Constipation in children

Constipation remains a frequent presentation to paediatricians, with significant health resource implications. We present a practical guide to the management of paediatric constipation and evaluate the current evidence for treatment regimens, to help the clinician in treating a condition that can be distressing and has a significant impact on affected families

TRA-935: REPAIRING HIGH VOLUME HMA HIGHWAYS WITH PRECAST CONCRETE INLAY PANELS

The pavements which make up Canada’s high volume highways are subjected to some of the most demanding conditions in the world. They must structurally be capable of supporting significant traffic loading, which can exceed an average of 30,000 trucks per day. They must be capable of supporting these loads throughout the wide variety of environmental conditions to which they are exposed, ranging from hot summers to cold winters. In order to achieve service lives which do not necessitate frequent maintenance and repair activities, these pavement structures are required to be very resilient. A complication to constructing the resilient pavement structures is that construction activities on high volume highways are generally limited to over-night construction windows that are six to eight hours long. At the end of this construction window, full traffic must typically be reinstated. Ontario’s Ministry of Transportation (MTO) has a number of high volume highways which have been reaching the end of their service lives prematurely due to deep-seated pavement rutting issues. These highways have previously been rehabilitated using a mill and replace strategy. In response to this issue and the restricted construction windows for rehabilitation operations, a new rehabilitation strategy has been developed for rehabilitating high volume hot mix asphalt (HMA) highways. This strategy is the use of Precast Concrete Inlay Panels (PCIPs) which are placed within a partially milled HMA pavement structure. A trial section of the PCIP strategy has been designed and proposed to the MTO for implementation and this paper outlines the development of the rehabilitation strategy, with specific focus on details produced to address to the unique nature of this rehabilitation strategy. These details include panel support conditions, built in design details, and construction specifications that address various constructability and performance concerns

Force distributions in a triangular lattice of rigid bars

We study the uniformly weighted ensemble of force balanced configurations on a triangular network of nontensile contact forces. For periodic boundary conditions corresponding to isotropic compressive stress, we find that the probability distribution for single-contact forces decays faster than exponentially. This super-exponential decay persists in lattices diluted to the rigidity percolation threshold. On the other hand, for anisotropic imposed stresses, a broader tail emerges in the force distribution, becoming a pure exponential in the limit of infinite lattice size and infinitely strong anisotropy.Comment: 11 pages, 17 figures Minor text revisions; added references and acknowledgmen

Profiling humoral immune responses to Clostridium difficile-specific antigens by protein microarray analysis

Clostridium difficile is an anaerobic, Gram-positive, and spore-forming bacterium that is the leading worldwide infective cause of hospital-acquired and antibiotic-associated diarrhea. Several studies have reported associations between humoral immunity and the clinical course of C. difficile infection (CDI). Host humoral immune responses are determined using conventional enzyme-linked immunosorbent assay (ELISA) techniques. Herein, we report the first use of a novel protein microarray assay to determine systemic IgG antibody responses against a panel of highly purified C. difficile-specific antigens, including native toxins A and B (TcdA and TcdB, respectively), recombinant fragments of toxins A and B (TxA4 and TxB4, respectively), ribotypespecific surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). Microarrays were probed with sera from a total of 327 individuals with CDI, cystic fibrosis without diarrhea, and healthy controls. For all antigens, precision profiles demonstrated<10% coefficient of variation (CV). Significant correlation was observed between microarray and ELISA in the quantification of antitoxin A and antitoxin B IgG. These results indicate that microarray is a suitable assay for defining humoral immune responses to C. difficile protein antigens and may have potential advantages in throughput, convenience, and cost

Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2) is essential for optimal L. monocytogenes T-cell priming. Here, we demonstrate that vacuole-constrained L. monocytogenes elicit reduced PGE2 production compared to wild-type strains in macrophages and dendritic cells ex vivo. In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE2 production early during infection whereas vacuole-constrained strains fail to induce PGE2 over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2+ or CD11c+ cells produce less PGE2, suggesting these cell subsets contribute to PGE2 levels in vivo, while depletion of phagocytes with clodronate abolishes PGE2 production completely. Taken together, this work demonstrates that optimal PGE2 production by phagocytes depends on L. monocytogenes access to the cytosol, suggesting that one reason cytosolic access is required to prime CD8+ T-cell responses may be to facilitate production of PGE2

Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium

Background: A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective: To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design: Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results: Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions: Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML

Palladium-coated kapton for use on dust detectors in low earth orbit: Performance under hypervelocity impact and atomic oxygen exposure

Observation of dust and debris in the near Earth environment is a field of great commercial and scientific interest, vital to maximising the operational and commercial life-cycle of satellites and reducing risk to increasing numbers of astronauts in Low Earth Orbit (LEO). To this end, monitoring and assessment of the flux of particles is of paramount importance to the space industry and wider socio-economic interests that depend upon data products/services from orbital infrastructure. We have designed a passive space dust detector to investigate the dust environment in LEO—the Orbital Dust Impact Experiment (ODIE). ODIE is designed for deployment in LEO for ~1 year, whereupon it would be returned to Earth for analysis of impact features generated by dust particles. The design emphasises the ability to distinguish between the orbital debris (OD) relating to human space activity and the naturally occurring micrometeoroid (MM) population at millimetre to submillimetre scales. ODIE is comprised of multiple Kapton foils, which have shown great potential to effectively preserve details of the impacting particles’ size and chemistry, with residue chemistry being used to interpret an origin (OD vs. MM). LEO is a harsh environment—the highly erosive effects of atomic oxygen damage Kapton foil—requiring the use of a protective coating. Common coatings available for Kapton (e.g., Al, SiO2, etc.) are problematic for subsequent analysis and interpretation of OD vs. MM origin, being a common elemental component of MM or OD, or having X-ray emission peaks overlapping with those of elements used to distinguish MM from OD. We thus propose palladium coatings as an alternative for this application. Here we report on the performance of palladium as a protective coating for a Kapton-based passive dust detector when exposed to atomic oxygen and impact. When subjected to impact, we observe that thicker coatings suffer delamination such that a coating of <50 nm is recommended. Analysis of atomic oxygen exposed samples shows a thin 10 nm coating of palladium significantly reduces the mass loss of Kapton, while coatings of 25 nm and over perform as well as or better than other commonly used coating

An Alu-derived intronic splicing enhancer facilitates intronic processing and modulates aberrant splicing in ATM

We have previously reported a natural GTAA deletion within an intronic splicing processing element (ISPE) of the ataxia telangiectasia mutated (ATM) gene that disrupts a non-canonical U1 snRNP interaction and activates the excision of the upstream portion of the intron. The resulting pre-mRNA splicing intermediate is then processed to a cryptic exon, whose aberrant inclusion in the final mRNA is responsible for ataxia telangiectasia. We show here that the last 40 bases of a downstream intronic antisense Alu repeat are required for the activation of the cryptic exon by the ISPE deletion. Evaluation of the pre-mRNA splicing intermediate by a hybrid minigene assay indicates that the identified intronic splicing enhancer represents a novel class of enhancers that facilitates processing of splicing intermediates possibly by recruiting U1 snRNP to defective donor sites. In the absence of this element, the splicing intermediate accumulates and is not further processed to generate the cryptic exon. Our results indicate that Alu-derived sequences can provide intronic splicing regulatory elements that facilitate pre-mRNA processing and potentially affect the severity of disease-causing splicing mutations

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

Objective: With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting: Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods: As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective: The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions: Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions