behavioral acceptability in terms of biophysical requirements that can help improve adherence in microbicide use ultimately enhancing microbicide effectiveness

Of, By, and For Which People? Government and Contested Heritage in the American Midwest

Two government-owned and managed heritage sites in Indiana, USA, offer an opportunity to explore the role of governments in adjudicating the competing paradigms of value and contested uses. Strawtown Koteewi is a Hamilton County park and Mounds State Park is part of the Indiana Department of Natural Resources statewide park system. Each site has come under scrutiny in recent years. Strawtown Koteewi is one of the most significant sites in the area for understanding the history of Native peoples. After almost a decade of archaeological excavations, several Native American groups, under the auspices of the Native American Graves Protection and Repatriation Act (NAGPRA), initiated repatriation processes for the recovery of human remains, and some objected to the ongoing archaeological research. At Mounds State Park a coalition of citizens opposed a planned dam project intended to ensure a safe and plentiful water supply and to spur economic development in the area. In each case, the government entities have had to navigate the political landscapes of competing claims about the sites. These case studies expose the fissures between authorized heritage discourse and the paradigms of meaning among the diverse constituencies of the sites, and they highlight the tenuous position of public governance in privileging competing cultural, economic, and social interests. While not unique, the state and county agencies’ positions within these fields of power and their strategic choices reveal some of the barriers and constraints that limit their actions as well as the deep-seated ideologies of policies that perpetuate settler colonial politics in the control and interpretation of indigenous heritage

Survey of information technology in Intensive Care Units in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>The Intensive Care Unit (ICU) is a data-rich environment where information technology (IT) may enhance patient care. We surveyed ICUs in the province of Ontario, Canada, to determine the availability, implementation and variability of information systems.</p> <p>Methods</p> <p>A self-administered internet-based survey was completed by ICU directors between May and October 2006. We measured the spectrum of ICU clinical data accessible electronically, the availability of decision support tools, the availability of electronic imaging systems for radiology, the use of electronic order entry and medication administration systems, and the availability of hardware and wireless or mobile systems. We used Fisher's Exact tests to compare IT availability and Classification and Regression Trees (CART) to estimate the optimal cut-point for the number of computers per ICU bed.</p> <p>Results</p> <p>We obtained responses from 50 hospitals (68.5% of institutions with level 3 ICUs), of which 21 (42%) were university-affiliated. The majority electronically accessed laboratory data and imaging reports (92%) and used picture archiving and communication systems (PACS) (76%). Other computing functions were less prevalent (medication administration records 46%, physician or nursing notes 26%; medication order entry 22%). No association was noted between IT availability and ICU size or university affiliation. Sites used clinical information systems from15 different vendors and 8 different PACS systems were in use. Half of the respondents described the number of computers available as insufficient. Wireless networks and mobile computing systems were used in 23 ICUs (46%).</p> <p>Conclusion</p> <p>Ontario ICUs demontrate a high prevalence of the use of basic information technology systems. However, implementation of the more complex and potentially more beneficial applications is low. The wide variation in vendors utilized may impair information exchange, interoperability and uniform data collection.</p