Search

OBJECTIVES: This study compared the prognostic value of a noncontrast CMR risk score for the composite of all-cause death, nonfatal myocardial infarction, and new congestive heart failure.BACKGROUND: A cardiovascular magnetic resonance (CMR) risk score including left ventricular ejection fraction (LVEF), myocardial infarct (MI) size, and microvascular obstruction (MVO) was recently proposed to risk-stratify patients with ST-segment elevation myocardial infarction (STEMI).METHODS: The Eitel CMR risk score and GRACE (Global Registry of Acute Coronary Events) score were used as a reference (Score 1: acute MI size ≥19% LV, LVEF ≤47%, MVO >1.4% LV and GRACE score). MVO was replaced by intramyocardial hemorrhage (IMH) in Score 2 (acute MI size ≥19% LV, LVEF ≤47%, IMH, and GRACE score). Score 3 included only LVEF ≤45%, IMH, and GRACE score.RESULTS: There were 370 patients in the derivation cohort and 234 patients in the validation cohort. In the derivation cohort, the 3 scores performed similarly and better than GRACE score to predict the 1-year composite endpoint with C-statistics of 0.83, 0.83, 0.82, and 0.74, respectively. In the validation cohort, there was good discrimination and calibration of score 3, with a C-statistic of 0.87 and P = 0.71 in a Hosmer-Lemeshow test for goodness of fit, on the 1-year composite outcome. Kaplan-Meier curves for 5-year composite outcome showed that those with LVEF ≤45% (high-risk) and LVEF >45% and IMH (intermediate-risk) had significantly higher cumulative events than those with LVEF >45% and no IMH (low-risk), log-rank tests: P = 0.02 and P = 0.03, respectively. The HR for the high-risk group was 2.3 (95% CI: 1.1-4.7) and for the intermediate-risk group was 2.0 (95% CI: 1.0-3.8), and these remained significant after adjusting for the GRACE score.CONCLUSIONS: This noncontrast CMR risk score has performance comparable to an established risk score, and patients with STEMI could be stratified into low risk (LVEF >45% and no IMH), intermediate risk (LVEF >45% and IMH), and high risk (LVEF ≤45%). (A Trial of Low-dose Adjunctive alTeplase During prIMary PCI [T-TIME]; NCT02257294) (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850).

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex., Salter et al. show that biallelic variants in PI4KA—which encodes the enzymatic core of the PI4KIIIα-TTC7-FAM126 complex—cause a clinically diverse disorder comprising neurological, intestinal and immunological abnormalities.

The increasing study of emerging wildlife pathogens and a lack of policy or legislation regulating their translocation and use has heightened concerns about laboratory escape, species spillover, and subsequent epizootics among animal populations. Responsible self-regulation by research laboratories, in conjunction with institutional-level safeguards, has an important role in mitigating pathogen transmission and spillover, as well as potential interspecies pathogenesis. A model system in disease ecology that highlights these concerns and related amelioration efforts is research focused on amphibian emerging infectious diseases. Whereas laboratory escape of amphibian pathogens has not been reported and may be rare compared with introduction events from trade or human globalization, the threat that novel disease outbreaks with mass mortality effects pose to wild populations warrants thorough biosecurity measures to ensure containment and prevent spillover. Here, we present a case study of the laboratory biosecurity concerns for the emerging amphibian fungal pathogen Batrachochytrium salamandrivorans. We conclude that proactive biosecurity strategies are needed to integrate researcher and institutional oversight of aquatic wildlife pathogens generally, and we call for increased national and international policy and legislative enforcement. Furthermore, taking professional responsibility beyond current regulations is needed as development of legal guidance can be slow at national and international levels. We outline the need for annual laboratory risk assessments, comprehensive training for all laboratory personnel, and appropriate safeguards specific to pathogens under study. These strategies are critical for upholding the integrity and credibility of the scientific community and maintaining public support for research on wildlife diseases.

Interstrand DNA cross-links (ICLs) block both replication and transcription, and are commonly repaired by the Fanconi anemia (FA) pathway. However, FA-independent repair mechanisms of ICLs remain poorly understood. Here we report a previously uncharacterized protein, SAN1, as a 5′ exonuclease that acts independently of the FA pathway in response to ICLs. Deletion of SAN1 in HeLa cells and mouse embryonic fibroblasts causes sensitivity to ICLs, which is prevented by re-expression of wild type but not nuclease-dead SAN1. SAN1 deletion causes DNA damage and radial chromosome formation following treatment with Mitomycin C, phenocopying defects in the FA pathway. However, SAN1 deletion is not epistatic with FANCD2, a core FA pathway component. Unexpectedly, SAN1 binds to Senataxin (SETX), an RNA/DNA helicase that resolves R-loops. SAN1-SETX binding is increased by ICLs, and is required to prevent cross-link sensitivity. We propose that SAN1 functions with SETX in a pathway necessary for resistance to ICLs., When DNA interstrand cross-links damage occurs, it causes disruption of replication and transcription. Here the authors identify FAM120B/SAN1, a 5′ exonuclease involved in the repair process of Interstrand Crosslinks independently of the Fanconi Anemia pathway.

Virtual globe programs such as Google Earth replicate real-world experiential learning of spatial and geographic concepts by allowing students to navigate across our planet without ever leaving campus. However, empirical evidence for the learning value of these technological tools and the experience students gain by exploration assignments framed within them remains to be quantified and compared by student demographics. This study examines the impact of a Google Earth-based exploration assignment on conceptual understanding in introductory geoscience courses at a research university in the US Midwest using predominantly traditional college-age students from a range of majors. Using repeated-measures ANOVA and paired-samples t tests, we test the significance of the activity using pretest and posttest scores on a subset of items from the Geoscience Concept Inventory, and the interactive effects of student gender and ethnicity on student score improvement. Analyses show that learning from the Google Earth exploration activity is highly significant overall and for all but one of the concept inventory items. Furthermore, we find no significant interactive effects of class format, student gender, or student ethnicity on the magnitude of the score increases. These results provide strong support for the use of experiential learning in virtual globe environments for students in introductory geoscience and perhaps other disciplines for which direct observation of our planet’s surface is conceptually relevant.

Background. Chronic pain is a significant health problem strongly associated with a wide range of physical and mental health problems, including addiction. The widespread prevalence of pain and the increasing rate of opioid prescriptions have led to a focus on how physicians are educated about chronic pain. This critical scoping review describes the current literature in this important area, identifying gaps and suggesting avenues for further research starting from patients’ standpoint. Methods. A search of the ERIC, MEDLINE, and Social Sciences Abstracts databases, as well as 10 journals related to medical education, was conducted to identify studies of the training of medical students, residents, and fellows in chronic noncancer pain. Results. The database and hand-searches identified 545 articles; of these, 39 articles met inclusion criteria and underwent full review. Findings were classified into four inter-related themes. We found that managing chronic pain has been described as stressful by trainees, but few studies have investigated implications for their well-being or ability to provide empathetic care. Even fewer studies have investigated how educational strategies impact patient care. We also note that the literature generally focuses on opioids and gives less attention to education in nonpharmacological approaches as well as nonopioid medications. Discussion. The findings highlight significant discrepancies between the prevalence of chronic pain in society and the low priority assigned to educating future physicians about the complexities of pain and the social context of those afflicted. This suggests the need for better pain education as well as attention to the “hidden curriculum.”

In their impressive meta-analysis, Cheng and colleagues find no meaningful evidence for the impact of psychosocial interventions that could be used in primary care situations to help patients maintain abstinence from alcohol.1 It …

The high tensile strength and biocompatibility of spider dragline silk makes it a desirable material in many engineering and tissue regeneration applications. Here, we present the feasibility to produce recombinant proteins in transgenic tobacco Nicotiana tabacum with sequences representing spider silk protein building blocks . Recombinant mini-spidroins contain native N- and C-terminal domains of major ampullate spidroin 1 (rMaSp1) or rMaSp2 flanking an abbreviated number (8, 16 or 32) of consensus repeat domains. Two different expression plasmid vectors were tested and a downstream chitin binding domain and self-cleavable intein were included to facilitate protein purification. We confirmed gene insertion and RNA transcription by PCR and reverse-transcriptase PCR, respectively. Mini-spidroin production was detected by N-terminus specific antibodies. Purification of mini-spidroins was performed through chitin affinity chromatography and subsequent intein activation with reducing reagent. Mini-spidroins, when dialyzed and freeze-dried, formed viscous gelatin-like fluids.

Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1's 5-phosphatase module in this process is well recognized, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin-coated intermediates, strongly implicating Sac domain's activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson's disease.

Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2 ), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2 , and mutations that disrupt complex function and/or formation cause profound consequences in cells. Surprisingly, mutations in this pathway are linked with neurological diseases, including Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis. Future studies of PI(3,5)P2 and PI5P are likely to expand the roles of these lipids in regulation of cellular functions, as well as provide new approaches for treatment of some neurological diseases.

Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC1), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORC1 as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORC1 activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic terminals. This novel mode of synaptic regulation conferred by dendritic mTORC1 is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatictrans-synaptic control of presynaptic function. Our findings thus reveal that mTORC1-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORC1 signaling.

Normal steady-state levels of the signalling lipids PI(3,5)P2 and PI(5)P require the lipid kinase FAB1/PIKfyve and its regulators, VAC14 and FIG4. Mutations in the PIKfyve/VAC14/FIG4 pathway are associated with Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis in humans, and profound neurodegeneration in mice. Hence, tight regulation of this pathway is critical for neural function. Here, we examine the localization and physiological role of VAC14 in neurons. We report that endogenous VAC14 localizes to endocytic organelles in fibroblasts and neurons. Unexpectedly, VAC14 exhibits a pronounced synaptic localization in hippocampal neurons, suggesting a role in regulating synaptic function. Indeed, the amplitude of miniature excitatory postsynaptic currents is enhanced in both Vac14−/− and Fig4−/− neurons. Re-introduction of VAC14 in postsynaptic Vac14−/− cells reverses this effect. These changes in synaptic strength in Vac14−/− neurons are associated with enhanced surface levels of the AMPA-type glutamate receptor subunit GluA2, an effect that is due to diminished regulated endocytosis of AMPA receptors. Thus, VAC14, PI(3,5)P2 and/or PI(5)P play a role in controlling postsynaptic function via regulation of endocytic cycling of AMPA receptors.

SummaryHomeostatic synaptic plasticity is important for maintaining stability of neuronal function, but heterogeneous expression mechanisms suggest that distinct facets of neuronal activity may shape the manner in which compensatory synaptic changes are implemented. Here, we demonstrate that local presynaptic activity gates a retrograde form of homeostatic plasticity induced by blockade of AMPA receptors (AMPARs) in cultured hippocampal neurons. We show that AMPAR blockade produces rapid (

Among many presumed-shape pdf approaches for modeling non-premixed turbulent combustion, the presumed ß-function pdf is widely used in the literature. However, numerical integration of the ß-function pdf may encounter singularity difficulties at mixture fraction values of Z = 0 or 1. To date, this issue has been addressed by few publications. The present study proposes the Piecewise Integration Method (PIM), an efficient, robust and accurate algorithm to overcome these numerical difficulties with the added benefit of improving computational efficiency. Comparison of this method to the existing numerical integration methods shows that the PIM exhibits better accuracy and greatly increases computational efficiency. The PIM treatment of the ß-function pdf integration is first applied to the Burke-Schumann solution in conjunction with the k - e turbulence model to simulate a CH4/H2 bluff-body turbulent flame. The proposed new method is then applied to the same flow using a more complex combustion model, the laminar flamelet model. Numerical predictions obtained by using the proposed ß-function pdf integration method are compared to experimental values of the velocity field, temperature and species mass fractions to illustrate the efficiency and accuracy of the present method.

Frozen section is a reliable technique in gynecologic pathology and is widely used to guide intraoperative management in patients presenting with ovarian masses. However, there are limited data regarding the diagnostic accuracy of frozen section in specific subtypes of ovarian neoplasia. Our impression that primary clear cell carcinoma (CCC) causes disproportionate diagnostic difficulty led us to review the intraoperative and final histopathologic reports from a consecutive series of 44 CCC that were subject to frozen-section assessment and to compare the results with a similar number of primary serous and endometrioid carcinomas. The original intraoperative slides from those CCC with discordant diagnoses were also reviewed. Review of the diagnostic reports showed that CCC was less frequently specifically identified than serous or endometrioid carcinomas on frozen section (44% cases compared with 55% and 65%, respectively), although the differences were not statistically significant. Difficulties in distinguishing primary ovarian carcinoma from tumors metastatic to the ovary occurred in a minority of cases of all histologic subtypes, but was slightly more frequent in CCC. Two CCC were misdiagnosed as borderline epithelial tumors and 1 case as a dysgerminoma. Review of the frozen-section slides from the CCC with discrepant intraoperative diagnoses showed features suggestive or indicative of the correct diagnosis in 7 (39%) of 18 cases.

Traumatic injuries continue to present a threat to the success of current and future spaceflight missions. The magnitude of this threat will grow as the frequency of extravehicular activities is increased and missions venture beyond low Earth orbit and further away from terrestrial medical support. The capability to render definitive treatment to crewmembers who suffer a serious traumatic injury while in space is relatively limited at present. While some research has focused on the development of specific surgical techniques for the microgravity environment, little attention has been given to how one might practically provide anesthetic care for injured crewmembers expected to undergo these procedures. While many logistical and practical obstacles exist to the provision of general anesthesia in microgravity, regional anesthesia could be used to overcome many of these problems. A regional anesthetic capability for spaceflight missions could be developed with minimal modifications to existing terrestrial techniques and would provide the ability to manage a wide range of potential injuries while in orbit. The capability to provide reliable regional anesthesia could be further augmented and improved using a range of imaging technologies currently in development; it is expected that these devices would have a range of terrestrial applications, including the ability to provide immediate, safe, and reliable anesthetic care to patients in remote locations, or under austere conditions such as the combat environment.

The paper outlines a modelling technique that predicts how woven fabric constructions will change shape when subjected to the application of hydrostatic pressure. The initial specification required for the technique is in terms of a triangulated pattern for each fabric piece in the construction and an initial 3D location for each node. Fabric types are characterised by look-up tables describing the warp and weft tensile and shear behaviours. The modelling proceeds by seeking to find the minimum energy state of the construction where material strain energy is balanced by the energy required to inflate the construction by the application of hydrostatic energy. Examples are provided to illustrate the operation of the technique.

With traditional two-dimensional based interfaces, many CAD surface models are difficult to design and edit due to their 3D nature. This paper discusses a technique for the deformation of CAD surface models with haptic interaction based on shape control functions. With the technique, designers can use a haptic interface to directly touch a native B-rep CAD model, and deform it in real-time by pushing, pulling and dragging its surfaces in a natural 3D environment. The deformation is governed by shape control functions. By using the shape functions, designers can specify the area of deformation, and also have greater controls on the shape of deformation. This technique is numerically efficient, and can deform complex surface models involving several thousand control points in real-time. The haptic-based deforming approach gives designers greater flexibility for the manipulation of complex CAD surfaces.

Full-length cDNA for a mouse gene A2-macroglobulin induced by pregnancy (A2mp) was cloned from mesometrial decidua at Gestation Day 10. The 4622-base pair cDNA encodes a protein of 1473 AA with >70% sequence identity and all typical domains of other A2M-family members in humans and rodents, despite unique absence of hepatic expression. The bait region is most distinct and has the greatest sequence similarity with rat acute-phase A2m. Northern blotting, reverse transcription and real-time-PCR, and in situ hybridization studies using C57Bl/6 mice revealed uterine induction of A2mp during decidualization and strong, midgestational association with modifying spiral arteries. Ovaries, testes, lactating mammary glands, heart, and kidney were the only additional organs with A2mp expression that was localized to granulosa and cumulus cells in secondary follicles; primary seminiferous epithelium, including Sertoli cells, mammary alveolar, and ductal epithelium; cardiac endothelium; and renal collecting tu...

Obesity is common in endometrial cancer and surgery for these patients is challenging. We compared total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) with respect to feasibility (operating time, estimated blood loss, length of hospital stay, and conversion to laparotomy) and safety (perioperative morbidity and mortality) in a retrospective analysis of 78 morbidly obese patients with endometrial cancer. Analysis is based on the intention to treat. The intention to treat was TLH in 47 patients and it could be successfully completed in 42 patients (89.4%). The mean weight for all patients was 118.7 kg, with patients in the TLH group weighing more and having higher ASA scores. Mean operating time and estimated blood loss were similar in both groups. Mean postoperative hospital stay was 4.4 (±3.9) days in the TLH group and 7.9 (±3.0) days in the TAH group (P < 0.0001). Wound infections occurred in 15 of 31 patients (48.4%) in the TAH group and in 1 of 47 patients (2.1%) in the TLH group. All other morbidity, as well as patterns of recurrence and survival were similar in both groups. These data justify a prospective randomized trial comparing TLH with TAH for the treatment of endometrial cancer

Escape extinction has been demonstrated to be an effective treatment for children exhibiting food refusal. To date, most studies have been conducted in inpatient treatment settings by trained clinicians. Few studies have evaluated the extent to which caregivers are able to implement efficacious interventions in their home for their food-selective child. This study evaluated a systematic strategy for training caregivers to implement escape extinction. A modified changing-criterion design was used to evaluate a clinic-based training procedure consisting of escape extinction and differential reinforcement. After participants met prespecified criteria with regard to the number of bites accepted and latency until acceptance, caregivers were taught to implement the procedure in the clinic. After criteria were met with caregivers feeding their children, caregivers were taught to implement the procedure during meals conducted at their home. Follow-up data conducted for three participants indicated that generalization across time and food types had occurred.

In this paper, a model for predicting the stresses within a strained anisotropic fabric is presented. The fabric is characterised by tensile test data in the warp and weft directions as well as shear behaviour. The data is in the form of look-up tables that are capable of representing the non-linear form of each response. The model operates simultaneously on a triangular representation for both the 2D pattern defined on an undistorted fabric and an equivalent triangulation of a 3D representation of the fabric. An energy relaxation technique is applied to the situation in order to predict how the 3D representation should react in order to reach a minimum energy state. Arbitrary constraining configurations can be applied by setting a flag for each node to indicate those fixed in 3D. The resultant forces on fixed nodes can be determined. The model has been successfully applied to two examples. In the second of these, validation took the form of measuring the physical force effects of the fabric on an experimental rig and comparing them with those predicted by the model. It was then demonstrated that the model could predict other forces that could not be easily measured.

Haptic devices (force feedback interfaces) show great promise for use in the design of CAD models. However, current haptic systems are used primarily to verify rather than to interact with CAD systems to design a model. The paper discusses a haptic-based CAD system—Virtual DesignWorks. It is the world's first haptic application for the design of CAD models based on component technology (COM+). With haptic devices, the system allows engineers, in virtual space, to directly touch a native B-Rep CAD model, and deform it by pushing, pulling and dragging its surfaces in a natural three-dimensional environment. Virtual DesignWorks adopts the novel COM-based haptic model, which demonstrates significant advantages compared to the traditional haptic models. Force feedback gives designers the greatest flexibility for the design of complex surfaces, and haptics has the potential to become a critical interface for design applications.