Year in Review 2015: Extracorporeal Membrane Oxygenation.
Extracorporeal membrane oxygenation (ECMO) is a modified form of cardiopulmonary bypass. Although early trials were plagued by severe bleeding and high rates of death, subsequent experience with neonates found good survival, and ECMO became an important tool in the care of critically ill infants with respiratory failure. Since the 1980s, expansion to other groups (children, patients with cardiac disease, etc) followed as experience was obtained. Today, there is a rapid growth of ECMO, especially in the adult population. To date, >73,000 patients receiving ECMO have been reported to the international Extracorporeal Life Support Organization registry. This rapid growth in the usage of ECMO has made it possible for it to be included in the management algorithm of certain disease processes, such as ARDS, cardiopulmonary arrest, and septic shock. Significant advances in technology have made it possible to support patients on ECMO for weeks or months with success. Reduction in sedative use and experience with "awake" patients has led to ambulatory and mobile ECMO. Changes in ventilator support while on ECMO, even to the point of extubation, are also occurring. This article will review briefly some of the literature related to criteria for severity of illness before ECMO and related to ECMO care and practice. Issues relating to the use of ECMO as a resuscitative tool in cardiac arrest as well as the controversial topic of volume and outcome will also be presented.


Designed, Helical Protein Nanotubes with Variable Diameters from a Single Building Block.
Due to their structural and mechanical properties, 1D helical protein assemblies represent highly attractive design targets for biomolecular engineering and protein design. Here we present a designed, tetrameric protein building block, Zn8R4, which assembles via Zn coordination interactions into a series of crystalline, helical nanotubes whose widths can be controlled by solution conditions. X-ray crystallography and transmission electron microscopy (TEM) measurements indicate that all classes of protein nanotubes are constructed through the same 2D arrangement of Zn8R4 tetramers held together by Zn coordination. The mechanical properties of these nanotubes are correlated with their widths. All Zn8R4 nanotubes are found to be highly flexible despite possessing crystalline order, owing to their minimal interbuilding-block interactions mediated solely by metal coordination.


Use of Plasma Metabolomics to Identify Diagnostic Biomarkers for Early Stage Epithelial Ovarian Cancer.
The early detection of ovarian carcinoma is difficult due to the absence of recognizable physical symptoms and a lack of sensitive screening methods. The currently available biomarkers (such as CA125 and HE4) are insufficiently reliable to distinguish early stage (I/II) epithelial ovarian cancer (EOC) patients from normal individuals because they possess a relatively poor sensitivity and specificity. To evaluate the application of metabolomics to biomarker discovery in the early stages of epithelial ovarian cancer (EOC), plasma samples from 21 early stage EOC patients and 31 healthy controls were analyzed with ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-Tof/MS) in conjunction with multivariate statistical analysis. Eighteen metabolites, including lysophospholipids, 2-piperidone and MG (18:2), were found to be disturbed in early stage EOC with satisfactory diagnostic accuracy (AUC=0.920). These biomarkers were specifically validated in the EOC nude mouse model, and five of the biomarkers (lysophospholipids, adrenoyl ethanolamide et al.) were highly suspected of being associated with EOC because they were differentially expressed with the same tendency in the EOC nude mice versus normal controls. In conclusion, the selected metabolic biomarkers have considerable utility and significant potential for diagnosing early ovarian cancer and investigating its underlying mechanisms.


Africans in the American Labor Market.
The number of migrants to the United States from Africa has grown exponentially since the 1930s. For the first time in America's history, migrants born in Africa are growing at a faster rate than migrants from any other continent. The composition of African-origin migrants has also changed dramatically: in the mid-twentieth century, the majority were white and came from only three countries; but today, about one-fifth are white, and African-origin migrants hail from across the entire continent. Little is known about the implications of these changes for their labor market outcomes in the United States. Using the 2000-2011 waves of the American Community Survey, we present a picture of enormous heterogeneity in labor market participation, sectoral choice, and hourly earnings of male and female migrants by country of birth, race, age at arrival in the United States, and human capital. For example, controlling a rich set of human capital and demographic characteristics, some migrants-such as those from South Africa/Zimbabwe and Cape Verde, who typically enter on employment visas-earn substantial premiums relative to other African-origin migrants. These premiums are especially large among males who arrived after age 18. In contrast, other migrants-such as those from Sudan/Somalia, who arrived more recently, mostly as refugees-earn substantially less than migrants from other African countries. Understanding the mechanisms generating the heterogeneity in these outcomes-including levels of socioeconomic development, language, culture, and quality of education in countries of origin, as well as selectivity of those who migrate-figures prominently among important unresolved research questions.


Optic disc dimensions and cup-disc ratios among healthy South Indians: The Chennai Glaucoma Study.
To present optic disc and cup dimensions, cup-disc ratios (CDRs) and asymmetry among healthy South Indians, and their associations with ocular and systemic variables. A total of 623 healthy phakic participants of the Chennai Glaucoma Study underwent complete eye examinations including optic disc stereo-photography. Planimetry was performed under stereo-viewing conditions. The morphological type of cupping (no cups, steep cups, partly sloping and fully sloping cups) was identified based on a modification of the classification by Jonas et al.( 11 ) The associations of planimetric measures (optic disc area, cup area and vertical cup-disc ratio [VCDR]) with age, gender, height, intraocular pressure, refraction, astigmatism, axial length and corneal thickness as explanatory variables were examined. The associations of asymmetries in the above planimetric measures with age, gender and asymmetries of the above explanatory variables were examined. Mean optic disc and cup areas were 2.82 ± 0.52 mm(2) and 0.53 ± 0.39 mm(2). Mean CDR was 0.36 ± 0.18. Men had larger discs (P = 0.03). Cup area and VCDR revealed significant associations with disc area (P <0.0001) and type of cupping (P < 0.0001). Mean disc and cup area asymmetries were 0.19 ± 0.16 mm(2) and 0.15 ± 0.15 mm(2). Mean VCDR asymmetry was 0.07 ± 0.08 mm(2). Cup area and VCDR asymmetries showed significant associations with disc area asymmetry (P < 0.0001, both) and asymmetry in the presence or absence of physiological cupping, i.e. subjects with physiological cupping in one eye and no cupping in the other (P < 0.0001, both). We present normative optic disc, cup and VCDR measures and asymmetries among healthy South Indians. We demonstrated the dependence of VCDR on the morphological type of cupping.


Injectable biomaterial shuttles for cell therapy in stroke.
Ischemic stroke (IS) is the leading cause of disability and contributes to a significant socio-economic cost in the western world. Brain repair strategies investigated in the pre-clinical models include the delivery of drug or cell-based therapeutics; which is hindered by the complex anatomy and functional organization of the brain. Biomaterials can be instrumental in alleviating some of these challenges by providing a structural support, localization, immunomodulation and/or modulating cellular cross-talk in the brain. This review addresses the significance of and challenges associated with cell therapy in an ischemic brain. This is followed by a detailed insight into the biomaterial-based delivery systems which have been designed to provide sustained trophic factor delivery for endogenous repair and to support transplanted cell survival and integration. A biomaterial intervention uses a multifaceted approach in enhancing the survival and engraftment of cells during transplantation and this has driven them as potential candidates for the treatment of IS. The biological processes that are activated as a response to the biomaterials and how to modulate them is one of the key factors contributing to the success of the biomaterial-based therapeutic approach. Future perspectives highlight the need of a combinative approach of merging the material design with disease biology to fabricate effective biomaterial-based intervention of stroke.


Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics.
The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na(+) currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 μM) and its optical isomers had a similar IC50 [40 and 47 μM for the (+) and (-) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na(+) channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders.


Distribution and seasonality of microbial indicators and thermophilic campylobacters in two freshwater bathing sites on the River Lune in northwest England.
Two freshwater bathing sites, the Crook O'Lune and the University Boathouse, on the River Lune in the north-west of England, were monitored over a 2 year period for the faecal indicators, faecal coliforms and faecal streptococci, the pathogens, Salmonella and Campylobacter, and compliance with the EU Directive on Bathing Water Quality. Faecal indicator numbers showed no seasonal variation, with numbers in the bathing season similar to those in the non-bathing season. They were consistently above the EU Guideline and Imperative standards so that if the EU Bathing Water Quality Directive (76/160/EEC) were applied, neither site would comply. Faecal indicator numbers in the sediments were an order of magnitude higher than in the overlying water. Campylobacter numbers showed seasonal variation in the water with higher counts in winter than in the summer, although numbers were low. Higher numbers were found in the sediments but there was no seasonal variation. Analysis of various inputs showed that indicators and campylobacters came from a mixture of sources, namely a sewage treatment works, agricultural run-off, streams and mallards. Microbial numbers in the water at the Crook O'Lune, which is closer to the sources of pollution, were twice those at the Boathouse. In the sediments they were six to eight times higher. Faecal coliforms were all identified as Escherichia coli of which 80% were a single biotype. Faecal streptococci were all enterococci of which 55% were E. avium, 38% E. faecalis and 7% E. durans. Salmonella was not isolated from either the water column or the sediments. Campylobacters were mainly Camp. jejuni, followed by Camp. coli, UPTC and Camp. lari.


Percutaneous vertebroplasty for the treatment of osteoporotic vertebral compression fractures: a preliminary report.
This report assesses the efficacy and safety of percutaneous vertebroplasty for osteoporotic vertebral compression fractures and reports on preliminary results of its use. The technique was used on 50 patients with 86 painful vertebral fractures, all of which had failed to respond to earlier conservative medical treatment. The technique involves percutaneous puncture of the involved vertebra via a transpedical approach followed by injection of polymethyl methacrylate (PMMA) into the compressed vertebra. Patients were asked to quantity their degree of pain on Huskisson's visual analogue scale (VAS) to assess the clinical symptoms and surgical results. The procedures were technically successful in all patients, and no complications relating to either the anesthesia or the surgical procedure were reported. The quantity of PMMA injected per vertebral body varied from 2.5 to 12 ml according to both the position of the damaged vertebra(e) and the severity of the compression fracture. Pain, as assessed on the Huskisson's VAS, decreased from 82 +/- 15 mm at the baseline to 37 +/- 22 mm on the first postoperative day, and 32 +/- 19 mm at 1 month. Reductions in pain from the baseline to the first day and to 1 month were both statistically significant (p < 0.05). All patients were able to return to their previous activity and quality of life. Through the expertise and attention of experienced surgeons, percutaneous vertebroplasty appears to provide a very good surgical choice for patients with vertebral compression fractures, as this surgical procedure is able to eliminate the risk of major spinal surgery, and through prompt pain relief, may provide early mobilization and rehabilitation for elderly polymorbid patients.


The relationship between hyperlactatemia and microcirculation in the thenar eminence as measured using near-infrared spectroscopy in patients with sepsis.
Near-infrared spectroscopy (NIRS)-derived variables during a vascular occlusion test (VOT) have recently been used to evaluate peripheral circulatory insufficiency in patients with sepsis. We investigated the relationship between NIRS-derived variables and the lactate concentration during sepsis. This was a prospective observational study. Forty-one patients with sepsis were divided into two groups according to their blood lactate concentration: a high lactate group (≥2.0 mmol/l; n=15) and a normal lactate group (<2.0 mmol/l; n=26). NIRS was used to evaluate the tissue oxygen index (TOI) at the thenar eminence before and after a VOT. VOT was performed by sphygmomanometer cuff inflation around upper arm for 3 min. The TOI value before VOT was defined as the TOI baseline, the TOI value immediately after VOT was defined as the minimum TOI and the TOI value after releasing the muscle from the VOT was defined as the TOI after VOT. The ΔTOI was defined as the difference between the TOI after VOT and minimum TOI. NIRS-derived variables had significant differences between the normal lactate group and the high lactate group with respect to the TOI baseline (median: 65% vs 55%, p=0.01), TOI after VOT (median: 65% vs 46%, p<0.001) and ΔTOI (median: 19% vs 6%, p<0.001). The lactate concentration was significantly correlated with the TOI after VOT (R=0.594, p<0.001), TOI baseline (R=0.513, p<0.001), ΔTOI (R=0.488, p=0.001) and minimum TOI (R=0.377, p=0.02). We revealed a significant correlation between NIRS-derived variables and the lactate concentration during sepsis.


Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease.
This randomized, double-blind, parallel trial assessed the influence of pomegranate juice consumption on anterior and posterior carotid intima-media thickness (CIMT) progression rates in subjects at moderate risk for coronary heart disease. Subjects were men (45 to 74 years old) and women (55 to 74 years old) with > or =1 major coronary heart disease risk factor and baseline posterior wall CIMT 0.7 to 2.0 mm, without significant stenosis. Participants consumed 240 ml/day of pomegranate juice (n = 146) or a control beverage (n = 143) for up to 18 months. No significant difference in overall CIMT progression rate was observed between pomegranate juice and control treatments. In exploratory analyses, in subjects in the most adverse tertiles for baseline serum lipid peroxides, triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, TGs/HDL cholesterol, total cholesterol/HDL cholesterol, and apolipoprotein-B100, those in the pomegranate juice group had significantly less anterior wall and/or composite CIMT progression versus control subjects. In conclusion, these results suggest that in subjects at moderate coronary heart disease risk, pomegranate juice consumption had no significant effect on overall CIMT progression rate but may have slowed CIMT progression in subjects with increased oxidative stress and disturbances in the TG-rich lipoprotein/HDL axis.


Cell cycle marker expression in benign and malignant intraductal papillary lesions of the breast.
The diagnosis of intraductal papillary lesions of the breast on core biopsy remains challenging in pathology, with most patients requiring formal surgical excision for a definitive diagnosis. The aim of this study was to determine whether a representative panel of proliferative cell cycle immunohistochemical markers (cyclin A2, cyclin B1 and cyclin D1) could improve the specificity of pathological diagnosis of these lesions. A series of 68 surgically excised intraductal papillary lesion cases were retrospectively selected, and immunohistochemistry for cyclin A2, cyclin B1 and cyclin D1 was performed. Cyclin B1 (OR 1.80, 95% CI 1.01 to 3.2, p=0.046) and cyclin D1 (OR 1.13, 95% CI 1.05 to 1.22, p=0.002) expression was independently associated with a diagnosis of malignancy in papillary lesions, although expression was frequently heterogeneous and only focal. Cyclin A2 expression (OR 0.76, 95% CI 0.41 to 1.4, p=0.38) was not associated with a malignant diagnosis in multivariable logistic regression models. All three cyclins displayed high sensitivity (80%-95%) for a diagnosis of malignancy, although cyclin B1 showed a superior specificity of 72.7% compared with the low specificity of cyclins A2 and D1. Our study has identified for the first time that the expression of key cell cycle markers differs between benign and malignant papillary breast lesions and identified changes to the mitotic marker, cyclin B1, as particularly significant. However, given the low level and heterogeneous nature of expression of these markers, there remains a significant risk of undersampling in core biopsies and thus they are unlikely to be useful in routine clinical practice.


Anaemic crisis in sickle cell disease.
Sixteen episodes of acute anaemia necessitating urgent blood transfusion have been investigated in 13 children with sickle cell anaemia. In five out of seven episodes there was evidence of increased haemolysis while in 10 out of 16 episodes a profound fall in reticulocyte count indicated marrow erythroid cell failure. Cold agglutinins active at room temperature were detected in 13 episodes, and anti-I specificity was demonstrated in 11. Warmed blood of homologous ABO and Rhesus groups was administered without complication despite difficulty with cross-matching. The exacerbation of anaemia was not due to folate lack, glucose-6-phosphate dehydrogenase deficiency or splenic sequestration, and an infectious agent appeared responsible. The degree of anaemia in homozygous sickle cell disease is usually constant during asymptomatic periods. An episode of sudden profound anaemia (anaemic crisis) may, however, result from marrow hypoplasia, an exacerbation of haemolysis, splenic sequestration, or folate deficiency.


Biodegradation and tissue integration of various polyethylene glycol matrices: a comparative study in rabbits.
To test whether or not chemical and/or physical modifications of polyethylene glycol (PEG) hydrogels influence degradation time, matrix/membrane stability, and integration into surrounding hard and soft tissues. In 28 rabbits, six treatment modalities were randomly applied to six sites on the rabbit skull: a dense network PEG hydrogel (PEG HD), a medium-dense network PEG hydrogel (PEG MD), a medium-dense network PEG hydrogel modified with an RGD sequence (PEG MD/RGD), a medium-dense network PEG hydrogel modified with RGD with reduced carboxymethyl cellulose (PEG MD/RGD_LV), a loose network PEG hydrogel modified with RGD (PEG LD/RGD), and a collagen membrane (BG). Descriptive histology and histomorphometry were performed at 1, 2, 4, and 6 weeks. PEG HD revealed the highest percentage of residual matrix at all time points starting with 47.2% (95% CI: 32.8-63.8%) at 1 week and ending with 23.4% (95% CI: 10.3-49.8%) at 6 weeks. The hydrogel with the loosest network (PEG LD/RGD) was stable the first 2 weeks and then degraded continuously with a final area of 8.3% (95% CI: 3.2-21.2%). PEG HD was the most stable and densely stained membrane, whereas PEG MD and PEG LD matrices integrated faster, but started to degrade to a higher degree between 2 and 4 weeks. PEG MD degradation was dependent on the addition of RGD and the amount of CMC. Chemical and/or physical modifications of PEG hydrogels influenced matrix stability. PEG MD/RGD demonstrated an optimal balance between degradation time and integration into the surrounding soft and hard tissues.


The fanconi anemia pathway limits human papillomavirus replication.
High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.


Behavioral medicine approaches to hypertension: an integrative analysis of theory and research.
This article compares behavioral and biological approaches to hypertension, highlights some of the practical, semantic, and theoretical issues involved, and attempts a constructive, behavioral medicine integration of these approaches. The major behavioral approaches to hypertension are described, with a focus on their conceptual limitations as stimulants to research into psychobiological mechanisms. A biobehavioral systems analysis of hypertension is outlined, emphasizing the role of the central nervous system as a common pathway relating environmental and behavioral factors to cardiovascular regulatory dynamics and disease. Schwartz's concept of blood pressure disregulation is discussed, by which behavioral "feedback loops" may be included in the pathogenesis of homeostatic disorders. A detailed discussion of concepts underlying the clinical pharmacological approach to hypertension is provided; parallels are drawn between the conceptual framework and the theoretical and practical questions facing behavioral researchers concerned with hypertension. Synergistic interactive effects of drug and behavioral treatments are proposed. A biobehavioral overview, which links pressor and depressor stimulus patterns to both pathogenesis and therapy, can serve to integrate the previous biobehavioral systems analysis, the conceptual framework of clinical pharmacology, and the notion of biobehavioral disregulation of blood pressure. Implications for future behavioral medicine research in hypertension are provided.


A population-based assessment of the burden of acute pancreatitis in the United States.
The aim of this study is to investigate the incidence and mortality of emergency department (ED) visits in the United States attributed to acute pancreatitis (AP) and quantify predictors of admission and mortality. Using the nationwide ED sample, all ED visits between 2006 and 2009 for AP were extracted. Multivariable analyses were fitted for prediction of admission and mortality. A weighted sample of 1,224,121 patient visits with AP was captured. Of those, 75.4% resulted in admission and 0.7% died. Between 2006 and 2009, the incidence of AP ED visits increased from 9.9 to 10.6 per 10,000 person-years. Patients were more likely to be admitted if sicker (Charlson Comorbidity Index score ≥ 3; OR, 6.48; P < 0.001) and if the etiology of pancreatitis was alcoholic versus biliary (OR, 2.20; P < 0.001). They were more likely to die if sicker (Charlson Comorbidity Index score ≥ 3; OR, 1.51; P < 0.001) and covered with Medicare or Medicaid versus private insurance (OR, 1.40; P < 0.001 and OR, 1.45; P < 0.001, respectively). Emergency department visits for AP represent a significant burden on US health care. Although mortality is lower than previously reported, significant disparities exist in patients presenting with AP with regard to admission and mortality rates. Further investigations are needed to assess these disparities.


Dynamic instability of microtubules: Monte Carlo simulation and application to different types of microtubule lattice.
Dynamic instability is the term used to describe the transition of an individual microtubule, apparently at random, between extended periods of slow growth and brief periods of rapid shortening. The typical sawtooth growth and shortening transition behavior has been successfully simulated numerically for the 13-protofilament microtubule A-lattice by a lateral cap model (Bayley, P. M., M. J. Schilstra, and S. R. Martin. 1990. J. Cell Sci. 95:33-48). This kinetic model is now extended systematically to other related lattice geometries, namely the 13-protofilament B-lattice and the 14-protofilament A-lattice, which contain structural "seams". The treatment requires the assignment of the free energies of specific protein-protein interactions in terms of the basic microtubule lattice. It is seen that dynamic instability is not restricted to the helically symmetric 13-protofilament A-lattice but is potentially a feature of all A- and B-lattices, irrespective of protofilament number. The advantages of this general energetic approach are that it allows a consistent treatment to be made for both ends of any microtubule lattice. Important features are the predominance of longitudinal interactions between tubulin molecules within the same protofilament and the implication of a relatively favorable interaction of tubulin-GDP with the growing microtubule end. For the three lattices specifically considered, the treatment predicts the dependence of the transition behavior upon tubulin concentration as a cooperative process, in good agreement with recent experimental observations. The model rationalizes the dynamic properties in terms of a metastable microtubule lattice of tubulin-GDP, stabilized by the kinetic process of tubulin-GTP addition. It provides a quantitative basis for the consideration of in vitro microtubule behaviour under both steady-state and non-steady-state conditions, for comparison with experimental data on the dilution-induced disassembly of microtubules. Similarly, the effects of small tubulin-binding molecules such as GDP and nonhydrolyzable GTP analogues are readily treated. An extension of the model allows a detailed quantitative examination of possible modes of substoichiometric action of a number of antimitotic drugs relevant to cancer chemotherapy.


Stenoparib, an Inhibitor of Cellular Poly(ADP-Ribose) Polymerase, Blocks Replication of the SARS-CoV-2 and HCoV-NL63 Human Coronaviruses In Vitro.
By late 2020, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new poly(ADP-ribose) polymerase (PARP) inhibitor, stenoparib, that recently advanced to phase II clinical trials for treatment of ovarian cancer, for activity against human respiratory coronaviruses, including SARS-CoV-2, in vitro Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to the human seasonal respiratory coronavirus HCoV-NL63. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and postentry processes, as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib-below the approximated 25.5 μM half-maximally effective concentration (EC50)-combined with 0.5 μM remdesivir suppressed coronavirus growth by more than 90%, indicating a potentially synergistic effect for this drug combination. Stenoparib as a stand-alone or as part of combinatorial therapy with remdesivir should be a valuable addition to the arsenal against COVID-19.IMPORTANCE New therapeutics are urgently needed in the fight against COVID-19. Repurposing drugs that are either already approved for human use or are in advanced stages of the approval process can facilitate more rapid advances toward this goal. The PARP inhibitor stenoparib may be such a drug, as it is currently in phase II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans have already been established. Our results indicate that stenoparib possesses strong antiviral activity against SARS-CoV-2 and other coronaviruses in vitro. This activity appears to be based on multiple modes of action, where both pre-entry and postentry viral replication processes are impeded. This may provide a therapeutic advantage over many current options that have a narrower target range. Moreover, our results suggest that stenoparib and remdesivir in combination may be especially potent against coronavirus infection.


Cardiac Murmurs in Children: A Challenge For The Primary Care Physician.
Congenital heart disease is present in almost 1% of live births and despite current progress in prenatal screening a significant percentage has delayed diagnosis or remain undiagnosed. A cardiac murmur may be the first or unique clinical sign of congenital heart disease in childhood, however, less than 1% of auscultated murmurs are of an organic cause. Distinguishing between an innocent and a pathologic murmur can be challenging and the experience of the examiner is crucial for identifying the distinctive properties of an innocent murmur. Timely diagnosis of underlying cardiovascular pathology is of great significance so that prompt management is provided and morbidity or mortality are restricted. Of similar importance is the avoidance of unnecessary anxiety for the parents and unreasonable referrals to Paediatric Cardiologists. Indications for referral include a medical history suggestive of a cardiac abnormality, such as the presence of relevant symptoms, the identification of abnormal findings on clinical examination, auscultatory findings suggestive of an organic murmur, and very young patient age. ECG and a chest X-ray are not usually part of the diagnostic approach of a child with a cardiac murmur, as they do not increase the success rate of diagnosing heart disease, as compared to a detailed medical history accompanied by a thorough physical examination. In conclusion, the recognition of suspicious distinctive features of cardiac murmurs is crucial and requires skills based on sufficient training and experience.


Mutation of FOXL2 in granulosa-cell tumors of the ovary.
Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C-->G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.


A gene expression screen identifies EARLI1 as a novel vernalization-responsive gene in Arabidopsis thaliana.
Vernalization promotes early flowering in late ecotypes of Arabidopsis thaliana. The mechanisms of vernalization are poorly understood. A subtractive hybridization approach was used to isolate vernalization-responsive genes from a late-flowering ecotype of Arabidopsis thaliana based on the premise that transcript levels of such genes would increase with cold treatment and remain high even after removal of the vernalization stimulus. EARLI1 is the first Arabidopsis gene shown to be stably activated by vernalization. The abundance of its RNA is progressively elevated by vernalization and remains high for at least 20 days at room temperature. The basal level of EARLI1 RNA is higher in early-flowering ecotypes, but is increased also after vernalization. Vernalization and subsequent growth in long-day photoperiods have an additive or synergistic effect on EARLI1 activation. EARLI1 RNA levels are also transiently induced by brief exposures to cold, but not to abscisic acid. EARLI1 is thus a novel vernalization-responsive gene in Arabidopsis thaliana that can be used to investigate vernalization-specific transcriptional regulation.


Meta-analysis of the impact of postoperative infective complications on oncological outcomes in colorectal cancer surgery.
Cancer outcomes are complex, involving prevention, early detection and optimal multidisciplinary care. Postoperative infection and surgical site-infection (SSI) are not only uncomfortable for patients and costly, but may also be associated with poor oncological outcomes. A meta-analysis was undertaken to assess the oncological effects of SSI in patients with colorectal cancer. An ethically approved PROSPERO-registered meta-analysis was conducted following PRISMA guidelines. PubMed and Scopus databases were searched for studies published between 2007 and 2017 reporting the effects of postoperative infective complications on oncological survival in colorectal cancer. Results were separated into those for SSI and those concerning anastomotic leakage. Articles with a Methodological Index for Non-Randomized Studies score of at least 18 were included. Hazard ratios (HRs) with 95 per cent confidence intervals were computed for risk factors using an observed to expected and variance fixed-effect model. Of 5027 articles were reviewed, 43 met the inclusion criteria, with a total of 154 981 patients. Infective complications had significant negative effects on overall survival (HR 1·37, 95 per cent c.i. 1·28 to 1·46) and cancer-specific survival (HR 2·58, 2·15 to 3·10). Anastomotic leakage occurred in 7·4 per cent and had a significant negative impact on disease-free survival (HR 1·14, 1·09 to 1·20), overall survival (HR 1·34, 1·28 to 1·39), cancer-specific survival (HR 1·43, 1·31 to 1·55), local recurrence (HR 1·18, 1·06 to 1·32) and overall recurrence (HR 1·46, 1·27 to 1·68). This meta-analysis identified a significant negative impact of postoperative infective complications on overall and cancer-specific survival in patients undergoing colorectal surgery.


Sex-Specific Prediction Models for Sleep Apnea From the Hispanic Community Health Study/Study of Latinos.
We developed and validated the first-ever sleep apnea (SA) risk calculator in a large population-based cohort of Hispanic/Latino subjects. Cross-sectional data on adults from the Hispanic Community Health Study/Study of Latinos (2008-2011) were analyzed. Subjective and objective sleep measurements were obtained. Clinically significant SA was defined as an apnea-hypopnea index ≥ 15 events per hour. Using logistic regression, four prediction models were created: three sex-specific models (female-only, male-only, and a sex × covariate interaction model to allow differential predictor effects), and one overall model with sex included as a main effect only. Models underwent 10-fold cross-validation and were assessed by using the C statistic. SA and its predictive variables; a total of 17 variables were considered. A total of 12,158 participants had complete sleep data available; 7,363 (61%) were women. The population-weighted prevalence of SA (apnea-hypopnea index ≥ 15 events per hour) was 6.1% in female subjects and 13.5% in male subjects. Male-only (C statistic, 0.808) and female-only (C statistic, 0.836) prediction models had the same predictor variables (ie, age, BMI, self-reported snoring). The sex-interaction model (C statistic, 0.836) contained sex, age, age × sex, BMI, BMI × sex, and self-reported snoring. The final overall model (C statistic, 0.832) contained age, BMI, snoring, and sex. We developed two websites for our SA risk calculator: one in English (https://www.montefiore.org/sleepapneariskcalc.html) and another in Spanish (http://www.montefiore.org/sleepapneariskcalc-es.html). We created an internally validated, highly discriminating, well-calibrated, and parsimonious prediction model for SA. Contrary to the study hypothesis, the variables did not have different predictive magnitudes in male and female subjects.


Multiple glassy dynamics in dipole functionalized triphenylene-based discotic liquid crystals revealed by broadband dielectric spectroscopy and advanced calorimetry - assessment of the molecular origin.
A selected series of dipole functionalized triphenylene-based discotic liquid crystals (DLCs) was synthesized and investigated in a systematic way to reveal the phase behavior and molecular dynamics. The later point is of particular importance to understand the charge transport in such systems which is the key property for their applications such as organic field-effect transistors, solar cells or as nanowires in molecular electronics, and also to tune the properties of DLCs. The mesomorphic properties were studied by polarizing optical microscopy, X-ray diffraction, and differential scanning calorimetry, which were compared to the corresponding unfunctionalized DLC. The molecular dynamics were investigated by a combination of state-of-the-art broadband dielectric spectroscopy (BDS) and advanced calorimetry such as fast scanning calorimetry (FSC) and specific heat spectroscopy (SHS). Besides localized fluctuations, surprisingly multiple glassy dynamics were detected for all materials for the first time. Glassy dynamics were proven for both processes unambiguously due to the extraordinary broad frequency range covered. The α1-process is attributed to fluctuations of the alky chains in the intercolumnar space because a polyethylene-like glassy dynamics is observed. This corresponds to a glass transition in a confined three-dimensional space. The α2-process found at temperatures lower than α1-process, is assigned to small scale rotational and/or translational in plane fluctuations of the triphenylene core inside distorted columns. This can be considered as a glass transition in a one-dimensional fluid. Therefore, obtained results are of general importance to understand the glass transition, which is an unsolved problem of condensed matter science.


Coronal computed tomography analysis of frontal cells.
Described by Schaefer in 1916, frontal cells have been implicated as a cause of frontal recess obstruction. In this cross-sectional study, we determine the prevalence of frontal cells and other anatomic variants and examine their relationships. Coronal computed tomography scans of the sinuses performed from January 2000 to June 2001 were evaluated for frontal cells, other anatomic variants, and sinus disease. Of 1009 scans evaluated, 768 scans were included for data collection. Frontal cells were classified. In this population, 20.4% of individuals had frontal cells (14.9% had type I, 3.1% had type II, 1.7% had type III, and 2.1% had type IV). The presence of frontal cells was positively associated with hyperpneumatization of the frontal sinus (p = 0.01) and negatively associated with hypopneumatization of the frontal sinus (p < 0.01). Individuals with frontal cells had an increased prevalence of concha bullosa compared with individuals without frontal cells (41.4% versus 24.1%, p < 0.01). The prevalence of frontal mucosal thickening was increased in individuals with type III and type IV cells compared with individuals without frontal cells (38.5 and 69.0% versus 17.1%, p = 0.04 and p < 0.01). The prevalence of frontal cells among a population undergoing sinus computed tomography is 20.4%. Frontal cells are associated with other variants of sinonasal pneumatization and should be suspected when these variants are noted. The presence of frontal cells does not invariably lead to frontal sinusitis but may contribute to the mechanical obstruction of the frontal recess and should be appropriately addressed during the surgical management of frontal sinusitis.


Gene targeting technologies in rats: zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats.
The laboratory rat has been widely used as an animal model in biomedical science for more than 150 years. Applying zinc-finger nucleases or transcription activator-like effector nucleases to rat embryos via microinjection is an efficient genome editing tool for generating targeted knockout rats. Recently, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonucleases have been used as an effective tool for precise and multiplex genome editing in mice and rats. In this review, the advantages and disadvantages of these site-specific nuclease technologies for genetic analysis and manipulation in rats are discussed.


Cost analysis of Human Papillomavirus-related cervical diseases and genital warts in Swaziland.
Human papillomavirus (HPV) has proven to be the cause of several severe clinical conditions on the cervix, vulva, vagina, anus, oropharynx and penis. Several studies have assessed the costs of cervical lesions, cervical cancer (CC), and genital warts. However, few have been done in Africa and none in Swaziland. Cost analysis is critical in providing useful information for economic evaluations to guide policymakers concerned with the allocation of resources in order to reduce the disease burden. A prevalence-based cost of illness (COI) methodology was used to investigate the economic burden of HPV-related diseases. We used a top-down approach for the cost associated with hospital care and a bottom-up approach to estimate the cost associated with outpatient and primary care. The current study was conducted from a provider perspective since the state bears the majority of the costs of screening and treatment in Swaziland. All identifiable direct medical costs were considered for cervical lesions, cervical cancer and genital warts, which were primary diagnoses during 2015. A mix of bottom up micro-costing ingredients approach and top-down approaches was used to collect data on costs. All costs were computed at the price level of 2015 and converted to dollars ($). The total annual estimated direct medical cost associated with screening, managing and treating cervical lesions, CC and genital warts in Swaziland was $16 million. The largest cost in the analysis was estimated for treatment of high-grade cervical lesions and cervical cancer representing 80% of the total cost ($12.6 million). Costs for screening only represented 5% of the total cost ($0.9 million). Treatment of genital warts represented 6% of the total cost ($1million). According to the cost estimations in this study, the economic burden of HPV-related cervical diseases and genital warts represents a major public health issue in Swaziland. Prevention of HPV infection with a national HPV immunization programme for pre-adolescent girls would prevent the majority of CC related deaths and associated costs.


Renovation of the egg extracellular matrix at fertilization.
Extracellular matrices are essential for cell survival and function. This is especially relevant for eggs, which establish a physical barrier at fertilization to protect a new embryo from additional sperm and pathogens. Formation of an extracellular matrix is most dramatic in sea urchins, in which fertilization was first observed in animals with the "sudden appearance of a perfectly transparent envelope" (A. Derbès, 1847). The process of assembling this extracellular "envelope" has been a topic of intense study ever since. Here we integrate the cellular and molecular events necessary to form this fertilization envelope within the first few minutes of a new embryo's life.


The Tuskegee Legacy Project: history, preliminary scientific findings, and unanticipated societal benefits.
This article is intended to provide a relatively complete picture of how a pilot study--conceived and initiated within an NIDCR-funded RRCMOH--matured into a solid line of investigation within that center and "with legs" into a fully funded study within the next generation of NIDCR centers on this topic of health disparities, the Centers for Research to Reduce Oral Health Disparities. It highlights the natural opportunity that these centers provide for multicenter. cross-disciplinary research and for research career pipelining for college and dental school students; with a focus, in this case, on minority students. Futhermore, this series of events demonstrates the rich potential that these types of research centers have to contribute in ways that far exceed the scientific outcomes that form their core. In this instance, the NMOHRC played a central--and critical, if unanticipated--role in contributing to two events of national significance, namely the presidential apology to the African American community for the research abuses of the USPHS--Tuskegee syphilis study and the establishment of the National Center for Bioethics in Research and Health Care at Tuskegee University. Research Centers supported by the NIH are fully intended to create a vortex of scientific activity that goes well beyond the direct scientific aims of the studies initially funded within those centers. The maxim is that the whole should be greater than the sum of its initial constituent studies or parts. We believe that NMOHRC did indeed achieve that maxim--even extending "the whole" to include broad societal impact. well beyond the scope of important, but mere, scientific outcomes--all within the concept and appropriate functions of a scientific NIH-funded research center.


Catchment delineation and morphometric analysis using geographical information system.
The geographical information system (GIS) has emerged as an efficient tool in delineation of drainage patterns of watershed planning and management. The morphometric parameters of basins can address linear, areal and relief aspects. The study deals with the integrated watershed management of Baliya micro-watersheds, located in the Udaipur district of Rajasthan, India. Morphometric analysis in hydrological investigation is an important aspect and it is inevitable in the development and management of drainage basins. The determination of linear, areal and relief parameters indicate fairly good significance. The low value of the bifurcation ratio of 4.19 revealed that the drainage pattern has not been distorted by structural disturbance. The high value of the elongation ratio (0.68) compared to the circulatory ratio (0.27) indicates an elongated shape of the watershed. The high value of drainage density (5.39 km/km(2)) and stream frequency (12.32) shows that the region has impermeable subsoil material under poor vegetative cover with a low relief factor. The morphometric parameters of relief ratio (0.041) and relative relief (0.99%) show that the watershed can be treated using GIS techniques to determine the morphometric presence of dendritic drainage pattern, with a view to selecting the soil and water conservation measures and water harvesting.


Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome.
Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.


Changes in hope and health-related quality of life in couples following acute myocardial infarction: a quantitative longitudinal study.
Acute myocardial infarction (AMI) is a life-changing event that affects both the patient and the family and can have an influence on hope as well as HRQoL during the recovery period. To compare self-rated scores of hope and health-related quality of life (HRQoL) 1, 7, 13 and 25 months, after an AMI with regard to (i) differences across time, and (ii) differences between patients and their partners. Explorative and longitudinal study. In this nonrandomized study, Short Form 36 Health Questionnaire (SF-36) and Herth Hope Index-Swedish (HHI-S) questionnaires were completed by thirteen post-AMI patients and their partners. Data were collected on four occasions. In general, hope as well as HRQoL scores increased over time. A 2 (groups) × 4 (times) anova for mixed design showed significant changes in mental as well as in physical health over time but no significant effect of group on mental or physical health. Calculation of the minimum detectable change (MDC-index) for HHI-S and SF-36 revealed that scores between data collection points were not stable. conclusion: Our results show that although hope and HRQoL scores increased, only a few of the changes were statistically significant. Neither HHI-S nor SF-36 seems to measure stable states. Changes in hope and HRQoL levels may be due to participants striving to adapt to the current situation. These results can be used in the training of nursing staff to enhance their understanding of the significance of a family-centred approach after an AMI.


Origin of a counterintuitive yellow light-emitting electrochemical cell based on a blue-emitting heteroleptic copper(i) complex.
This work provides the synthesis, structural characterization, electrochemical and photophysical features, as well as the application in light-emitting electrochemical cells (LECs) of a novel heteroleptic copper(i) complex - [Cu(impy)(POP)][PF6], where impy is 3-(2-methoxyphenyl)-1-(pyridine-2-yl)imidazo[1,5-a]pyridine and POP is bis{2-(diphenylphosphanyl)phenyl}ether. This compound shows blue photoluminescence (PL, λ = 450 nm) in solution and solid-state and excellent redox stability. Despite these excellent features, the electroluminescence (EL) response is located at ∼550 nm. Although the EL spectrum of LECs is typically red-shifted compared to the PL of the electroluminescent material, a shift of ca. 100 nm represents the largest one reported in LECs. To date, the large shift phenomena have been attributed to (i) a change in the nature of the lowest emitting state due to a concentration effect of the films, (ii) a reversible substitution of the ligands due to the weak coordination to the Cu(i), and (iii) a change in the distribution of the excited states due to polarization effects. After having discarded these along with others like the irreversible degradation of the emitter during device fabrication and/or under operation conditions, driving conditions, active layer composition, and changes in the excited states under different external electrical stimuli, we attribute the origin of this unexpected shift to a lack of a thermally activated delayed fluorescence (TADF) process due to the solely ligand-centered character of the excited states. As such, the lack of a charge transfer character in the excited states leads to a blue-fluorescence and yellow-phosphorescence photo- and electro-responses, respectively. This corroborates recent studies focused on the design of TADF for heteroleptic copper(i) complexes. Overall, this work is a clear insight into the design of new copper(i) complexes towards the preparation of blue LECs, which are still unexplored.


An evidence-based approach to the adoption of new technology.
New orthopaedic technology is constantly being developed to help improve patient care. New technology may lead to a waste of resources or lead to harm for the patient if it is not properly evaluated before it is accepted as a standard of care. The purpose of this article is to assess how new technology can be implemented safely while maintaining an environment that allows for surgical innovation through an evidence-based approach. Although randomized controlled trials (Level-I evidence) are typically seen as the so-called gold standard with regard to treatment efficacy, randomized trials may not be the most effective form of evaluating a new technology. In many circumstances, a prospective cohort series or large registry that documents outcomes and adverse events may be more effective and practical for the evaluation of a new surgical technology.


Stable predictive markers for Phytophthora sojae avirulence genes that impair infection of soybean uncovered by whole genome sequencing of 31 isolates.
The interaction between oomycete plant pathogen Phytophthora sojae and soybean is characterized by the presence of avirulence (Avr) genes in P. sojae, which encode for effectors that trigger immune responses and resistance in soybean via corresponding resistance genes (Rps). A recent survey highlighted a rapid diversification of P. sojae Avr genes in soybean fields and the need to deploy new Rps genes. However, the full genetic diversity of P. sojae isolates remains complex and dynamic and is mostly characterized on the basis of phenotypic associations with differential soybean lines. We sequenced the genomes of 31 isolates of P. sojae, representing a large spectrum of the pathotypes found in soybean fields, and compared all the genetic variations associated with seven Avr genes (1a, 1b, 1c, 1d, 1k, 3a, 6) and how the derived haplotypes matched reported phenotypes in 217 interactions. We discovered new variants, copy number variations and some discrepancies with the virulence of previously described isolates with Avr genes, notably with Avr1b and Avr1c. In addition, genomic signatures revealed 11.5% potentially erroneous phenotypes. When these interactions were re-phenotyped, and the Avr genes re-sequenced over time and analyzed for expression, our results showed that genomic signatures alone accurately predicted 99.5% of the interactions. This comprehensive genomic analysis of seven Avr genes of P. sojae in a population of 31 isolates highlights that genomic signatures can be used as accurate predictors of phenotypes for compatibility with Rps genes in soybean. Our findings also show that spontaneous mutations, often speculated as a source of aberrant phenotypes, did not occur within the confines of our experiments and further suggest that epigenesis or gene silencing do not account alone for previous discordance between genotypes and phenotypes. Furthermore, on the basis of newly identified virulence patterns within Avr1c, our results offer an explanation why Rps1c has failed more rapidly in the field than the reported information on virulence pathotypes.


The effects of exogenous melatonin and melatonin receptor blockade on aggression and estrogen-dependent gene expression in male California mice (Peromyscus californicus).
Photoperiodic regulation of aggression has been well established in several vertebrate species, with rodents demonstrating increased aggression in short day photoperiods as compared to long day photoperiods. Previous work suggests that estrogens regulate aggression via rapid nongenomic pathways in short days and act more slowly in long days, most likely via genomic pathways. The current study therefore examines the role of melatonin in mediating aggression and estrogen-dependent gene transcription. In Experiment 1, male California mice were housed under long day photoperiods and were treated with either 0.3 μg/g of melatonin, 40 mg/kg of the melatonin receptor antagonist luzindole, or vehicle for 10 days. We found that melatonin administration significantly increased aggression as compared to mice receiving vehicle, but this phenotype was not completely ameliorated by luzindole. In Experiment 2, male California mice were injected with either 1mg/kg of the aromatase inhibitor letrozole or vehicle, and oxytocin receptor (OTR), estrogen receptor alpha (ERα), and c-fos gene expression was examined in the bed nucleus of the stria terminalis (BNST) and medial preoptic area (MPOA). In the BNST, but not MPOA, OTR mRNA was significantly downregulated following letrozole administration, indicating that OTR is an estrogen-dependent gene in the BNST. In contrast, ERα was not estrogen dependent in either brain region. In the MPOA, OTR mRNA was inhibited by melatonin, and luzindole suppressed this effect. C-fos and ERα did not differ between treatments in any brain region examined. These results suggest that it is unlikely that melatonin facilitates aggression via broad spectrum regulation of estrogen-dependent gene expression. Instead, melatonin may act via regulation of other transcription factors such as extracellular signal regulated kinase.


Factors Moderating the Relationship Between Childhood Trauma and Premorbid Adjustment in First-Episode Schizophrenia.
Childhood trauma is a recognised risk factor for schizophrenia. It has been proposed that childhood trauma interferes with normal neurodevelopment, thereby establishing a biological vulnerability to schizophrenia. Poor premorbid adjustment is frequently a precursor to schizophrenia, and may be a manifestation of neurodevelopmental compromise. We investigated the relationship between childhood trauma and premorbid adjustment in 77 patients with first-episode schizophrenia spectrum disorders. We also investigated possible mediating roles for other selected risk factors in the relationship. We found several significant correlations between different trauma types and both social and academic premorbid adjustment from childhood to late adolescence. There were no significant moderating effects for family history of schizophrenia or family history of psychiatric disorder. History of obstetric complications, substance abuse and poor motor coordination weakened some of the associations between childhood trauma and premorbid adjustment, while poor sequencing of motor acts strengthened the association. Our results confirm previous studies indicating an association between childhood trauma and premorbid adjustment. Results indicate a general rather than specific association, apparent with different types of trauma, and affecting both social and academic components of premorbid adjustment across childhood, early and late adolescence. Further, our results suggest a complex interplay of various risk factors, supporting the notion of different pathways to psychosis.


Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage.
Epoxyeicosatrienoic acids, hydrolyzed by soluble epoxide hydrolase (sEH), have multiple biological functions, including the regulation of vascular tone, renal tubular transport, and being anti-inflammatory. Inhibitors of sEH have been demonstrated to be antihypertensive and renal protective. To elucidate the role of sEH in glomerulonephritis, we first determined the expression of sEH in human kidney by examining biopsies from 153 patients with a variety of glomerulonephritis, including minimal-change, membranous, and IgA nephropathy. Immunohistochemical staining of frozen kidney biopsy samples revealed sEH preferentially expressed in the renal proximal tubular cells, and its expression increased in all patients with glomerulonephritis. The level of sEH in the cortex was positively correlated with proteinuria and negatively with serum albumin level. To investigate the role of sEH in proteinuria-induced renal damage, we incubated purified urine protein from patients with rat renal proximal tubular epithelial cells in vitro. The level of sEH was elevated, as were monocyte chemoattractant protein 1 and the process of tubular epithelial-to-mesenchymal transition, characterized with increased α-smooth muscle actin (α-SMA) and decreased E-cadherin. These effects were attenuated by administration of a potent sEH inhibitor and mimicked with adenovirus-mediated sEH overexpression. In adriamycin-induced nephropathic mice, sEH inhibitor did not ameliorate proteinuria or level of serum albumin but reduced the long-term elevated serum creatinine level, interstitial inflammation, fibrosis, and α-SMA expression. Thus upregulation of sEH in proximal tubular cells in chronic proteinuric kidney diseases may mediate proteinuria-induced renal damage; sEH inhibition by increasing renal eicosanoid levels could prevent the progression of chronic proteinuric kidney diseases.


RGS2 is a primary terminator of β₂-adrenergic receptor-mediated G(i) signaling.
Two major β-adrenergic receptor (βAR) subtypes, β(1)AR and β(2)AR, are expressed in mammalian heart with β(1)AR coupling to G(s) and β(2)AR dually coupling to G(s) and G(i) proteins. In many types of chronic heart failure, myocardial contractile response to both β(1)AR and β(2)AR stimulation is severely impaired. The dysfunction of βAR signaling in failing hearts is largely attributable to an increase in G(i) signaling, because disruption of the G(i) signaling restores myocardial contractile response to β(1)AR as well as β(2)AR stimulation. However, the mechanism terminating the β(2)AR-G(i) signaling remains elusive, while it has been shown activation of the G(i) signaling is dependent on agonist stimulation and subsequent PKA-mediated phosphorylation of the receptor. Here we demonstrate that regulator of G protein signaling 2 (RGS2) is a primary terminator of the β(2)AR-G(i) signaling. Specifically, prolonged absence of agonist stimulation for 24h impairs the β(2)AR-G(i) signaling, resulting in enhanced β(2)AR- but not β(1)AR-mediated contractile response in cultured adult mouse cardiomyocytes. Increased β(2)AR contractile response is accompanied by a selective upregulation of RGS2 in the absence of alterations in other major cardiac RGS proteins (RGS3-5) or G(s), G(i) or βAR subtypes. Administration of a βAR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the β(2)AR-G(i) signaling in cultured cells. Furthermore, RGS2 ablation, similar to βAR agonist stimulation, sustains the β(2)AR-G(i) signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated β(2)AR-G(i) signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the β(2)AR-G(i) signaling but also provide a potential novel target for the treatment of chronic heart failure.


Removal of free fatty acid in Azadirachta indica (Neem) seed oil using phosphoric acid modified mordenite for biodiesel production.
In this study free fatty acids present in Azadirachta indica (Neem) oil were esterified with our synthesized phosphoric acid modified catalyst. During the esterification, the acid value was reduced from 24.4 to 1.8 mg KOH/g oil. Synthesized catalyst was characterized by NH(3) TPD, XRD, SEM, FTIR and TGA analysis. During phosphoric acid modification hydrophobic character and weak acid sites of the mordenite were increased, which lead to better esterification when compared to H-mordenite. A kinetic study demonstrates that the esterification reaction followed pseudo-first order kinetics. Thermodynamic studies were also done based on the Arrhenius model.


Evoked responses to clicks and electroencephalographic stages of sleep in man.
The form of the average evoked response to clicks is highly correlated with the background electroencephalogram. However, the response during the emergent low-voltage "dreaming" stage is different from that seen during the low-voltage phase at the beginning of sleep. The results provide additional evidence that the emergent low-voltage stage is a neurophysiologically unique phase.


Potentially toxic elements contamination in urban soils: a comparison of three European cities.
Studies on several cities around the world confirm that urban soils are subject to heavy anthropogenic disturbance. However, these surveys are difficult to compare due to a lack of common sampling and analytical protocols. In this study the soils of Ljubljana (Slovenia), Sevilla (Spain), and Torino (Italy) were extensively sampled and analyzed using common procedures. Results highlighted similarities across the cities, despite their differences in geography, size, climate, etc. Potentially toxic elements (PTE) showed a wide range in concentration reflecting a diffuse contamination. Among the "urban" elements Pb exceeded the legislation threshold in 45% of Ljubljana, 43% of Torino, and 11% of Sevilla samples while Zn was above the limits in 20, 43, and 2% of the soils of Ljubljana, Torino, and Sevilla, respectively. The distribution of PTE showed no depth-dependant changes, while general soil properties seemed more responsive to anthropogenic influences. Multivariate statistics revealed similar associations between PTE in the three cities, with Cu, Pb, and Zn in a group, and Ni and Cr in another, suggesting an anthropogenic origin for the former group and natural one for the latter. Chromium and Ni were unaffected by land use, except for roadside soils, while Cu, Pb, and Zn distribution appeared to be more dependent on the distance from emission sources. Regardless of the location, climate, and size, the "urban" factor--integrating type and intensity of contaminant emission and anthropogenic disturbance--seems to prevail in determining trends of PTE contamination.


Education to Improve Dementia Care: Impact of a Structured Clinical Reasoning Approach.
Dementia often goes undiagnosed. A workshop was developed to provide primary care clinicians with a structured clinical reasoning approach to dementia diagnosis and brain map tool to differentiate type of dementia. The purpose of this study was to examine the impact of this approach on self-perceived changes in knowledge, confidence, and ability to assess and manage memory problems and on self-reported application of learning to clinical practice. Participants of 20 workshops (N=392) were invited to complete a reaction survey and of these, participants of 12 consecutive workshops (N=242) were invited to complete a 3-month follow-up survey to assess application of new learning to clinical practice and challenges experienced in doing so. In total, 355 reaction and 108 follow-up surveys were completed. Mean ratings of usefulness reflected that participants considered the clinical reasoning approach and brain map very useful to learning and knowledge transfer. At follow-up, the majority of respondents reported they were more confident (79%) and better able to assess (79%) persons with cognitive impairment and more confident (88%) and better able to manage (86%) persons with cognitive impairment. A number of practice changes and challenges were identified. These results add to a growing literature on strategies to improve dementia care with effective continuing medical education. A structured clinical reasoning approach to cognitive impairment is effective in improving confidence and ability to assess and manage patients with cognitive impairment, although participants continue to experience challenges in managing this complex condition.


Maternal preconception body mass index and offspring cord blood DNA methylation: exploration of early life origins of disease.
Maternal obesity is associated with a variety of common diseases in the offspring. One possible underlying mechanism could be maternal obesity induced alterations in DNA methylation. However, this hypothesis is yet to be tested. We performed epigenomic mapping of cord blood among 308 Black mother-infant pairs delivered at term at the Boston Medical Center using the Illumina HumanMethylation27 BeadChip. Linear regression and pathway analyses were conducted to evaluate the associations between DNA methylation levels and prepregnancy maternal BMI (<25, 25-30, ≥30 kg/m(2) ). The methylation levels of 20 CpG sites were associated with maternal BMI at a significance level of P-value <10(-4) in the overall sample, and boys and girls, separately. One CpG site remained statistically significant after correction for multiple comparisons (FDR corrected P-value = 0.04) and was annotated to a potential cancer gene, ZCCHC10. Some of the other CpG site annotated genes appear to be critical to the development of cancers and cardiovascular diseases (i.e., WNT16, C18orf8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). Significant findings from pathway analysis, such as infectious and inflammatory and lipid metabolism pathways, lends support for the potential impact of maternal BMI on the above stated disorders. This study demonstrates that prepregnancy maternal BMI might lead to alterations in offspring DNA methylation in genes relevant to the development of a range of complex chronic diseases, providing evidence of trans-generational influence on disease susceptibility via epigenetic mechanism.


Differences and similarities between bulimia nervosa, compulsive buying and gambling disorder.
The objective of the study was to analyse shared commonalities and differences between bulimia nervosa (BN) and certain impulse-related disorders, namely compulsive buying (CB) and gambling disorder (GD), with respect to general psychopathology and personality traits. A total of 188 female patients [50 BN without comorbid CB (BN-CB), 49 BN with comorbid CB (BN+CB), 53 GD and 36 CB] and 50 comparison non-psychiatric women participated in the current study. All patients were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth revised edition, the Temperament and Character Inventory-Revised, and other clinical indices. A positive-growing trend was observed in psychopathology and personality traits across the four clinical groups. Comorbid BN with CB was associated with highest eating psychopathology and social anxiety. On Novelty Seeking, the CB, GD and BN+CB were similar to each other, whereas BN-CB presented a distinct profile. Moreover, the BN+CB group displayed more dysfunctional personality traits and higher general psychopathology. The clinical groups demonstrated overall higher levels of psychopathology compared with the control group. The results of this study demonstrate that disorders with impulsive traits (CB, GD, BN+CB and BN-CB) follow a linear trend in general psychopathology and specific personality traits, but differ along specific personality and psychopathological dimensions.


Comparison of Group Medical Visits Combined With Intensive Weight Management vs Group Medical Visits Alone for Glycemia in Patients With Type 2 Diabetes: A Noninferiority Randomized Clinical Trial.
Traditionally, group medical visits (GMVs) for persons with diabetes improved glycemia by intensifying medications, which infrequently led to weight loss. Incorporating GMVs with intensive dietary change could enable weight loss and improve glycemia while decreasing medication intensity. To examine whether a program of GMVs combined with intensive weight management (WM) is noninferior to GMVs alone for change in glycated hemoglobin (HbA1c) level at 48 weeks (prespecified margin of 0.5%) and superior to GMVs alone for hypoglycemic events, diabetes medication intensity, and weight loss. This randomized clinical trial identified via the electronic medical record 2814 outpatients with type 2 diabetes, uncontrolled HbA1c, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 27 or higher from Veterans Affairs Medical Center clinics in Durham and Greenville, North Carolina. Between January 12, 2015, and May 30, 2017, 263 outpatients started the intervention. Participants randomized to the GMV group (n = 136) received counseling about diabetes-related topics with medication optimization every 4 weeks for 16 weeks, then every 8 weeks (9 visits). Participants randomized to the WM/GMV group (n = 127) received low-carbohydrate diet counseling with baseline medication reduction and subsequent medication optimization every 2 weeks for 16 weeks followed by an abbreviated GMV intervention every 8 weeks (13 visits). Outcomes included HbA1c level, hypoglycemic events, diabetes medication effect score, and weight at 48 weeks analyzed using hierarchical generalized mixed models to account for clustering within group sessions. Among 263 participants (mean [SD] age, 60.7 [8.2] years; 235 [89.4%] men; 143 [54.4%] black), baseline HbA1c level was 9.1% (1.3%) and BMI was 35.3 (5.1). At 48 weeks, HbA1c level was improved in both study arms (8.2% in the WM/GMV arm and 8.3% in the GMV arm; mean difference, -0.1%; 95% CI, -0.5% to 0.2%; upper 95% CI, <0.5% threshold; P = .44). The WM/GMV arm had lower diabetes medication use (mean difference in medication effect score, -0.5; 95% CI, -0.6 to -0.3; P < .001) and greater weight loss (mean difference, -3.7 kg; 95% CI, -5.5 to -1.9 kg; P < .001) than did the GMV arm at 48 weeks and approximately 50% fewer hypoglycemic events (incidence rate ratio, 0.49; 95% CI, 0.27 to 0.71; P < .001) during the 48-week period. In GMVs for diabetes, addition of WM using a low-carbohydrate diet was noninferior for lowering HbA1c levels compared with conventional medication management and showed advantages in other clinically important outcomes. ClinicalTrials.gov identifier: NCT01973972.


Predicting the effects of deep brain stimulation using a reduced coupled oscillator model.
Deep brain stimulation (DBS) is known to be an effective treatment for a variety of neurological disorders, including Parkinson's disease and essential tremor (ET). At present, it involves administering a train of pulses with constant frequency via electrodes implanted into the brain. New 'closed-loop' approaches involve delivering stimulation according to the ongoing symptoms or brain activity and have the potential to provide improvements in terms of efficiency, efficacy and reduction of side effects. The success of closed-loop DBS depends on being able to devise a stimulation strategy that minimizes oscillations in neural activity associated with symptoms of motor disorders. A useful stepping stone towards this is to construct a mathematical model, which can describe how the brain oscillations should change when stimulation is applied at a particular state of the system. Our work focuses on the use of coupled oscillators to represent neurons in areas generating pathological oscillations. Using a reduced form of the Kuramoto model, we analyse how a patient should respond to stimulation when neural oscillations have a given phase and amplitude, provided a number of conditions are satisfied. For such patients, we predict that the best stimulation strategy should be phase specific but also that stimulation should have a greater effect if applied when the amplitude of brain oscillations is lower. We compare this surprising prediction with data obtained from ET patients. In light of our predictions, we also propose a new hybrid strategy which effectively combines two of the closed-loop strategies found in the literature, namely phase-locked and adaptive DBS.


eHealth in integrated care programs for people with multimorbidity in Europe: Insights from the ICARE4EU project.
Care for people with multimorbidity requires an integrated approach in order to adequately meet their complex needs. In this respect eHealth could be of help. This paper aims to describe the implementation, as well as benefits and barriers of eHealth applications in integrated care programs targeting people with multimorbidity in European countries, including insights on older people 65+. Within the framework of the ICARE4EU project, in 2014, expert organizations in 24 European countries identified 101 integrated care programs based on selected inclusion criteria. Managers of these programs completed a related on-line questionnaire addressing various aspects including the use of eHealth. In this paper we analyze data from this questionnaire, in addition to qualitative information from six programs which were selected as 'high potential' for their innovative approach and studied in depth through site visits. Out of 101 programs, 85 adopted eHealth applications, of which 42 focused explicitly on older people. In most cases Electronic Health Records (EHRs), registration databases with patients' data and tools for communication between care providers were implemented. Percentages were slightly higher for programs addressing older people. eHealth improves care integration and management processes. Inadequate funding mechanisms, interoperability and technical support represent major barriers. Findings seems to suggest that eHealth could support integrated care for (older) people with multimorbidity.


Back pain in children surveyed with weekly text messages - a 2.5 year prospective school cohort study.
Back pain is reported to occur already in childhood, but its development at that age is not well understood. The aims of this study were to describe BP in children aged 6-12 years, and to investigate any sex and age differences. Data on back pain (defined as pain in the neck, mid back and/or lower back) were collected once a week from parents replying to automated text-messages over 2.5 school years from 2008 till 2011. The prevalence estimates were presented as percentages and 95% confidence intervals. Differences between estimates were considered significant if confidence intervals did not overlap. A test for trend, using a multi-level mixed-effects logistic regression extended to the longitudinal and multilevel setting, was performed to see whether back pain reporting increased with age. Depending on the age group, 13-38% children reported back pain at least once per survey year, and 5-23% at least twice per survey year. The average weekly prevalence estimate ranged between 1% and 5%. In the final survey year more girls than boys reported back pain at least twice. The prevalence estimates did not increase monotonically with age but showed a greater increase in children younger than 9/10, after which they remained relatively stable up to the age of 12 years. We found that back pain was not a common problem in this age group and recommend health professionals be vigilant if a child presents with constant or recurring back pain. Our results need to be supplemented by a better understanding of the severity and consequences of back pain in childhood. It would be productive to study the circumstances surrounding the appearance of back pain in childhood, as well as, how various bio-psycho-social factors affect its onset and later recurrence. Knowledge about the causes of back pain in childhood might allow early prevention.


Microevolution and speciation in Thalassiosira weissflogii (Bacillariophyta).
In this study five different molecular markers were used to: (1) infer the phylogeographic differentiation of Thalassiosira weissflogii in the Atlantic and Pacific Oceans; and (2) address the biological species status of the inferred geographic lineages. The results of the ribosomal RNA data analyses suggested that the Hawaiian isolate evolved first after which the Indonesian and the Atlantic/California strains diverged. In contrast, the tree derived from the partial sexually induced gene 1 (Sig1) data exhibited an initial divergence between the Eastern Atlantic/Western Atlantic/California and the Hawaiian/Indonesian groups after which the latter evolved into the Hawaiian and Indonesian lineages. The partial beta-tubulin phylogeny discerns an early "split" between an Eastern Atlantic/Western Atlantic clade and an Indonesia/California/Hawaii group which later differentiated into distinct Hawaiian and Indonesian/California "branches". The number of compensatory base changes (CBCs) in the ITS2 indicated that the "Atlantic group", including the California isolate, constituted a single reproductive unit and that the Indonesian and Hawaiian T. weissflogii are two different biological species with regard to each other and to the "Atlantic clade". The beta-tubulin tree contradicts the reproductive units recovered by the compensatory base change analysis due to the close affinity of the California and Indonesia strains whereas the sexually induced gene 1 phylogeny supports the existence of three biological species, despite exhibiting a temporal sequence of geographic diversification that is different from that seen in topologies derived from the ribosomal RNA data. It is hypothesized that the tree derived from the sexually induced gene 1 reflects the relative order of the evolution of reproductive isolation in the different T. weissflogii strains while the lineages in the other phylogenies depict time elapsed since common ancestry. The current investigation is the first to have shown concordance in the pattern of variation between a reasonably good biological species marker (CBCs in the ITS2) and a protein hypothesized to be involved in sperm-egg recognition/adhesion in diatoms (Sig1). It was further discussed that the Pacific/Indonesian T. weissflogii species complex most likely evolved in the presence of gene flow and "local" environmental selection. Three hypotheses which potentially can explain the genetic diversification/similarity between the Atlantic T. weissflogii samples and the isolate obtained off the coast of California were proposed and discussed.


Clinical implications of phosphorylated STAT3 expression in De Novo diffuse large B-cell lymphoma.
Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited. We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations. pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL. The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL.


Creating healthy nursing home environment via lighting interventions: a theoretical approach.
In the Netherlands long-term care facilities made investments in order to improve the well-being of their residents and to support healthcare professionals in their daily task. Light is one of the technical solutions that might be contribute to support the well-being of older residents in long-term care facilities. This study investigates which possibilities are available to enrich the current situation to support the well-being, activities of daily living, and quality of life of older residents from lighting perspective. The light measurements show that the conditions are low and the value of 750 lux mainly reached on measurements points close to the window area. In this field study the light conditions are improved through a static lighting system. Further research is needed in order to investigate how the new light plan affect the quality of life and to define light guidelines for long-term care facilities.


Safety of transtympanic application of 4 % manuka honey in a chinchilla animal model.
The antimicrobial and anti-biofilm properties of manuka honey (MH) are currently being explored in the treatment of chronic recalcitrant rhinosinusitis. Due to similarities between chronic rhinosinusitis and chronic otitis, manuka honey may find applications in the management of challenging cases of chronic otitis media implicating biofilms. The goal of this study was to investigate the safety of topical application of 4 % MH in the middle ear. Eleven adult female chinchillas had one of their ears randomly assigned to receive transtympanic 4 % MH, while the contralateral ear served as control. Auditory brainstem-evoked response (ABR) was performed before and after MH application. The facial nerve function and vestibular system were assessed clinically. The animals were euthanized one month following the last application, and the cochleae samples were processed for light and scanning electron microscopy. There was no statistically significant differences between ABR thresholds in both control and experimental ears before and after the application of MH. No morphological differences were seen in both groups of cochleae. The outer hair cell counts for both groups were comparable. Our results suggest that 4 % MH appears not toxic to the cells of the cochlea after 4 weeks of application. The long-term effects of prolonged contact on the structure and function of the cochlea however need further investigations.


Virtual medical trainer. Patient assessment and trauma care simulator.
The Virtual Medical Trainer (VMET) combines multimedia sound and graphics with physiological engines, medical-procedures databases, and 3-D patients to produce an interactive environment that can mimic the cognitive pre-hospital assessment and care demands of a real emergency. VMET uses a reconfigurable component software and training framework that allows a uniform user interface, ease of increasing training complexity, and expansion of the software components. VMET provides an opportunity to experience a range of trauma scenarios prior to the challenge of an actual trauma situation.


Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.
The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. DERR1-10.2196/36261.


Selection of head and whisker coordination strategies during goal-oriented active touch.
In the rodent whisker system, a key model for neural processing and behavioral choices during active sensing, whisker motion is increasingly recognized as only part of a broader motor repertoire employed by rodents during active touch. In particular, recent studies suggest whisker and head motions are tightly coordinated. However, conditions governing the selection and temporal organization of such coordinated sensing strategies remain poorly understood. We videographically reconstructed head and whisker motions of freely moving mice searching for a randomly located rewarded aperture, focusing on trials in which animals appeared to rapidly "correct" their trajectory under tactile guidance. Mice orienting after unilateral contact repositioned their whiskers similarly to previously reported head-turning asymmetry. However, whisker repositioning preceded head turn onsets and was not bilaterally symmetric. Moreover, mice selectively employed a strategy we term contact maintenance, with whisking modulated to counteract head motion and facilitate repeated contacts on subsequent whisks. Significantly, contact maintenance was not observed following initial contact with an aperture boundary, when the mouse needed to make a large corrective head motion to the front of the aperture, but only following contact by the same whisker field with the opposite aperture boundary, when the mouse needed to precisely align its head with the reward spout. Together these results suggest that mice can select from a diverse range of sensing strategies incorporating both knowledge of the task and whisk-by-whisk sensory information and, moreover, suggest the existence of high level control (not solely reflexive) of sensing motions coordinated between multiple body parts.


Background factors and clinical symptoms of major depression with silent cerebral infarction.
We previously reported that major depression developing during or after the presenile period is frequently combined with silent cerebral infarction and that these patients have a high risk of stroke. Therefore, we investigated whether the background factors and clinical symptoms of patients with major depression with silent cerebral infarction [SCI(+)] different from those in patients with major depression without silent cerebral infarction [SCI(-)] before medical treatment. Patients with major depression with onset after 50 years of age were classified based on magnetic resonance imaging findings into the SCI(+) (n = 37) or SCI(-) (n = 20) group. The diagnostic criteria for major depression were those of the American Psychiatry Association (DSM-III-R). Patients with stroke or focal neurological symptoms were excluded. The SCI(+) group was subclassified according to whether the infarction area was perforating, cortical, or mixed artery. Family history of affective disorder, risk factors for stroke, and Zung's Self-rated Depression Scale (SDS) score before medical treatment of the group were compared. The SCI(+) group had a significantly lower (P < .05) frequency of family history of affective disorder but a significantly higher (P < .01) frequency of hypertension than did the SCI(-) group. The mean SDS score in the SCI(+) group was significantly higher than that in the SCI(-) group (P < .01). The mean SDS score of the mixed artery infarction group was higher than that of the perforating artery infarction group (P < .05). Patients with major depression with silent cerebral infarction present more marked neurological factors and more severe depressive symptoms than do those without silent cerebral infarction. Because these features were more prominent in the patients with mixed artery infarction with broad obstructions, we consider that the area of brain damage caused by cerebral infarction is positively related to the severity of depressive symptoms.


Shoot-and-Trap: use of specific x-ray damage to study structural protein dynamics by temperature-controlled cryo-crystallography.
Although x-ray crystallography is the most widely used method for macromolecular structure determination, it does not provide dynamical information, and either experimental tricks or complementary experiments must be used to overcome the inherently static nature of crystallographic structures. Here we used specific x-ray damage during temperature-controlled crystallographic experiments at a third-generation synchrotron source to trigger and monitor (Shoot-and-Trap) structural changes putatively involved in an enzymatic reaction. In particular, a nonhydrolyzable substrate analogue of acetylcholinesterase, the "off-switch" at cholinergic synapses, was radiocleaved within the buried enzymatic active site. Subsequent product clearance, observed at 150 K but not at 100 K, indicated exit from the active site possibly via a "backdoor." The simple strategy described here is, in principle, applicable to any enzyme whose structure in complex with a substrate analogue is available and, therefore, could serve as a standard procedure in kinetic crystallography studies.


Novel candidate cancer genes identified by a large-scale cross-species comparative oncogenomics approach.
Comparative genomic hybridization (CGH) can reveal important disease genes but the large regions identified could sometimes contain hundreds of genes. Here we combine high-resolution CGH analysis of 598 human cancer cell lines with insertion sites isolated from 1,005 mouse tumors induced with the murine leukemia virus (MuLV). This cross-species oncogenomic analysis revealed candidate tumor suppressor genes and oncogenes mutated in both human and mouse tumors, making them strong candidates for novel cancer genes. A significant number of these genes contained binding sites for the stem cell transcription factors Oct4 and Nanog. Notably, mice carrying tumors with insertions in or near stem cell module genes, which are thought to participate in cell self-renewal, died significantly faster than mice without these insertions. A comparison of the profile we identified to that induced with the Sleeping Beauty (SB) transposon system revealed significant differences in the profile of recurrently mutated genes. Collectively, this work provides a rich catalogue of new candidate cancer genes for functional analysis.