A Hybrid Approach to Finding Relevant Social Media Content for Complex Domain Specific Information Needs.
While contemporary semantic search systems offer to improve classical keyword-based search, they are not always adequate for complex domain specific information needs. The domain of prescription drug abuse, for example, requires knowledge of both ontological concepts and "intelligible constructs" not typically modeled in ontologies. These intelligible constructs convey essential information that include notions of intensity, frequency, interval, dosage and sentiments, which could be important to the holistic needs of the information seeker. In this paper, we present a hybrid approach to domain specific information retrieval that integrates ontology-driven query interpretation with synonym-based query expansion and domain specific rules, to facilitate search in social media on prescription drug abuse. Our framework is based on a context-free grammar (CFG) that defines the query language of constructs interpretable by the search system. The grammar provides two levels of semantic interpretation: 1) a top-level CFG that facilitates retrieval of diverse textual patterns, which belong to broad templates and 2) a low-level CFG that enables interpretation of specific expressions belonging to such textual patterns. These low-level expressions occur as concepts from four different categories of data: 1) ontological concepts, 2) concepts in lexicons (such as emotions and sentiments), 3) concepts in lexicons with only partial ontology representation, called lexico-ontology concepts (such as side effects and routes of administration (ROA)), and 4) domain specific expressions (such as date, time, interval, frequency and dosage) derived solely through rules. Our approach is embodied in a novel Semantic Web platform called PREDOSE, which provides search support for complex domain specific information needs in prescription drug abuse epidemiology. When applied to a corpus of over 1 million drug abuse-related web forum posts, our search framework proved effective in retrieving relevant documents when compared with three existing search systems.


CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.
Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.


Finite Element Analysis of a New Pedicle Screw-Plate System for Minimally Invasive Transforaminal Lumbar Interbody Fusion.
Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is increasingly popular for the surgical treatment of degenerative lumbar disc diseases. The constructs intended for segmental stability are varied in MI-TLIF. We adopted finite element (FE) analysis to compare the stability after different construct fixations using interbody cage with posterior pedicle screw-rod or pedicle screw-plate instrumentation system. A L3-S1 FE model was modified to simulate decompression and fusion at L4-L5 segment. Fixation modes included unilateral plate (UP), unilateral rod (UR), bilateral plate (BP), bilateral rod (BR) and UP+UR fixation. The inferior surface of the S1 vertebra remained immobilized throughout the load simulation, and a bending moment of 7.5 Nm with 400N pre-load was applied on the L3 vertebra to recreate flexion, extension, lateral bending, and axial rotation. Range of motion (ROM) and Von Mises stress were evaluated for intact and instrumentation models in all loading planes. All reconstructive conditions displayed decreased motion at L4-L5. The pedicle screw-plate system offered equal ROM to pedicle screw-rod system in unilateral or bilateral fixation modes respectively. Pedicle screw stresses for plate system were 2.2 times greater than those for rod system in left lateral bending under unilateral fixation. Stresses for plate were 3.1 times greater than those for rod in right axial rotation under bilateral fixation. Stresses on intervertebral graft for plate system were similar to rod system in unilateral and bilateral fixation modes respectively. Increased ROM and posterior instrumentation stresses were observed in all loading modes with unilateral fixation compared with bilateral fixation in both systems. Transforaminal lumbar interbody fusion augmentation with pedicle screw-plate system fixation increases fusion construct stability equally to the pedicle screw-rod system. Increased posterior instrumentation stresses are observed in all loading modes with plate fixation, and bilateral fixation could reduce stress concentration.


Discographic, MRI and psychosocial determinants of low back pain disability and remission: a prospective study in subjects with benign persistent back pain.
A range of morphologic and psychosocial variables has been suggested as risk factors for serious low back pain (LBP) illness. Although the relative contributions of structural and psychosocial variables are intensely debated, the validity of differing hypotheses has proven difficult to test because the incidence of serious disabling LBP illness is low in healthy subjects. These factors dictate the requirement for large sample sizes, extensive structural imaging and extended longitudinal study. Previous studies included either small cohorts with intensive imaging testing or large population studies that do not establish a detailed morphologic baseline. To establish, using a strict patient sample design, the relative contribution of structural and psychosocial determinants of serious LBP illness among subjects with no previous LBP disability or clinical LBP illness. A prospective, longitudinal study of subjects with high risk factors for serious LBP as determined by structural and psychosocial characteristics. One hundred subjects with known mild persistent low back pain and a 2:1 ratio of chronic (non-lumbar) pain syndrome were recruited from a study population with a predisposition to disc degenerative disease, to undergo baseline examination, testing and 5-year follow-up. Observations were made at 6-month intervals over 4 to 6 years (mean, 5.3) for the after primary outcomes measures: episodes of serious back pain (visual analogue scale [VAS] > or =6), episodes of occupational disability less than 1 week, episodes of occupational disability for 1 week, remission episodes of all back pain symptoms at least 6 months and medical visits primarily for LBP evaluation and treatment. Lumbar magnetic resonance imaging (MRI), lumbar provocative discography (in psychometrically normal subjects), physical examinations, medical and work histories and psychometric testing were performed at baseline. Imaging and psychometric testing were graded by blinded examiners. A scripted interview was conducted every 6 months during follow-up by independent research assistants who also were blinded to patient baseline data. The interview covered interval medical, occupational and accident or injury histories. Psychosocial variables strongly predicted both long- and short-term disability events, duration and health-care visits for LBP problems (p<0.0001-0.004). The likelihood of a sustained remission from the baseline persistent (subclinical) LBP appeared to be linked to occupation factors (leaving a heavy labor occupation; p=0.0001), neurophysiologic variables (chronic nonlumbar pain; p=0.0002) and psychometric profiles at baseline (DRAM and FABQ-PA; p=0.003-0.002). Of the structural findings measured only moderate or severe Modic changes of the vertebral end plate were weakly associated with an adverse outcome. A positive provocative discogram at baseline did not predict any future adverse event. The development of serious LBP disability in a cohort of subjects with both structural and psychosocial risk factors was strongly predicted by baseline psychosocial variables. Structural variables on both MRI and discography testing at baseline had only weak association with back pain episodes and no association with disability or future medical care.


Psychological Science and Innovative Strategies for Informing Health Care Redesign: A Policy Brief.
Recent health care legislation and shifting health care financing strategies are transforming health and behavioral health (a broad term referring to mental health, substance use, and health behavior) care in the United States. Advances in knowledge regarding effective treatment and services coupled with incentives for innovation in health and behavioral health care delivery systems make this a unique time for mobilizing our science to enhance the success of health and behavioral health care redesign. To optimize the potential of our current health care environment, a team was formed composed of leaders from the Societies of Clinical Child & Adolescent Psychology, Pediatric Psychology, and Child and Family Policy and Practice (Divisions 53, 54, and 37 of the American Psychological Association). This team was charged with reviewing the scientific and policy literature with a focus on five major issues: (a) improving access to care and reducing health disparities, (b) integrating behavioral health care within primary care, (c) preventive services, (d) enhancing quality and outcomes of care, and (e) training and workforce development. The products of that work are summarized here, including recommendations for future research, clinical, training, and policy directions. We conclude that the current emphasis on accountable care and evaluation of the outcomes of care offer numerous opportunities for psychologists to integrate science and practice for the benefit of our children, families, and nation. The dramatic changes that are occurring in psychological and behavioral health care services and payment systems also require evolution in our practice and training models.


Effect of confinement on electric field induced orientation of a nematic liquid crystal.
We report the effect of confinement on the electric field induced orientation of a nematic liquid crystal, 4-cyano-4'-hexylbiphenyl (6CB), between mica surfaces. The resonance shear measurement was employed for monitoring changes in the viscosity of 6CB at various surface separation distances (D) with and without an applied electric field. The viscosity depended on the surface separations, and the behaviour for D < ca. 20 nm was quite different from that at D > ca. 20 nm. For D > ca. 20 nm, the viscosity values obtained in the presence of the electric field (ac 1 kHz, 1.87 kV mm(-1), homeotropic orientation) were ca. 2 times higher than the values obtained without the electric field (0 kV mm(-1), planar orientation) due to the difference in the molecular orientation, and were nearly constant. At D < ca. 20 nm, the viscosity of 6CB both with and without the electric field sharply increased and they merged into an identical value at D = 12.5 ± 1.3 nm (Dc), then exhibited a plateau up to D = 6 nm. With the decreasing distance below 6 nm, the viscosity of confined 6CB both with and without the electric field further increased up to more than 100 N s m(-1) at the hard wall thickness of D = ca. 4.0 nm. These results indicated that 6CB molecules both with and without the electric field had the same orientation at D < Dc. The most likely orientation of 6CB was parallel to the surfaces because 6CB was originally in a planar orientation on the mica surface. These results demonstrated for the first time that the effect of confinement exceeded the electric field, thus 6CB molecules could not change their orientation under the electric field at the surface separation below Dc.


Use of alternative medicine in Israeli chronic rhinosinusitis patients.
The worldwide interest in the use of complementary and alternative medicine (CAM) has been established in multiple surveys. Chronic rhinosinusitis (CRS) is often an unremitting disease with frequent troubling relapses, and despite wide use of endoscopic sinus surgery, conventional medicine may have a smaller contribution than expected. Because of prevalent use of CAM among patients, it is important that physicians acquire basic knowledge of this subject. We studied the prevalence of CAM use among CRS patients in Israel. Use of CAM was evaluated in a cohort of consecutive adult patients with CRS. An outpatient clinic in a tertiary medical centre. Patients were asked to fill out an anonymous questionnaire containing demographic data and data pertaining to allergy, traditional medical and surgical treatment use of CAM, and modalities used. Ninety patients were included. Nineteen of them (21%) reported CAM use. This included herbal medicine, vitamins, homeopathy, acupuncture, massage, reflexology, yoga, and chiropractics. There was a tendency, although not statistically significant, for patients with allergy and a history of sinus surgery to use CAM. The prevalence of CAM use among patients with CRS in Israel is high and may correlate with the presence of allergies and a history of sinus surgery.


Lead and copper release from full and partially replaced harvested lead service lines: Impact of stagnation time prior to sampling and water quality.
Partial lead service line replacement (PLSLR) results in the addition of a new galvanic connection and can increase lead concentrations at the tap. Focus has been given to minimizing lead release after PLSLR, but little information is available on the impact of lead remedial actions on copper concentrations, especially before passivation occurs. The impact of water quality (decreased chloride-to-sulfate mass ratio from 0.9 to 0.3; addition of orthoP; pH increase to 8.3) on lead and copper concentrations was investigated after stagnation (30 min-336 h) in a pipe rig comparing full lead service line (LSL), and two configurations of partial LSLs (Cu-Pb and Pb-Cu). Results show different trends for lead and copper: maximum lead concentrations were reached in 16 h while copper concentrations continued to increase over 336 h. Lead release rates were also the highest in the first 16 h of stagnation and were strongly impacted by water quality and the configuration of PLSLR (Cu-Pb vs Pb-Cu). Increasing the sampling flow rate from 5 to 15 LPM drastically increased the particulate lead release (78-fold) in Pb-Cu configurations; this effect was however not observed in 100% Pb or Cu-Pb configurations. High velocity flushing prior to 16 h stagnation decreased total Pb release by a factor of 12-fold for Cu-Pb, 1.6-fold for Pb-Cu and 2.0-fold for 100% Pb. Results support the definition of sampling protocols targeted for the detection of lead and copper sources and the proscription of flushing prior to sampling.


High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.
Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes. Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies. Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments. We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.


A descriptive survey study of violence management and priorities among psychiatric staff in mental health services, across seventeen european countries.
In mental health services what is commonplace across international frontiers is that to prevent aggressive patients from harming themselves, other patients or staff, coercive measures and foremost, violence management strategies are required. There is no agreement, recommendations or direction from the EU on which measures of coercion should be practiced across EU countries, and there is no overall one best practice approach. The project was conceived through an expert group, the European Violence in Psychiatry Research Group (EViPRG). The study aimed to incorporate an EU and multidisciplinary response in the determination of violence management practices and related research and education priorities across 17 European countries. From the EVIPRG members, one member from each country agreed to act as the national project coordinator for their country. Given the international spread of respondents, an eDelphi survey approach was selected for the study design and data collection. A survey instrument was developed, agreed and validated through members of EVIPRG. The results included a total of 2809 respondents from 17 countries with 999 respondents who self-selected for round 2 eDelphi. The majority of respondents worked in acute psychiatry, 54% (n = 1511); outpatient departments, 10.5% (n = 295); and Forensic, 9.3% (n = 262). Other work areas of respondents include Rehabilitation, Primary Care and Emergency. It is of concern that 19.5% of respondents had not received training on violence management. The most commonly used interventions in the management of violent patients were physical restraint, seclusion and medications. The top priorities for education and research included: preventing violence; the influence of environment and staff on levels of violence; best practice in managing violence; risk assessment and the aetiology and triggers for violence and aggression. In many European countries there is an alarming lack of clarity on matters of procedure and policy pertaining to violence management in mental health services. Violence management practices in Europe appear to be fragmented with no identified ideological position or collaborative education and research. In Europe, language differences are a reality and may have contributed to insular thinking, however, it must not be seen as a barrier to sharing best practice.


Expression of the soluble vascular endothelial growth factor receptor-1 in cutaneous melanoma: role in tumour progression.
Vascular endothelial growth factor (VEGF)-A, placenta growth factor (PlGF) and their corresponding membrane receptors are involved in autocrine and paracrine regulation of melanoma growth and metastasis. Besides the membrane receptors, a soluble form of the VEGF receptor (VEGFR)-1 (sVEGFR-1) has been identified, that behaves both as a decoy receptor, sequestering VEGF-A and PlGF, and as an extracellular matrix (ECM) molecule, promoting endothelial cell adhesion and migration through the interaction with α5β1 integrin. To analyse whether sVEGFR-1 plays a role during melanoma progression. sVEGFR-1 expression was evaluated in a panel of 36 melanoma cell lines and 11 primary human melanocyte cultures by quantitative real-time polymerase chain reaction analysis and in specimens of primary or metastatic melanoma lesions from 23 patients by immunohistochemical analysis. sVEGFR-1 expression was highly upregulated in melanoma cell lines with respect to human melanocytes. Interestingly, cell lines obtained from cutaneous metastases showed a significant reduction of sVEGFR-1 expression, as compared with cell lines derived from primary tumours. These results were confirmed by immunohistochemical analysis of sections from primary skin melanomas and the corresponding cutaneous metastases, suggesting that modulation of sVEGFR-1 expression influences ECM invasion by melanoma cells and metastasis localization. Moreover, we provide evidence that adhesion of melanoma cells to sVEGFR-1 is favoured by the activation of a VEGF-A/VEGFR-2 autocrine loop. Our data strongly suggest that sVEGFR-1 plays a role in melanoma progression and that low sVEGFR-1/VEGF-A and sVEGFR-1/transmembrane VEGFR-1 ratios might predict a poor outcome in patients with melanoma.


Population-Wide Associations between Common Viral Pathogens and Self-Reported Arthritis: NHANES 2009-2012.
Persistent infectious agents have been implicated in chronic and recurrent inflammation, which may trigger or worsen many types of arthritis. Our objective was to determine whether exposure to herpes simplex virus (HSV) and human papillomavirus (HPV) is associated with self-reported arthritis among US adults. We used data from two consecutive cycles of the National Health and Nutrition Examination Survey (NHANES) from 2009 until 2012 (N of examined adults ages 20-69 = 9483). Participants were classified as having arthritis by self-report. Viral serology for HSV-1 and HSV-2 and HPV PCR studies from oral rinse and vaginal swabs were available for analysis. We compared HSV-1 and HSV-2 seropositivity as well as oral and vaginal HPV DNA positivity between participants with self-reported arthritis vs. those without, adjusting for age, gender, race, income, education, BMI, and the use of immunosuppressive medications. We used three comparator outcomes, gout, kidney stones, and hypertension, to evaluate whether the associations were specific or not to arthritis. Arthritis was associated with older age, female gender, non-Hispanic White and Non-Hispanic Black race, higher BMI, and lower socioeconomic status. HSV-2 seropositivity, but not HSV-1 seropositivity, was independently associated with arthritis after adjustment for age, gender, race, income, education, BMI, and the use of immunosuppressive medications: AOR 1.48 (1.10-1.99). Oral HPV DNA positivity was also independently associated with arthritis: AOR 1.63 (1.17-2.28). After adjustment, there was no statistically significant difference in vaginal HPV DNA positivity between those with vs. those without arthritis: AOR 1.22 (0.90-1.66). There were no significant associations between viral exposures and any of the comparator outcomes. HSV-2 seropositivity and oral HPV DNA positivity were associated with self-reported arthritis and not with comparator outcomes, after adjustment for multiple potential confounders. These findings should be confirmed in longitudinal studies.


Adherence to Oral Glucose-Lowering Therapies and Associations With 1-Year HbA1c: A Retrospective Cohort Analysis in a Large Primary Care Database.
The impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication. Data were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction. In CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c. Reduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use.


Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man.
1. 11-beta-Hydroxysteroid dehydrogenase is an enzyme complex consisting of 11 beta-dehydrogenase and 11-oxoreductase responsible for the interconversion of cortisol to cortisone in man. Inhibition of 11 beta-dehydrogenase (e.g. after liquorice ingestion) results in cortisol acting as a potent mineralocorticoid. We have evaluated the effect of the synthetic liquorice derivative, carbenoxolone, on this enzyme complex. 2. Carbenoxolone given to six volunteers in metabolic balance produced sodium retention with suppression of the renin-angiotensin-aldosterone system. Plasma potassium fell, although there was no kaliuresis. This was associated with inhibition of 11 beta-dehydrogenase (as measured by a rise in the plasma half-life of [11 alpha-3H]cortisol). Unlike liquorice, however, carbenoxolone also inhibited 11-oxoreductase (as measured by the generation of cortisol after oral cortisone acetate). 3. The mineralocorticoid activity of carbenoxolone, like liquorice, is mediated via cortisol by inhibition of 11 beta-dehydrogenase. Carbenoxolone, however, also inhibits 11-oxoreductase activity and this may relate to its effect on renal potassium excretion.


Epidemiology of injuries from fire, heat and hot substances: global, regional and national morbidity and mortality estimates from the Global Burden of Disease 2017 study.
Past research has shown how fires, heat and hot substances are important causes of health loss globally. Detailed estimates of the morbidity and mortality from these injuries could help drive preventative measures and improved access to care. We used the Global Burden of Disease 2017 framework to produce three main results. First, we produced results on incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years from 1990 to 2017 for 195 countries and territories. Second, we analysed these results to measure mortality-to-incidence ratios by location. Third, we reported the measures above in terms of the cause of fire, heat and hot substances and the types of bodily injuries that result. Globally, there were 8 991 468 (7 481 218 to 10 740 897) new fire, heat and hot substance injuries in 2017 with 120 632 (101 630 to 129 383) deaths. At the global level, the age-standardised mortality caused by fire, heat and hot substances significantly declined from 1990 to 2017, but regionally there was variability in age-standardised incidence with some regions experiencing an increase (eg, Southern Latin America) and others experiencing a significant decrease (eg, High-income North America). The incidence and mortality of injuries that result from fire, heat and hot substances affect every region of the world but are most concentrated in middle and lower income areas. More resources should be invested in measuring these injuries as well as in improving infrastructure, advancing safety measures and ensuring access to care.


Characterization of citrate synthase from Geobacter sulfurreducens and evidence for a family of citrate synthases similar to those of eukaryotes throughout the Geobacteraceae.
Members of the family Geobacteraceae are commonly the predominant Fe(III)-reducing microorganisms in sedimentary environments, as well as on the surface of energy-harvesting electrodes, and are able to effectively couple the oxidation of acetate to the reduction of external electron acceptors. Citrate synthase activity of these organisms is of interest due to its key role in acetate metabolism. Prior sequencing of the genome of Geobacter sulfurreducens revealed a putative citrate synthase sequence related to the citrate synthases of eukaryotes. All citrate synthase activity in G. sulfurreducens could be resolved to a single 49-kDa protein via affinity chromatography. The enzyme was successfully expressed at high levels in Escherichia coli with similar properties as the native enzyme, and kinetic parameters were comparable to related citrate synthases (kcat= 8.3 s(-1); Km= 14.1 and 4.3 microM for acetyl coenzyme A and oxaloacetate, respectively). The enzyme was dimeric and was slightly inhibited by ATP (Ki= 1.9 mM for acetyl coenzyme A), which is a known inhibitor for many eukaryotic, dimeric citrate synthases. NADH, an allosteric inhibitor of prokaryotic hexameric citrate synthases, did not affect enzyme activity. Unlike most prokaryotic dimeric citrate synthases, the enzyme did not have any methylcitrate synthase activity. A unique feature of the enzyme, in contrast to citrate synthases from both eukaryotes and prokaryotes, was a lack of stimulation by K+ ions. Similar citrate synthase sequences were detected in a diversity of other Geobacteraceae members. This first characterization of a eukaryotic-like citrate synthase from a prokaryote provides new insight into acetate metabolism in Geobacteraceae members and suggests a molecular target for tracking the presence and activity of these organisms in the environment.


Comparing protein sequence-based and predicted secondary structure-based methods for identification of remote homologs.
We have compared a novel sequence-structure matching technique, FORESST, for detecting remote homologs to three existing sequence based methods, including local amino acid sequence similarity by BLASTP, hidden Markov models (HMMs) of sequences of protein families using SAM, HMMs based on sequence motifs identified using meta-MEME. FORESST compares predicted secondary structures to a library of structural families of proteins, using HMMs. Altogether 45 proteins from nine structural families in the database CATH were used in a cross-validated test of the fold assignment accuracy of each method. Local sequence similarity of a query sequence to a protein family is measured by the highest segment pair (HSP) score. Each of the HMM-based approaches (FORESST, MEME, amino acid sequence-based HMM) yielded log-odds score for the query sequence. In order to make a fair comparison among these methods, the scores for each method were converted to Z-scores in a uniform way by comparing the raw scores of a query protein with the corresponding scores for a set of unrelated proteins. Z-Scores were analyzed as a function of the maximum pairwise sequence identity (MPSID) of the query sequence to sequences used in training the model. For MPSID above 20%, the Z-scores increase linearly with MPSID for the sequence-based methods but remain roughly constant for FORESST. Below 15%, average Z-scores are close to zero for the sequence-based methods, whereas the FORESST method yielded average Z-scores of 1.8 and 1.1, using observed and predicted secondary structures, respectively. This demonstrates the advantage of the sequence-structure method for detecting remote homologs.


Using computer-vision and machine learning to automate facial coding of positive and negative affect intensity.
Facial expressions are fundamental to interpersonal communication, including social interaction, and allow people of different ages, cultures, and languages to quickly and reliably convey emotional information. Historically, facial expression research has followed from discrete emotion theories, which posit a limited number of distinct affective states that are represented with specific patterns of facial action. Much less work has focused on dimensional features of emotion, particularly positive and negative affect intensity. This is likely, in part, because achieving inter-rater reliability for facial action and affect intensity ratings is painstaking and labor-intensive. We use computer-vision and machine learning (CVML) to identify patterns of facial actions in 4,648 video recordings of 125 human participants, which show strong correspondences to positive and negative affect intensity ratings obtained from highly trained coders. Our results show that CVML can both (1) determine the importance of different facial actions that human coders use to derive positive and negative affective ratings when combined with interpretable machine learning methods, and (2) efficiently automate positive and negative affect intensity coding on large facial expression databases. Further, we show that CVML can be applied to individual human judges to infer which facial actions they use to generate perceptual emotion ratings from facial expressions.


Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx.
Bruton's tyrosine kinase (Btk), a member of the Tec family of protein-tyrosine kinases, has been shown to be crucial for B cell development, differentiation, and signaling. Mutations in the Btk gene lead to X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice. Using a co-transfection approach, we present evidence here that Btk interacts physically with caveolin-1, a 22-kDa integral membrane protein, which is the principal structural and regulatory component of caveolae membranes. In addition, we found that native Bmx, another member of the Tec family kinases, is associated with endogenous caveolin-1 in primary human umbilical vein endothelial cells. Second, in transient transfection assays, expression of caveolin-1 leads to a substantial reduction in the in vivo tyrosine phosphorylation of both Btk and its constitutively active form, E41K. Furthermore, a caveolin-1 scaffolding peptide (amino acids 82--101) functionally suppressed the autokinase activity of purified recombinant Btk protein. Third, we demonstrate that mouse splenic B-lymphocytes express substantial amounts of caveolin-1. Interestingly, caveolin-1 was found to be constitutively phosphorylated on tyrosine 14 in these cells. The expression of caveolin-1 in B-lymphocytes and its interaction with Btk may have implications not only for B cell activation and signaling, but also for antigen presentation.


Nutritional supplementation with N-3 fatty acids and antioxidants in patients with Crohn's disease in remission: effects on antioxidant status and fatty acid profile.
In patients with Crohn's disease (CD), malnutrition is frequently observed and is generally accepted to be an important issue. The aim of this study was to investigate the effects of 3 months of supplementation with a liquid formula containing either antioxidants (AO) or n-3 fatty acids plus AO on the antioxidant status and fatty acid profile of plasma phospholipids and adipose tissue, respectively, in patients with long-standing CD currently in remission. In a randomized, double-blind placebo-controlled study, CD patients received either placebo, AO, or n-3 fatty acids plus AO for 3 months in addition to their regular diet. In all, 25/37 CD patients completed the study. AO status was assessed by blood biochemical parameters. A statistical per-protocol analysis was performed. Serum concentrations of selenium, vitamin C, and vitamin E, the activity of superoxide dismutase and total antioxidant status were significantly (p < 0.05) increased after AO supplementation. Furthermore, compared with controls, serum concentrations of beta-carotene, selenium, and vitamin C and the activity of glutathione peroxidase (GPx) were significantly (p < 0.05) lower before supplementation; however, after AO supplementation these levels were not significantly different from controls (except for GPx). N-3 fatty acids plus AO supplementation significantly (p < 0.05) decreased the proportion of arachidonic acid, and increased the proportion of eicosapentanoic acid and docosahexanoic acid in both plasma phospholipids and adipose tissue. Supplementation with antioxidants improved antioxidant status in patients with CD in remission. In addition, supplementation with n-3 fatty acids plus antioxidants significantly changed the eicosanoid precursor profile, which may lead to the production of eicosanoids with attenuated proinflammatory activity. This study indicates that an immunomodulating formula containing n-3 fatty acids and/or AO may have the potential to play a role in the treatment of CD.


A 3620-Year Temperature Record from Fitzroya cupressoides Tree Rings in Southern South America.
A tree-ring width chronology of alerce trees (Fitzroya cupressoides) from southern Chile was used to produce an annually resolved 3622-year reconstruction of departures from mean summer temperatures (December to March) for southern South America. The longest interval with above-average temperatures was from 80 B.C. to A.D. 160. Long intervals with below-average temperatures were recorded from A.D. 300 to 470 and from A.D. 1490 to 1700. Neither this proxy temperature record nor instrumental data for southern South America for latitudes between 35 degrees and 44 degrees S provide evidence of a warming trend during the last decades of this century that could be related to anthropogenic causes. The data also indicate that alerce is the second longest living tree after the bristlecone pine (Pinus Iongaeva).


FSIM: a feature similarity index for image quality assessment.
Image quality assessment (IQA) aims to use computational models to measure the image quality consistently with subjective evaluations. The well-known structural similarity index brings IQA from pixel- to structure-based stage. In this paper, a novel feature similarity (FSIM) index for full reference IQA is proposed based on the fact that human visual system (HVS) understands an image mainly according to its low-level features. Specifically, the phase congruency (PC), which is a dimensionless measure of the significance of a local structure, is used as the primary feature in FSIM. Considering that PC is contrast invariant while the contrast information does affect HVS' perception of image quality, the image gradient magnitude (GM) is employed as the secondary feature in FSIM. PC and GM play complementary roles in characterizing the image local quality. After obtaining the local quality map, we use PC again as a weighting function to derive a single quality score. Extensive experiments performed on six benchmark IQA databases demonstrate that FSIM can achieve much higher consistency with the subjective evaluations than state-of-the-art IQA metrics.


Regulation of protein A synthesis by the sar and agr loci of Staphylococcus aureus.
The synthesis of protein A in Staphylococcus aureus is regulated by global regulatory loci such as sar and agr. Phenotypic data indicate that both sar and agr suppress protein A synthesis; like agr, sar also regulates protein A production at the transcriptional level. To determine the genetic requirement of sar in protein A suppression, we transformed shuttle plasmids containing various sar fragments into a sar mutant. Our results indicated that the 560-bp sarA transcript, or, more probably, the SarA protein (13.5 kDa), is sufficient for suppressing protein A gene transcription when introduced on a multicopy plasmid or as a single copy in the chromosome. Immunoblot analysis with a chicken anti-protein A antibody also confirmed the reduction in protein A expression in these sar mutant clones. Complementation studies revealed that the transcription of the protein A gene can be suppressed in a sar mutant background by a plasmid containing RNAIII. Surprisingly, in agr deletion mutant clones and in clones derived from the agr-sar double mutant, protein A gene transcription can also be suppressed by plasmids containing the sarA transcript plus additional upstream sequence but not the sarA transcript alone. These data suggest that the sar locus can down-modulate protein A gene transcription via both RNAIII-dependent and RNAIII-independent pathways. Consistent with the hypothesis of an RNAIII-independent pathway is an additional genetic requirement for protein A suppression in the agr deletion mutant RN6911 as well as the isogenic double sar-agr mutant, whereas in the sar mutant background, the sarA transcript encoding the SarA protein alone is sufficient. These data suggested that both sar and agr are coregulators of protein A synthesis in S. aureus.


[Legal settlements of medical accidents].
When an accident occurs during the course of clinical treatment, it is important to record the series of events as objectively as and in the most precise detail possible. The causes of the accident should be investigated with all due speed, and an accurate, consistent account should be rendered to the patient's family. When the cause of a patient's death is not clear, a pathological autopsy should be performed. It is the legal responsibility of physicians to notify the police of unexpected death when medical malpractice is suspected, and in compliance with the law an autopsy must be performed. A malpractice suit brought against a medical institution can be settled by two means: out-of-court settlement; and court decision. An out-of-court settlement in the event of obvious medical error is the more desirable option from the viewpoint of immediate relief of patients and/or ther families. At present, an average of three years elapses before a medical malpractice suit can be resolved in the courts. One of the main reasons for this delay in the settlement of court case is the difficulty in obtaining competent expert witnesses, and therefore members of the Japan Surgical Society should cooperate actively with the legal authorities in medical malpractice suits.


Evolution of MHC class I in the order Crocodylia.
The major histocompatibility complex (MHC) is a dynamic genomic region with an essential role in the adaptive immunity of jawed vertebrates. The evolution of the MHC has been dominated by gene duplication and gene loss, commonly known as the birth-and-death process. Evolutionary studies of the MHC have mostly focused on model species. However, the investigation of this region in non-avian reptiles is still in its infancy. To provide insights into the evolutionary mechanisms that have shaped the diversity of this region in the Order Crocodylia, we investigated MHC class I exon 3, intron 3, and exon 4 across 20 species of the families Alligatoridae and Crocodilidae. We generated 124 DNA sequences and identified 31 putative functional variants as well as 14 null variants. Phylogenetic analyses revealed three gene groups, all of which were present in Crocodilidae but only one in Alligatoridae. Within these groups, variants generally appear to cluster at the genus or family level rather than in species-specific groups. In addition, we found variation in gene copy number and some indication of interlocus recombination. These results suggest that MHC class I in Crocodylia underwent independent events of gene duplication, particularly in Crocodilidae. These findings enhance our understanding of MHC class I evolution and provide a preliminary framework for comparative studies of other non-avian reptiles as well as diversity assessment within Crocodylia.


Differentiating functional constipation from constipation-predominant irritable bowel syndrome: management implications.
Symptoms of constipation are commonly seen in medical practice. Once other medical causes have been excluded, distinguishing patients who have constipation-predominant irritable bowel syndrome (IBS) from those with functional constipation has been considered useful in terms of planning management. However, the criteria used to distinguish IBS from functional constipation are arguably arbitrary, and the availability of new therapeutic approaches may render such distinctions of little practical relevance. In this article, the author presents a review of the management implications of differentiating constipation-predominant IBS from functional constipation.


Cellular foundation of curcumin-induced apoptosis in follicular lymphoma cell lines.
Although responsive to first-line treatments, follicular lymphoma (FL) remains a fatal disease of increasing worldwide incidence. In efforts to find novel approaches to inhibit proliferation and induce apoptosis in FL cells, we examined the action of naturally occurring compound curcumin in the three recently established FL cell lines. Cytotoxic effects and determination of apoptotic attributes upon curcumin treatment were analyzed using growth inhibition, [(3)H]-thymidine, fluorescence microscopy, and flow cytometry assays, as well as Western blotting. Chemical inhibitor studies for the assessment of caspase and cathepsin contribution were applied. Expression of 10 members of the bcl-2 family proteins was evaluated by immunoblotting. Curcumin inhibited proliferation and growth, and induced profound apoptosis associated with a shift in the balance of the bcl-2 family proteins, in all cell lines tested. Strikingly, we observed that curcumin-induced caspase-dependent apoptosis is also associated with lysosomal rupture (LMP). An increase in intracellular ROS generation appeared critical for curcumin-evoked LMP, loss of Deltapsi(m,) caspase activation, and cell death, as well as ascorbic acid-mediated enhancement of curcumin's action. We have demonstrated for the first time that curcumin is an efficient inducer of apoptosis in FL cell lines, meriting its further evaluation in vivo.


Histologic assessment and grading of the exocrine pancreas in the dog.
Histologic grading schemes for canine inflammatory conditions are sparse, and in the case of the canine pancreas, have not been previously described. In a previous study, we determined that histologic lesions of the exocrine pancreas occurred much more frequently than gross lesions. The intention of the current study was to develop a histologic grading scheme for nonneoplastic lesions following extensive assessment of the exocrine pancreas from dogs presented for necropsy examination. The parameters of the proposed scheme include neutrophilic inflammation, lymphocytic inflammation, pancreatic necrosis, pancreatic fat necrosis, edema, fibrosis, atrophy, and hyperplastic nodules. In this case series, the most common lesion was pancreatic hyperplastic nodules (80.2%), followed by lymphocytic inflammation (52.5%), fibrosis (49.5%), atrophy (46.5%), neutrophilic inflammation (31.7%), pancreatic fat necrosis (25.7%), pancreatic necrosis (16.8%), and edema (9.9%). Only 8 of the 101 animals had no evidence of any of the lesions in any of the sections examined. Fibrosis, atrophy, and/or lymphocytic infiltration most commonly accompanied nodules. Neutrophilic inflammation, when present, was often associated with necrosis (pancreatic necrosis, pancreatic fat necrosis, or both) and occasionally with hyperplastic nodules. The utilization of a grading scheme for exocrine pancreatic lesions will be useful in advancing the classification of exocrine pancreatic disease in the dog, which may lead to multicenter studies of exocrine pancreatic disorders in the dog and in other species.


Effects of vitamin E supplementation on erythrocyte antioxidant defence mechanisms of smoking and non-smoking men.
1. During all aerobic metabolism, free radicals generated by the partial reduction of oxygen are potentially injurious to cells. Highly efficient antioxidant defence systems exist to inhibit oxidative damage to cellular lipids and proteins. Specific enzymes have a crucial role in these antioxidant defences, and their activity may be induced by regulatory mechanisms that respond to oxygen metabolite concentration. 2. To assess whether smoking induces an additional adaptive response, we compared antioxidant defence systems in erythrocytes from smokers and non-smokers and assessed whether a high intake of vitamin E (280 mg/day), a major lipophilic free-radical-scavenging antioxidant, affects the activity of antioxidant enzymes. 3. A total of 100 men, 50 smokers and 50 non-smokers, were allocated to four treatment groups in a 2 x 2 factorial design (smokers versus non-smokers and placebo versus vitamin E). For 10 weeks each subject took one capsule per day of either 280 mg dl-alpha-tocopherol acetate or a visually identical placebo (hydrogenated coconut oil with negligible vitamin E content). 4. Despite increased erythrocyte cytosolic antioxidant enzyme activities in smokers compared with non-smokers, erythrocytes from smokers were more susceptible to hydrogen peroxide-induced lipid peroxidation in vitro. 5. Vitamin E supplementation further increased erythrocyte catalase (EC 126.96.36.199) activity in both smokers and non-smokers (P < 0.001) and erythrocyte glutathione peroxidase (EC 220.127.116.11) and glutathione reductase (EC 18.104.22.168) activities in non-smokers (P < 0.001). After supplementation with vitamin E there was a concomitant fall in erythrocyte superoxide dismutase (EC 126.96.36.199) activity (P < 0.001) and total glutathione concentration (P < 0.01). Furthermore, in both smokers and non-smokers there was a significant decrease in the susceptibility of erythrocytes to peroxidation (P < 0.001). 6. Various endogenous and exogenous factors exert control over cellular protection against reactive oxygen species, and our data suggest that one such factor is the supply of vitamin E.


Health of undocumented migrants in primary care in Switzerland.
Undocumented migrants endure adverse living conditions while facing barriers to access healthcare. Evidence is lacking regarding their healthcare needs, notably in regards to chronic diseases. Our goal was to investigate health conditions in undocumented migrants attended in primary care setting. This study was conducted at the primary care outpatient clinic, Geneva University Hospitals, Switzerland. We retrospectively recorded and coded all medical conditions of a random sample of 731 undocumented migrants using the International Classification of Primary Care, 2nd version (ICPC-2). We dichotomized conditions as chronic or non-chronic and considered multimorbidity in the presence of three or more chronic conditions. Participants originated from 72 countries and were mainly female (65.5%) with a mean age of 42.4 (standard deviation [SD]: 11.4) years. They presented a mean of 2.9 (SD: 2.1; range: 1-17) health conditions. In multivariable analysis, the number of conditions was associated with female gender (p = 0.011) and older age (p <0.001), but not with origin (p = 0.373). The body systems most frequently affected were endocrine, metabolic and nutritional (n = 386; 18.4%), musculoskeletal (n = 308, 14.7%) and digestive (n = 266, 12.8%). Hypertension (17.9%; 95% CI: 15.2%, 29.9%), obesity or overweight (16%; 95% CI: 13.4%, 18.9%) and gastric problems (14.1%; 95% CI: 11.6%, 16.8%) were most prevalent. Overall, 71.8% (95% CI: 68.5%, 75%) participants had at least one chronic condition while 20% (95% CI: 17.2%, 23.1%) had three or more. In multivariable analysis, age (p <0.001) was the only predictor of presenting at least one or three or more chronic conditions. Undocumented migrants present multiple health problems in primary care settings and bear an important burden of chronic diseases. The extent of multimorbidity highlights the need to provide and facilitate the access to comprehensive and long-term primary healthcare services.


A Mathematical Approach with Fractional Calculus for the Modelling of Children's Physical Development.
From birth to now, it is getting more and more important to keep track of the children development, because knowing and determining the factors related to the physical development of the children would provide better and reliable results for children care. In this study, we developed a mathematical approach to have the ability of analysing and examining factors such as weight, height, and body mass index with respect to the age. We used 7 groups for weight, height, and body mass index in Percentage Chart of Turkey. We developed a continuous curve which is valid for any time interval by using discrete weight, height, and body mass index data of 0-18 years old children and the least squares method. By doing so, it became possible to find the percentage and location of the children in Percentage Chart. We advanced a new mathematical model with the help of fractional calculus theory. The results are quite successful and better compared to linear and Polynomial Model analysis. The method provides the opportunity to predict expected values of the children for the future by using previous data obtained in the development of the children.


EviNet: a web platform for network enrichment analysis with flexible definition of gene sets.
The new web resource EviNet provides an easily run interface to network enrichment analysis for exploration of novel, experimentally defined gene sets. The major advantages of this analysis are (i) applicability to any genes found in the global network rather than only to those with pathway/ontology term annotations, (ii) ability to connect genes via different molecular mechanisms rather than within one high-throughput platform, and (iii) statistical power sufficient to detect enrichment of very small sets, down to individual genes. The users' gene sets are either defined prior to upload or derived interactively from an uploaded file by differential expression criteria. The pathways and networks used in the analysis can be chosen from the collection menu. The calculation is typically done within seconds or minutes and the stable URL is provided immediately. The results are presented in both visual (network graphs) and tabular formats using jQuery libraries. Uploaded data and analysis results are kept in separated project directories not accessible by other users. EviNet is available at https://www.evinet.org/.


Coinfections identified from metagenomic analysis of cervical lymph nodes from tularemia patients.
Underlying coinfections may complicate infectious disease states but commonly go unnoticed because an a priori clinical suspicion is usually required so they can be detected via targeted diagnostic tools. Shotgun metagenomics is a broad diagnostic tool that can be useful for identifying multiple microbes simultaneously especially if coupled with lymph node aspirates, a clinical matrix known to house disparate pathogens. The objective of this study was to analyze the utility of this unconventional diagnostic approach (shotgun metagenomics) using clinical samples from human tularemia cases as a test model. Tularemia, caused by the bacterium Francisella tularensis, is an emerging infectious disease in Turkey. This disease commonly manifests as swelling of the lymph nodes nearest to the entry of infection. Because swollen cervical nodes are observed from many different types of human infections we used these clinical sample types to analyze the utility of shotgun metagenomics. We conducted an unbiased molecular survey using shotgun metagenomics sequencing of DNA extracts from fine-needle aspirates of neck lymph nodes from eight tularemia patients who displayed protracted symptoms. The resulting metagenomics data were searched for microbial sequences (bacterial and viral). F. tularensis sequences were detected in all samples. In addition, we detected DNA of other known pathogens in three patients. Both Hepatitis B virus (HBV) and Human Parvovirus B-19 were detected in one individual and Human Parvovirus B-19 alone was detected in two other individuals. Subsequent PCR coupled with Sanger sequencing verified the metagenomics results. The HBV status was independently confirmed via serological diagnostics, despite evading notice during the initial assessment. Our data highlight that shotgun metagenomics of fine-needle lymph node aspirates is a promising clinical diagnostic strategy to identify coinfections. Given the feasibility of the diagnostic approach demonstrated here, further steps to promote integration of this type of diagnostic capability into mainstream clinical practice are warranted.


The regulation of growth in glycogen storage disease type 1.
To study endocrine and metabolic variables that affect growth in patients with glycogen storage disease type 1 (GSD-1) receiving standard dietary therapy. Observational study. Thirty-eight patients with GSD-1, age range 0.6-32.9 years, were investigated on their usual dietary regimens. Data on height, height velocity in prepubertal children, endocrine and metabolic responses to oral glucose load, 24-h serum cortisol and GH concentration profiles and serum IGF-1 concentrations were collected. The population studied was shorter than average, with a median height standard deviation score (SDS) of -1.60, but significantly taller than a historical population studied at the same institution that had not received dietary therapy at the time of study. A wide range of height SDS was encountered (-5.28 to 1.21) and a subset still exhibit marked growth failure. Median body mass index (BMI) SDS was 0.72 (range -1.34 to 3.96). Those patients with the greatest BMI SDS had the lowest serum GH concentrations but serum IGF-1 concentrations were within the normal range. Patients with the poorest growth exhibit low serum insulin concentration responses to glucose load, GH insensitivity and higher mean 24-h plasma cortisol levels when compared to those patients who were better grown. This study shows that overall the growth of this group of patients with glycogen storage disease type 1 has improved compared to that of a historical control group. There remains a subset of this population with poor growth despite therapy. The measured endocrine responses in this subset are similar to those reported for untreated patients. To improve the growth further in these individuals it will be necessary to understand whether this is failure of prescribed therapy or failure to comply with therapy.


Molecular basis of ion selectivity, block, and rectification of the inward rectifier Kir3.1/Kir3.4 K(+) channel.
The glycine-tyrosine-glycine (GYG) sequence in the p-loop of K+ channel subunits lines a narrow pore through which K+ ions pass in single file intercalated by water molecules. Mutation of the motif can give rise to non-selective channels, but it is clear that other structural features are also required for selectivity because, for instance, a recently identified class of cyclic nucleotide-gated pacemaker channels has the GYG motif but are poorly K+ selective. We show that mutation of charged glutamate and arginine residues behind the selectivity filter in the Kir3.1/Kir3.4 K+ channel reduces or abolishes K+ selectivity, comparable with previously reported effects in the Kir2.1 K+ channel. It has been suggested that a salt bridge exists between the glutamate-arginine residue pair. Molecular modeling indicates that the salt bridge does exist, and that it acts as a "bowstring" to maintain the rigid bow-like structure of the selectivity filter and restrict selectivity to K+. The modeling shows that relaxation of the bowstring by mutation of the residue pair leads to enhanced flexibility of the p-loop, allowing permeation of other cations, including polyamines. In experiments, mutation of the residue pair can also abolish polyamine-induced inward rectification. The latter effect occurs because polyamines now permeate rather than block the channel, to the remarkable extent that large polyamine currents can be measured.


The Role of Mobile Phone Camera Recordings in the Diagnosis of Meniere's Disease and Pathophysiological Implications.
This study aimed to understand if videos of the patients' nystagmus recorded by themselves during the attacks can help in the diagnosis of Meniere's disease (MD). Sixty patients (age range 32-78 years) who had vestibular attacks and hearing complaints admitted to Çukurova University Hospital Otolaryngology Department and a private office between September 2013 and January 2017 were included in this randomized clinical trial study. Two groups with 30 patients each were formed. The first group was asked to send eye-videos recorded during the attack, while the patients in the second group were followed with conventional methods. Twenty-six patients in the first group were able to send satisfactory eye movement videos; four patients were excluded due to repeated recording faults. Twenty-seven patients in the second group could be followed; three patients were lost to follow-up. The number of attacks and time needed to diagnose both groups were compared. The video group could be diagnosed in a shorter period compared to the control group. The diagnosis was made within two attacks (38 days) in the video group and within four attacks (92 days) in the control group. This study shows that cell phone camera recordings of nystagmus of the patients are very helpful to diagnose MD. These recordings can also be used as an adjunct to understand the pathophysiology of the disease.


Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach?
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes that is associated with axonal atrophy, demyelination, blunted regenerative potential, and loss of peripheral nerve fibers. The development and progression of DPN is due in large part to hyperglycemia but is also affected by insulin deficiency and dyslipidemia. Although numerous biochemical mechanisms contribute to DPN, increased oxidative/nitrosative stress and mitochondrial dysfunction seem intimately associated with nerve dysfunction and diminished regenerative capacity. Despite advances in understanding the etiology of DPN, few approved therapies exist for the pharmacological management of painful or insensate DPN. Therefore, identifying novel therapeutic strategies remains paramount. Because DPN does not develop with either temporal or biochemical uniformity, its therapeutic management may benefit from a multifaceted approach that inhibits pathogenic mechanisms, manages inflammation, and increases cytoprotective responses. Finally, exercise has long been recognized as a part of the therapeutic management of diabetes, and exercise can delay and/or prevent the development of painful DPN. This review presents an overview of existing therapies that target both causal and symptomatic features of DPN and discusses the role of up-regulating cytoprotective pathways via modulating molecular chaperones. Overall, it may be unrealistic to expect that a single pharmacologic entity will suffice to ameliorate the multiple symptoms of human DPN. Thus, combinatorial therapies that target causal mechanisms and enhance endogenous reparative capacity may enhance nerve function and improve regeneration in DPN if they converge to decrease oxidative stress, improve mitochondrial bioenergetics, and increase response to trophic factors.


The RD5000 database: facilitating clinical, genetic, and therapeutic studies on inherited retinal diseases.
Inherited retinal diseases (IRDs) represent a clinical and genetic heterogeneous group of chorioretinal disorders. The frequency of persons affected by an IRD due to mutations in the same gene varies from 1 in 10,000 to less than 1 in a million. To perform meaningful genotype-phenotype analyses for rare genetic conditions, it is necessary to collect data from sizable populations. Although several standardized functional tests are used widely, ophthalmologic data usually are stored in local databases and not in multicenter databases that are linked with other centers. To be able to register ophthalmologic data of all Dutch patients with IRDs into one database, we developed the RD5000 database (RD5000db), which can harbor all ophthalmologic and selected genetic data. Authorization rights for the management, data entry, and data sharing have been set up, rendering this database into a user-friendly, secure, and widely used repository that will facilitate future studies into molecular genetics and therapies for IRDs. The RD5000db database has the potential to grow into a European standard for the registration of data from IRDs.


Effect of Biologic Material Reinforcement on Surgical Anastomosis After Gastrectomy-A Pilot Study.
Background: Acellular dermal matrix is a biologic material derived from the skin of human cadaveric donors. It has been used successfully in the past to reduce complications in breast surgery and hernia repair. This investigation was aimed at assessing the feasibility of using acellular dermal matrix to support the anastomosis after gastrectomy with the aim of reducing anastomotic site leakage complications. Methods: Patients were randomly assigned to standard anastomotic reconstruction (control arm) or anastomotic reconstruction with acellular dermal matrix reinforcement (intervention arm). Surgical outcomes related to anastomotic complications were collected. Because actual anastomotic leaks found on imaging studies are infrequent and thus require a very high number of patient recruitment to detect statistically significant difference between the two groups, in this pilot investigation other clinical and laboratory measures that have been shown to correlate to or predict anastomotic leaks were also collected. Each surgical outcome was compared. Results: A total of 94 patients (intervention arm: 50, control arm: 44), were included in the analysis. Two patients in the control arm (4.55%) and one patient in the intervention arm (2.00%) experienced anastomotic leakage (p = 0.598), a difference without statistical significance. However, average postoperative C-reactive protein (CRP) levels and NUn scores, both of which have been shown to reflect likelihood of progressing to anastomotic leakage, were significantly lower for the intervention arm. The control arm showed an average CRP level of 128.77 mg/dL (SD: 97.08) while the intervention arm showed 77.38 mg/dL (SD: 49.08, p = 0.049). Conclusions: Leakage rate reduction with acellular dermal matrix reinforcement of anastomotic site was not detected in this investigation. However, postoperative inflammation levels and numerical predictors of anastomotic leakage development were significantly lower with acellular dermal matrix reinforcement of surgical anastomosis. This finding is worthy of further investigation, as reduction of inflammation with anastomotic site reinforcement is a novel finding, and more in-depth research may lead to discoveries on the physiologic role of the surgical anastomosis in post-gastrectomy patients. In addition, lower CRP and NUn scores for the intervention arm suggest potential for larger studies to detect reduction in clinical leak rates after acellular dermal matrix reinforcement.


Hyaluronan synthase 1: a mysterious enzyme with unexpected functions.
Hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. Interest in HAS1 has been limited because its role in hyaluronan production seems to be insignificant compared to the two other isoenzymes, HAS2 and HAS3, which have higher enzymatic activity. Furthermore, in most cell types studied so far, the expression of its gene is low and the enzyme requires high concentrations of sugar precursors for hyaluronan synthesis, even when overexpressed in cell cultures. Both expression and activity of HAS1 are induced by pro-inflammatory factors like interleukins and cytokines, suggesting its involvement in inflammatory conditions. Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. In addition, both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma. Interestingly, immunostainings of tissue sections have demonstrated the role of HAS1 as a poor predictor in breast cancer, and is correlated with high relapse rate and short overall survival. Utilization of fluorescently tagged proteins has revealed the intracellular distribution pattern of HAS1, distinct from other isoenzymes. In all cell types studied so far, a high proportion of HAS1 is accumulated intracellularly, with a faint signal detected on the plasma membrane and its protrusions. Furthermore, the pericellular hyaluronan coat produced by HAS1 is usually thin without induction by inflammatory agents or glycemic stress and depends on CD44-HA interactions. These specific interactions regulate the organization of hyaluronan into a leukocyte recruiting matrix during inflammatory responses. Despite the apparently minor enzymatic activity of HAS1 under normal conditions, it may be an important factor under conditions associated with glycemic stress like metabolic syndrome, inflammation, and cancer.


LHRH neurons express cJun protein during the proestrous surge of luteinizing hormone.
LHRH neurons express cFos on the afternoon of proestrus in association with the ovulatory LH surge. This study determined whether LHRH neurons express another proto-oncogene product, Jun, during the estrous cycle. By using immunocytochemical double staining techniques, localization of Jun proteins and LHRH was compared with expression of cFos in LHRH neurons. LHRH neurons expressed Jun proteins on the afternoon of proestrus with detection of Jun through the morning of estrus. The time course of Jun expression in LHRH neurons during proestrus suggests a common stimulus for both Jun and cFos expression in LHRH neurons, with Jun proteins persisting somewhat longer than cFos. Pentobarbital, which blocks the preovulatory LH surge and cFos expression in LHRH neurons, blocked Jun expression in LHRH neurons; the LHRH neurons similarly expressed Jun and cFos on the following afternoon at the time of the expected delayed LH surge. There was a similarity in the patterns (in terms of numbers and distribution) of Jun-positive and cFos-positive LHRH neurons. Both were localized in the preoptic area and anterior hypothalamus; LHRH neurons above the anterior commissure or rostral to the OVLT did not express Jun or cFos. For the first time, these data provide direct evidence that both proto-oncogene products, Jun and cFos, are expressed in LHRH neurons in association with the proestrous LH surge. Taken together, these results suggest that changes in gene expression mediated by Jun-cFos heterodimers may accompany LHRH activation on the afternoon of proestrus.


Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC).
The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients. To develop a new model based on real-world patients. Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011. First-line, platinum-based, combination chemotherapy. The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms. A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670). We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC. We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.


Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. http://www.clinicaltrials.gov. Unique identifier: NCT01035255.


Neuronal M2 muscarinic receptor function in guinea-pig lungs is inhibited by indomethacin.
The function of M2 muscarinic autoreceptors on pulmonary parasympathetic nerves was investigated in the absence and presence of cyclooxygenase inhibitors in vivo. Guinea pigs were anesthetized, paralyzed, and artificially ventilated. Pulmonary inflation pressure, heart rate, and blood pressure were recorded. Electrical stimulation of vagus nerves produced bronchoconstriction (measured as an increase in pulmonary inflation pressure) and bradycardia. In control guinea pigs, pilocarpine (1 to 100 micrograms/kg) given intravenously stimulated inhibitory M2 muscarinic receptors on pulmonary parasympathetic nerves, thus attenuating vagally induced bronchoconstriction. Conversely, blockade of these autoreceptors by the selective M2 antagonist gallamine (0.1 to 10 mg/kg given intravenously) potentiated vagally induced bronchoconstriction. Separate groups of animals were given either indomethacin or naproxen. These cyclooxygenase inhibitors potentiated vagally induced bronchoconstriction. Furthermore, in those animals pretreated with either indomethacin or [+] naproxen, pilocarpine did not inhibit and gallamine did not potentiate vagally induced bronchoconstriction. In the heart, the effects of pilocarpine and gallamine on M2 muscarinic receptors were not altered by either cyclooxygenase inhibitor. Neither intravenously administered indomethacin (1 mg/kg) nor [+] naproxen (5 mg/kg) altered baseline pulmonary inflation pressure or baseline heart rate in the treated guinea pigs. These studies demonstrate that inhibitory M2 muscarinic receptors on pulmonary parasympathetic nerves do not function in the presence of cyclooxygenase inhibitors. Loss of M2 receptor function may contribute to aspirin-induced airway hyperresponsiveness.


Enhancement of immunohistochemical detection of HIV-1 p24 antigen in brain by tyramide signal amplification.
Human immunodeficiency virus type 1 (HIV-1) infection of the brain has been demonstrated in formalin fixed, paraffin embedded post-mortem brain tissue (PM) by chromogenic immunohistochemistry for the HIV p24 antigen. The sensitivity of antigen detection is increased significantly by tyramide signal amplification (TSA) compared to the conventional peroxidase labelled Avidin-Biotin complex (ABC) technique. The TSA method also permitted the use of a lower concentration of primary antibody than is conventionally used. Sensitivity was enhanced further by microwave irradiation of the paraffin embedded tissues in citrate buffer. HIV-1 p24 antigen was also detected in PM brain tissue by TSA enhanced immunofluorescence and demonstrated increased sensitivity compared to the conventional immunofluorescence technique with a greatly reduced autofluorescence background.


Antimicrobial activity against intraosteoblastic Staphylococcus aureus.
Although Staphylococcus aureus persistence in osteoblasts, partly as small-colony variants (SCVs), can contribute to bone and joint infection (BJI) relapses, the intracellular activity of antimicrobials is not currently considered in the choice of treatment strategies for BJI. Here, antistaphylococcal antimicrobials were evaluated for their intraosteoblastic activity and their impact on the intracellular emergence of SCVs in an ex vivo osteoblast infection model. Osteoblastic MG63 cells were infected for 2 h with HG001 S. aureus. After killing the remaining extracellular bacteria with lysostaphin, infected cells were incubated for 24 h with antimicrobials at the intraosseous concentrations reached with standard therapeutic doses. Intracellular bacteria and SCVs were then quantified by plating cell lysates. A bactericidal effect was observed with fosfomycin, linezolid, tigecycline, oxacillin, rifampin, ofloxacin, and clindamycin, with reductions in the intracellular inocula of -2.5, -3.1, -3.9, -4.2, -4.9, -4.9, and -5.2 log10 CFU/100,000 cells, respectively (P < 10(-4)). Conversely, a bacteriostatic effect was observed with ceftaroline and teicoplanin, whereas vancomycin and daptomycin had no significant impact on intracellular bacterial growth. Ofloxacin, daptomycin, and vancomycin significantly limited intracellular SCV emergence. Overall, ofloxacin was the only molecule to combine an excellent intracellular activity while limiting the emergence of SCVs. These data provide a basis for refining the choice of antibiotics to prioritise in the management of BJI, justifying the combination of a fluoroquinolone for its intracellular activity with an anti-biofilm molecule, such as rifampin.


An Evaluation of Clinical Economics and Cases of Cost-effectiveness.
In order to maintain and develop a universal health insurance system, it is crucial to utilize limited medical resources effectively. In this context, considerations are underway to introduce health technology assessments (HTAs), such as cost-effectiveness analyses (CEAs), into the medical treatment fee system. CEAs, which is the general term for these methods, are classified into four categories, such as cost-effectiveness analyses based on performance indicators, and in the comparison of health technologies, the incremental cost-effectiveness ratio (ICER) is also applied. When I comprehensively consider several Japanese studies based on these concepts, I find that, in the results of the analysis of the economic performance of healthcare systems, Japan shows the most promising trend in the world. In addition, there is research indicating the superior cost-effectiveness of Rituximab against refractory nephrotic syndrome, and it is expected that health economics will be actively applied to the valuation of technical innovations such as drug discovery.


Characteristics of infant homicides: findings from a U.S. multisite reporting system.
The purpose of this study was to describe homicides of infants (children <2 years of age) in the U.S. Cases were derived from the National Violent Injury Statistics System; 71 incidents involving 72 infant homicides were in the data set. Type 1 involved beating/shaking injuries inflicted by a caretaker; type 2 involved all other homicides (including neonaticide, intimate partner problem-related homicide, crime-related death, and other types). Seventy-five percent of the incidents were type 1 incidents, perpetrated mainly by men (83%; typically the infant's father or the boyfriend of the infant's mother). In 85% of the type 1 incidents, the infant was transported to the hospital, usually at the initiative of the perpetrator or another household member. In almost one half of the type 1 incidents, a false story was offered initially to explain the injuries. In contrast, the type 2 incidents (16 cases) were perpetrated mainly by women (11 of 16 cases) and involved methods such as poisoning, drowning, sharp instruments, or withdrawal of food and water; most infants were not taken to the hospital. Although 93% of incidents were perpetrated by caretakers, the large differences between the 2 incident types suggest different avenues for prevention. The circumstances involved in the type 1 homicides (beatings by caretakers) suggested that those attacks occurred impulsively, death was unintended, and emergency care was summoned, often with a false story. Previous abuse was suspected in more than one half of those incidents.


Exercise proteinuria and hematuria: current knowledge and future directions.
Transient proteinuria and hematuria are apparently benign sequelae of intensive physical activity. However, there is a need to establish underlying causes and reasons for progression to chronic renal damage, as well as effects of training in healthy individuals and in those with microalbuminuria. The Ovid/Health Star database was searched from 1994 to November 2014. Terms for the kidneys (adverse effects, blood supply, epidemiology, injuries, pathology, physiology and secretion) and proteinuria (classification, complications, epidemiology, etiology, mortality, physiopathology, prevention and control) with terms related to physical activity (physical activity/motor activity, exercise/exercise therapy, fitness/physical fitness, physical education/physical education and training, and rehabilitation). Review of 519 abstracts yielded 194 relevant hits, supplemented by 70 items from other sources. This material related to both healthy adults (125 items) and renal disease (139 items). The prevalence (18-100%) and duration (1-6 days) of exercise proteinuria varied widely, with risks affected by exercise intensity, posture, age, heat load, altitude and disease. Moderate training reduced exercise proteinuria in healthy individuals and in chronic renal disease. Factors contributing to exercise proteinuria may include vascular changes, hypoxia, lactate accumulation, oxidant stress, hormonal changes and sepsis. Exercise hematuria is frequent; some potential causes are similar to those for proteinuria, but foot-strike and bladder trauma are probably more important. Progression to permanent renal damage is rare. Exercise proteinuria and hematuria are generally transient. However, there remains a need to clarify causation and factors leading to permanent renal damage.


Clinical effectiveness of treatment with hyperbaric oxygen for neonatal hypoxic-ischaemic encephalopathy: systematic review of Chinese literature.
To investigate the clinical effectiveness of treatment with hyperbaric oxygen for neonates with hypoxic-ischaemic encephalopathy. This treatment is frequently used in China but much less often in the West. Western (Cochrane controlled trials register and database of systematic reviews, Medline, Embase, CINAHL, and HealthSTAR) and Chinese (China Hospital Digital Library, Chinese Medical Journal Network) databases and hand search of Chinese journals. No language restrictions. Randomised or quasi-randomised controlled trials of treatment with hyperbaric oxygen compared with "usual care" in term neonates with hypoxic-ischaemic encephalopathy. Outcomes included mortality and long term neurological sequelae. Standardised forms were used to extract and compare data. Criteria of York Centre for Reviews and Dissemination were used to assess quality. Analysis was mainly qualitative but included meta-analysis. 20 trials were found, mainly from Chinese sources. The reporting quality of trials was poor by Western (CONSORT) standards. Treatment with hyperbaric oxygen had better outcomes than the comparator in almost all trials. The odds ratios of the meta-analyses were 0.26 (95% confidence interval 0.14 to 0.46) for mortality and 0.41 (0.27 to 0.61) for neurological sequelae. Treatment with hyperbaric oxygen possibly reduces mortality and neurological sequelae in term neonates with hypoxic-ischaemic encephalopathy. Because of the poor quality of reporting in all trials and the possibility of publication bias, an adequately powered, high quality randomised controlled trial is needed to investigate these findings. The Chinese medical literature may be a rich source of evidence to inform clinical practice and other systematic reviews.


Deletion of a previously uncharacterized flagellar-hook-length control gene fliK modulates the sigma54-dependent regulon in Campylobacter jejuni.
A previously unannotated, putative fliK gene was identified in the Campylobacter jejuni genome based on sequence analysis; deletion mutants in this gene had a 'polyhook' phenotype characteristic of fliK mutants in other genera. The mutants greatly overexpressed the sigma(54)-dependent flagellar hook protein FlgE, to form unusual filamentous structures resembling straight flagella in addition to polyhooks. The genome sequence reveals only one gene predicted to encode an orthologue of the NtrC-family activator required for sigma(54)-dependent transcription. Hence, all sigma(54)-dependent genes in the genome would be overexpressed in the fliK mutant together with flgE. Microarray analysis of genome-wide transcription in the mutant showed increased transcription of a subset of genes, often downstream of sigma(54)-dependent promoters identified by a quality-predictive algorithm applied to the whole genome. Assessment of genome-wide transcription in deletion mutants in rpoN, encoding sigma(54), and in the sigma(54)-activator gene flgR, showed reciprocally reduced transcription of genes that were overexpressed in the fliK mutant. The fliA (sigma(28))-dependent regulon was also analysed. Together the data clearly define the roles of the alternative sigma factors RpoN and FliA in flagellar biogenesis in C. jejuni, and identify additional putative members of their respective regulons.


Using the METRICS model for defining routes to scholarship in healthcare simulation.
In this paper, we explored the utility and value of the METRICS model for modeling scholarship in healthcare simulation by: (1) describing the distribution of articles in four healthcare simulation journals across the seven areas of METRICS scholarship; and (2) appraising patterns of scholarship expressed in three programs of simulation scholarship and reflecting on how these patterns potentially influence the pursuit of future scholarly activities. Two raters reviewed abstracts of papers published between January 2015 and August 2017 in four healthcare simulation journals and coded them using METRICS. Descriptive statistics were calculated for scholarship type and distribution across journals. Twenty-eight articles from three scholars were reviewed, with patterns of scholarship within articles mapped to METRICS. Descriptive synthesis was constructed through discussion between two reviewers. A total of 432 articles from four journals were reviewed. The three most commonly published areas of scholarship were: 32.2% (139/432) evaluation, 18.8% (81/432) innovation, and 15.3% (66/432) conceptual. The METRICS model was able to represent different kinds of scholarship expressed in all of the papers reviewed and across programs of research. Reflecting on patterns of scholarship within their scholarly programs was helpful for research in planning future directions. The METRICS model for scholarship can describe a wide range of patterns of simulation scholarship within individual articles, programs of research, or across journals.


Intravenous therapy team and peripheral venous catheter-associated complications. A prospective controlled study.
A prospective controlled trial was conducted on four similar inpatient medical wards to test the hypothesis that a trained intravenous therapy (IVT) team would substantially reduce the incidence of peripheral intravenous (IV) catheter-related complications. We followed 863 IV catheters. The overall incidence of phlebitis in the ward staff-maintained IV catheters was 32% as compared with 15% for those maintained by the IVT team. The incidence of two more serious complications (cellulitis and suppurative phlebitis) was reduced tenfold from 2.1% to 0.2%. We conclude that an IVT team can substantially reduce the iatrogenic complications related to IV catheters.


Rationale and Design for a GRADE Substudy of Continuous Glucose Monitoring.
Background: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. Methods: The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. Conclusions: The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities.


Single Molecule Assay for Ultrasensitive Detection of Cathepsin B in Human Blood.
Cathepsin B (catB) is a lysosomal cysteine protease expressed in several cells and organs, where it plays a role in protein degradation and turnover. Extracellular, secreted catB has utility as a biomarker for a host of pathological or physiological states, including a myriad of cancers or neurological diseases and injuries. Analytical or diagnostic assessment may be limited by biological sample volume availability. Pathologically relevant changes in catB levels may occur at low-moderate concentrations that require accurate measurement to differentiate from basal levels. Furthermore, biological samples like plasma and serum, often occlude accurate catB measurements because of background and high variance, vastly limiting the ability to detect catB as a peripheral biomarker. Techniques for ultrasensitive protein detection that require low volumes of sample are necessary. To overcome these challenges, a digital enzyme-linked immunosorbent assay (ELISA) was developed for differential detection of catB within less than 5 μL of serum and plasma using the single molecule array (SiMoA) platform, which offers 1000-times more sensitivity and vastly reduced variance compared to colorimetric tests. In buffer, curve-fitting estimated the limit of detection (LoD) to be ∼1.56 and ∼8.47 pg/mL using two-step or three-step assay configurations, respectively. After correcting for endogenous levels, the estimated LoD was ∼4.7 pg/mL in the serum or plasma with the two-step assay. The lower limit of quantitation was ∼2.3 pg/mL in the buffer and ∼9.4 pg/mL in the serum or plasma, indicting the ability to measure small changes above endogenous levels within blood samples.


The effects of dietary sodium on hypertension and stroke development in female stroke-prone spontaneously hypertensive rats.
Previous studies on male stroke-prone spontaneously hypertensive rats (SHRSP) have shown that a high-salt diet accelerated the onset of hypertension and stroke, resulting in an increased mortality rate at a younger age. The purpose of this study was to examine whether a similar effect is present in female SHRSP. After weaning at 4 weeks of age, 32 female SHRSP were placed on a Japanese-style rat diet containing either 0.3% NaCl or 4% NaCl. Blood pressure (BP), heart rate, and body weight were measured weekly. Beginning at 9 weeks of age, the SHRSP on the 4% NaCl diet began to show a consistently and significantly higher BP than those in the 0.3% NaCl group, reaching an average BP of 245 +/- 9 mmHg at 16 weeks of age as compared to 184 +/- 3 mmHg in the 0.3% NaCl group. Some female SHRSP in the 4% NaCl group started to exhibit behavioral signs of stroke at 12 weeks of age and 100% mortality was found by 20 weeks. There was 0% mortality in the 0.3% NaCl group at that age. A positive correlation was found between the age at which BP surpassed 220 mmHg and the age death occurred due to stroke. No significant difference was noted in the heart rate or body weight measurements between the two groups. The increased mortality rate in the 4% NaCl diet group was accompanied by organ damage as evidenced by the presence of left ventricular hypertrophy, edematous kidneys, renal malfunction, kidney lesions, and cerebral lesions in these female SHRSP. It is concluded that a high-salt diet exacerbates hypertension and caused an increased mortality rate. This increased mortality rate was associated with an increased left ventricular hypertrophy, kidney damage and subsequent malfunction, and cerebrovascular lesions in these female SHRSP.


Free-to-play: About addicted Whales, at risk Dolphins and healthy Minnows. Monetarization design and Internet Gaming Disorder.
Video games are not only changing due to technical innovation, but also because of new game design and monetization approaches. Moreover, elite gamer groups with financial in-game-investments co-finance all users of free-to-play-games. Besides questions on youth protection, the growing popularity of free-to-play games has fostered discussions on supposed associations to Internet Gaming Disorder (IGD). Children and adolescents using free-to-play browser games were examined in a German school-based representative study (N=3967; age range 12 to 18). Based on a clinical self-report AICA-S (Wölfling et al., 2011), students were categorized into non-problematic, risky, and addicted users. Psycho-social problems (SDQ; Goodman, 1997), perceived stress (PSS; Cohen, Kamarck & Mermelstein, 1983), coping strategies (BriefCOPE; Carver, 1997), and Average Revenue per (Paying) User (ARPU) were investigated as dependent variables. Furthermore, an industry classification (Freeloaders, Minnows, Dolphins, and Whales) for free-to-play gamers was used for additional relations regarding IGD, SDQ, PSS, BriefCOPE, and ARPU. Among free-to-play gamers the prevalence of IGD amounted to 5.2%. Subjects classified with IGD displayed higher psycho-social symptoms than non-problematic users, reported higher degrees of perceived stress, and applied dysfunctional coping strategies more frequently. Additionally, we found a higher ARPU among subjects with IGD. ARPU is significantly associated with IGD. Whales share significant characteristics with addicted video gamers; Dolphins might be classified as risky consumers; Minnows and Freeloaders are rather non-pathological gamers. Vulnerability for stress, dysfunctional coping, and free-to-play gaming represent an unhealthy combination.