An i2b2-based, generalizable, open source, self-scaling chronic disease registry

Objective: Registries are a well-established mechanism for obtaining high quality, disease-specific data, but are often highly project-specific in their design, implementation, and policies for data use. In contrast to the conventional model of centralized data contribution, warehousing, and control, we design a self-scaling registry technology for collaborative data sharing, based upon the widely adopted Integrating Biology & the Bedside (i2b2) data warehousing framework and the Shared Health Research Information Network (SHRINE) peer-to-peer networking software. Materials and methods Focusing our design around creation of a scalable solution for collaboration within multi-site disease registries, we leverage the i2b2 and SHRINE open source software to create a modular, ontology-based, federated infrastructure that provides research investigators full ownership and access to their contributed data while supporting permissioned yet robust data sharing. We accomplish these objectives via web services supporting peer-group overlays, group-aware data aggregation, and administrative functions. Results: The 56-site Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry and 3-site Harvard Inflammatory Bowel Diseases Longitudinal Data Repository now utilize i2b2 self-scaling registry technology (i2b2-SSR). This platform, extensible to federation of multiple projects within and between research networks, encompasses >6000 subjects at sites throughout the USA. Discussion We utilize the i2b2-SSR platform to minimize technical barriers to collaboration while enabling fine-grained control over data sharing. Conclusions: The implementation of i2b2-SSR for the multi-site, multi-stakeholder CARRA Registry has established a digital infrastructure for community-driven research data sharing in pediatric rheumatology in the USA. We envision i2b2-SSR as a scalable, reusable solution facilitating interdisciplinary research across diseases

Ca2+-induced secretion by electropermeabilized human neutrophils. The roles of Ca2+, nucleotides and protein kinase C

Studies of stimulus-response coupling have benefitted from the availability of permeabilization techniques, whereby putative second messengers and intracellular modulators can be introduced into the cell interior. Electropermeabilization, which uses high-intensity electric fields to breach the plasma membrane, creates small pores, permitting access of solutes with molecular masses below 700 KDa. Neutrophils permeabilized by this technique, but not intact cells, discharged lysosomal constituents when exposed to micromolar levels of Ca2+. Secretion by electroporated neutrophils was significantly enhanced by the presence of Mg-ATP (0.3-1.0 mM). Contrary to expectations, it was determined that ATP was not the only nucleotide which enhanced Ca2+-induced secretion in the presence of Mg2+. Not only could GTP, XTP, ITP, UTP or ADP partially or completely replace ATP, but even non-hydrolyzable nucleotides such as ADP[beta]S ATP[gamma]S, and App[NH]p were effective. GTP[gamma]S and GDP[beta]S were inhibitory, while Gpp[NH]p was inactive. None of these nucleotides induced secretion on its own. In contrast, neutrophils which were permeabilized and then washed, were only slightly activated by Mg-ATP and other nucleotides; even the response to Ca2+ alone was less. This hyporesponsiveness of washed cells proved to be due to a time-dependent deactivation of the permeabilized neutrophils taking place at 4[deg] C. In an effort to assess the role for protein kinase C (PKC) in secretion in this system, we examined the effects of phorbol myristate acetate (PMA), a PKC agonist. PMA enhanced degranulation induced by Ca2+ by lowering the requirement for this divalent cation; enhancement by PMA was not dependent upon exogenous ATP. Three inhibitors of PKC with varying specificity, namely H-7, K-252a, and staurosporine, all abrogated PMA-enhanced secretion. These agents also inhibited secretion stimulated by Ca2+ plus ATP in parallel with that induced by Ca2+ plus PMA, strongly suggesting a role for PKC in modulation of degranulation by ATP. Our results show that electroper-meabilized neutrophils provide a convenient, useful model for stimulus-secretion coupling. These data also suggest that the `requirement' for Mg-ATP, which has been observed in other permeabilized cell systems, is not simply for metabolic energy or as a substrate for kinases. It is possible that these nucleotides all interact with a recently described neutrophil receptor for adenine nucleotides or with a recently postulated exocytosis-linked G-protein.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28620/1/0000432.pd

IL-1β Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity.

Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1β in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1β (IL-1β(-/-)), or treated with the soluble IL-1βR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1β acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1β that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity

Mediterranean Diet Adherence and Health-Related Quality of Life during Pregnancy: Is the Mediterranean Diet Beneficial in Non-Mediterranean Countries?

This study aimed to examine the association of Mediterranean diet (MD) adherence and MD components with health-related quality of life (HRQoL) in pregnant women from Spain and Sweden. A total of 138 pregnant women from Spain (age: 32.9 ± 4.6 years old) and 302 pregnant women from Sweden (age: 31.3 ± 4.1 years old) were included. MD adherence was assessed with the Mediterranean food pattern (i.e., a MD index) at the 14–16th gestational weeks. HRQoL was assessed with the Spanish and Swedish versions of the 36-item Short-Form Health Survey (SF-36 and RAND-36, respectively) at the 14–16th and 34–37th gestational weeks. A greater MD adherence was associated with better physical functioning, bodily pain, vitality, emotional role, and mental health in cross-sectional associations (2nd trimester) in the Spanish sample (all p < 0.05). Furthermore, a greater MD adherence was associated with lower bodily pain in both Spanish and Swedish samples (both p < 0.05) in the 3rd trimester. The associations of MD adherence with pain seem to be explained by a greater intake of fiber, fish, fruits, nuts, and legumes (all p < 0.05). A greater MD adherence, driven by a higher intake of fiber, fish, fruits, nuts, and legumes, was associated with lower pain throughout pregnancy in both Mediterranean and non-Mediterranean populations

Signal and Noise Analysis in TRION -Time-Resolved Integrative Optical Fast Neutron Detector

TRION is a sub-mm spatial resolution fast neutron imaging detector, which employs an integrative optical time-of-flight technique. The detector was developed for fast neutron resonance radiography, a method capable of detecting a broad range of conventional and improvised explosives. In this study we have analyzed in detail, using Monte-Carlo calculations and experimentally determined parameters, all the processes that influence the signal and noise in the TRION detector. In contrast to event-counting detectors where the signal-to-noise ratio is dependent only on the number of detected events (quantum noise), in an energy-integrating detector additional factors, such as the fluctuations in imparted energy, number of photoelectrons, system gain and other factors will contribute to the noise. The excess noise factor (over the quantum noise) due to these processes was 4.3, 2.7, 2.1, 1.9 and 1.9 for incident neutron energies of 2, 4, 7.5, 10 and 14 MeV, respectively. It is shown that, even under ideal light collection conditions, a fast neutron detection system operating in an integrative mode cannot be quantum-noise-limited due to the relatively large variance in the imparted proton energy and the resulting scintillation light distributions.Comment: 18 page

Pediatric interventional radiography equipment: safety considerations

This paper discusses pediatric image quality and radiation dose considerations in state-of-the-art fluoroscopic imaging equipment. Although most fluoroscopes are capable of automatically providing good image quality on infants, toddlers, and small children, excessive radiation dose levels can result from design deficiencies of the imaging device or inappropriate configuration of the equipment’s capabilities when imaging small body parts. Important design features and setup choices at installation and during the clinical use of the imaging device can improve image quality and reduce radiation exposure levels in pediatric patients. Pediatric radiologists and cardiologists, with the help of medical physicists, need to understand the issues involved in creating good image quality at reasonable pediatric patient doses. The control of radiographic technique factors by the generator of the imaging device must provide a large dynamic range of mAs values per exposure pulse during both fluoroscopy and image recording as a function of patient girth, which is the thickness of the patient in the posterior–anterior projection at the umbilicus (less than 10 cm to greater than 30 cm). The range of pulse widths must be limited to less than 10 ms in children to properly freeze patient motion. Variable rate pulsed fluoroscopy can be leveraged to reduce radiation dose to the patient and improve image quality. Three focal spots with nominal sizes of 0.3 mm to 1 mm are necessary on the pediatric unit. A second, lateral imaging plane might be necessary because of the child’s limited tolerance of contrast medium. Spectral and spatial beam shaping can improve image quality while reducing the radiation dose. Finally, the level of entrance exposure to the image receptor of the fluoroscope as a function of operator choices, of added filter thickness, of selected pulse rate, of the selected field-of-view and of the patient girth all must be addressed at installation

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener&apos;s) : an ARChiVe Cohort Study

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n\u2009=\u200948) or GPA (n\u2009=\u2009183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding