Neurologic Injury in Adults Supported With Veno-Venous Extracorporeal Membrane Oxygenation for Respiratory Failure: Findings From the Extracorporeal Life Support Organization Database.
To assess in-hospital neurologic (CNS) complications in adult patients undergoing veno-venous extracorporeal membrane oxygenation for respiratory failure. Retrospective analysis of the Extracorporeal Life Support Organization's data registry. Data reported to Extracorporeal Life Support Organization from 350 international extracorporeal membrane oxygenation centers during 1992-2015. Adults (≥ 18 yr old) supported with veno-venous extracorporeal membrane oxygenation for respiratory failure. None. We included 4,988 adults supported with veno-venous extracorporeal membrane oxygenation for respiratory failure. Neurologic injury was defined as brain death, seizures, stroke, and intracranial hemorrhage occurring during extracorporeal membrane oxygenation support. We used multivariable logistic regression to explore patient and extracorporeal membrane oxygenation factors associated with neurologic injury. Median age of the study cohort was 46 (interquartile range, 32-58). Four hundred twenty-six neurologic complications were reported in 356 patients (7.1%), and included 181 intracranial hemorrhage (42.5%), 100 brain deaths (23.5%), 85 stroke (19.9%), and 60 seizure events (14.1%). In-hospital mortality was significantly higher for those with CNS complications (75.8% vs 37.8%; p < 0.001) and varied by type of CNS injury; mortality was 79.6% in patients with intracranial hemorrhage, 68.2% in patients with stroke, and 50% in patients with seizures. Pre-extracorporeal membrane oxygenation cardiac arrest, continuous veno-venous hemofiltration, and hyperbilirubinemia during extracorporeal membrane oxygenation were associated with increased odds of neurologic injury. Approximately 7% of adults supported with veno-venous extracorporeal membrane oxygenation for respiratory failure had neurologic injury. Intracranial hemorrhage was the most frequent type, and survival for patients with neurologic injury was poor. Future investigations should evaluate anticoagulation management as well as brain/extracorporeal membrane oxygenation interaction to reduce these life-threatening events.


Systematic review: the effects of growth hormone on athletic performance.
Human growth hormone is reportedly used to enhance athletic performance, although its safety and efficacy for this purpose are poorly understood. To evaluate evidence about the effects of growth hormone on athletic performance in physically fit, young individuals. MEDLINE, EMBASE, SPORTDiscus, and Cochrane Collaboration databases were searched for English-language studies published between January 1966 and October 2007. Randomized, controlled trials that compared growth hormone treatment with no growth hormone treatment in community-dwelling healthy participants between 13 and 45 years of age. 2 authors independently reviewed articles and abstracted data. 44 articles describing 27 study samples met inclusion criteria; 303 participants received growth hormone, representing 13.3 person-years of treatment. Participants were young (mean age, 27 years [SD, 3]), lean (mean body mass index, 24 kg/m2 [SD, 2]), and physically fit (mean maximum oxygen uptake, 51 mL/kg of body weight per minute [SD, 8]). Growth hormone dosage (mean, 36 microg/kg per day [SD, 21]) and treatment duration (mean, 20 days [SD, 18] for studies giving growth hormone for >1 day) varied. Lean body mass increased in growth hormone recipients compared with participants who did not receive growth hormone (increase, 2.1 kg [95% CI, 1.3 to 2.9 kg]), but strength and exercise capacity did not seem to improve. Lactate levels during exercise were statistically significantly higher in 2 of 3 studies that evaluated this outcome. Growth hormone-treated participants more frequently experienced soft tissue edema and fatigue than did those not treated with growth hormone. Few studies evaluated athletic performance. Growth hormone protocols in the studies may not reflect real-world doses and regimens. Claims that growth hormone enhances physical performance are not supported by the scientific literature. Although the limited available evidence suggests that growth hormone increases lean body mass, it may not improve strength; in addition, it may worsen exercise capacity and increase adverse events. More research is needed to conclusively determine the effects of growth hormone on athletic performance.


Smartphones and pediatric apps to mobilize the medical home.
To assess digital access and mobile health in urban pediatric clinics by measuring demographics of smartphone ownership, primary uses of mobile devices by teens vs parents/caregivers, and interest levels in using smartphone health apps. This cross-sectional survey studied teenagers and caregivers from 2 urban pediatric practices in Bronx, New York; 148 surveys were administered verbally in waiting rooms using a 24-item "iHealthNYC" questionnaire. A demonstration of smartphone health apps was then conducted and data analyzed using bivariate analysis and χ(2) statistics. Overall, 84% of subjects were smartphone owners, with 57% using smartphones as their primary internet source. There was no statistical difference in smartphone ownership between age groups or demographics of sex, ethnicity, and socioeconomic status. Smartphone users had a mean 14.5 apps, with 70.4% accessing apps >3 times a day. The majority of participants stated interest in medical apps, although caregivers were significantly more motivated. Likewise, caregivers are more likely to search health topics via their phone (76.7% vs 47.9%, P < .01) and own medical apps vs teens (35.1% vs 16.9%, P = .02). The prevalence of smartphone and app use in urban pediatric populations is high. With increased interest in mobile health, smartphones are an attractive modality for patient education, disease management, and streamlining health care communication in diverse settings, thus "mobilizing" the medical home. Further research is needed so that pediatricians can promote evidence-based apps, thus enabling patients to take ownership of their health.


Do unto others or treat yourself? The effects of prosocial and self-focused behavior on psychological flourishing.
When it comes to the pursuit of happiness, popular culture encourages a focus on oneself. By contrast, substantial evidence suggests that what consistently makes people happy is focusing prosocially on others. In the current study, we contrasted the mood- and well-being-boosting effects of prosocial behavior (i.e., doing acts of kindness for others or for the world) and self-oriented behavior (i.e., doing acts of kindness for oneself) in a 6-week longitudinal experiment. Across a diverse sample of participants (N = 473), we found that the 2 types of prosocial behavior led to greater increases in psychological flourishing than did self-focused and neutral behavior. In addition, we provide evidence for mechanisms explaining the relative improvements in flourishing among those prompted to do acts of kindness-namely, increases in positive emotions and decreases in negative emotions. Those assigned to engage in self-focused behavior did not report improved psychological flourishing, positive emotions, or negative emotions relative to controls. The results of this study contribute to a growing literature supporting the benefits of prosocial behavior and challenge the popular perception that focusing on oneself is an optimal strategy to boost one's mood. People striving for happiness may be tempted to treat themselves. Our results, however, suggest that they may be more successful if they opt to treat someone else instead. (PsycINFO Database Record


Predator traits determine food-web architecture across ecosystems.
Predator-prey interactions in natural ecosystems generate complex food webs that have a simple universal body-size architecture where predators are systematically larger than their prey. Food-web theory shows that the highest predator-prey body-mass ratios found in natural food webs may be especially important because they create weak interactions with slow dynamics that stabilize communities against perturbations and maintain ecosystem functioning. Identifying these vital interactions in real communities typically requires arduous identification of interactions in complex food webs. Here, we overcome this obstacle by developing predator-trait models to predict average body-mass ratios based on a database comprising 290 food webs from freshwater, marine and terrestrial ecosystems across all continents. We analysed how species traits constrain body-size architecture by changing the slope of the predator-prey body-mass scaling. Across ecosystems, we found high body-mass ratios for predator groups with specific trait combinations including (1) small vertebrates and (2) large swimming or flying predators. Including the metabolic and movement types of predators increased the accuracy of predicting which species are engaged in high body-mass ratio interactions. We demonstrate that species traits explain striking patterns in the body-size architecture of natural food webs that underpin the stability and functioning of ecosystems, paving the way for community-level management of the most complex natural ecosystems.


'Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.
To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated relapsing disease. In this UK-based, multicentre study, 31 children with MOG antibody-associated relapsing disease were studied retrospectively. Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow-up (p<0.001). 'Leukodystrophy-like' MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3-year follow-up was mild to moderate, and most patients continued to relapse, despite disease-modifying treatments. MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody-associated disease present with age-related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody-mediated mechanisms of damage. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination manifest with an age-related phenotype. Children with MOG antibody and 'leukodystrophy-like' imaging patterns tend to have poor response to second-line immunotherapy.


Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling.
Carbon dioxide (CO(2)) is increasingly being appreciated as an intracellular signaling molecule that affects inflammatory and immune responses. Elevated arterial CO(2) (hypercapnia) is encountered in a range of clinical conditions, including chronic obstructive pulmonary disease, and as a consequence of therapeutic ventilation in acute respiratory distress syndrome. In patients suffering from this syndrome, therapeutic hypoventilation strategy designed to reduce mechanical damage to the lungs is accompanied by systemic hypercapnia and associated acidosis, which are associated with improved patient outcome. However, the molecular mechanisms underlying the beneficial effects of hypercapnia and the relative contribution of elevated CO(2) or associated acidosis to this response remain poorly understood. Recently, a role for the non-canonical NF-κB pathway has been postulated to be important in signaling the cellular transcriptional response to CO(2). In this study, we demonstrate that in cells exposed to elevated CO(2), the NF-κB family member RelB was cleaved to a lower molecular weight form and translocated to the nucleus in both mouse embryonic fibroblasts and human pulmonary epithelial cells (A549). Furthermore, elevated nuclear RelB was observed in vivo and correlated with hypercapnia-induced protection against LPS-induced lung injury. Hypercapnia-induced RelB processing was sensitive to proteasomal inhibition by MG-132 but was independent of the activity of glycogen synthase kinase 3β or MALT-1, both of which have been previously shown to mediate RelB processing. Taken together, these data demonstrate that RelB is a CO(2)-sensitive NF-κB family member that may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung.


An open-source tool for the validation of finite element models using three-dimensional full-field measurements.
Three-dimensional (3D) full-field measurements provide a comprehensive and accurate validation of finite element (FE) models. For the validation, the result of the model and measurements are compared based on two respective point-sets and this requires the point-sets to be registered in one coordinate system. Point-set registration is a non-convex optimization problem that has widely been solved by the ordinary iterative closest point algorithm. However, this approach necessitates a good initialization without which it easily returns a local optimum, i.e. an erroneous registration. The globally optimal iterative closest point (Go-ICP) algorithm has overcome this drawback and forms the basis for the presented open-source tool that can be used for the validation of FE models using 3D full-field measurements. The capability of the tool is demonstrated using an application example from the field of biomechanics. Methodological problems that arise in real-world data and the respective implemented solution approaches are discussed.


Determining breast cancer histological grade from RNA-sequencing data.
The histologic grade (HG) of breast cancer is an established prognostic factor. The grade is usually reported on a scale ranging from 1 to 3, where grade 3 tumours are the most aggressive. However, grade 2 is associated with an intermediate risk of recurrence, and carries limited information for clinical decision-making. Patients classified as grade 2 are at risk of both under- and over-treatment. RNA-sequencing analysis was conducted in a cohort of 275 women diagnosed with invasive breast cancer. Multivariate prediction models were developed to classify tumours into high and low transcriptomic grade (TG) based on gene- and isoform-level expression data from RNA-sequencing. HG2 tumours were reclassified according to the prediction model and a recurrence-free survival analysis was performed by the multivariate Cox proportional hazards regression model to assess to what extent the TG model could be used to stratify patients. The prediction model was validated in N=487 breast cancer cases from the The Cancer Genome Atlas (TCGA) data set. Differentially expressed genes and isoforms associated with HGs were analysed using linear models. The classification of grade 1 and grade 3 tumours based on RNA-sequencing data achieved high accuracy (area under the receiver operating characteristic curve = 0.97). The association between recurrence-free survival rate and HGs was confirmed in the study population (hazard ratio of grade 3 versus 1 was 2.62 with 95 % confidence interval = 1.04-6.61). The TG model enabled us to reclassify grade 2 tumours as high TG and low TG gene or isoform grade. The risk of recurrence in the high TG group of grade 2 tumours was higher than in low TG group (hazard ratio = 2.43, 95 % confidence interval = 1.13-5.20). We found 8200 genes and 13,809 isoforms that were differentially expressed between HG1 and HG3 breast cancer tumours. Gene- and isoform-level expression data from RNA-sequencing could be utilised to differentiate HG1 and HG3 tumours with high accuracy. We identified a large number of novel genes and isoforms associated with HG. Grade 2 tumours could be reclassified as high and low TG, which has the potential to reduce over- and under-treatment if implemented clinically.


Innate lymphoid cells in the skin.
Innate lymphoid cells (ILCs) are part of a heterogeneous family of innate immune cells with newly identified roles in mediating immunity, tissue homeostasis, and pathologic inflammation. Here, we review recent studies delineating the roles of ILCs in the pathogenesis of multiple inflammatory skin disorders and their unique effector functions. Finally, we address how these studies have informed our understanding of the regulation of ILCs and the therapeutic potential of targeting these cells in the context of skin inflammation.


Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells.
Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.


Bioenergetics failure and oxidative stress in brain stem mediates cardiovascular collapse associated with fatal methamphetamine intoxication.
Whereas sudden death, most often associated with cardiovascular collapse, occurs in abusers of the psychostimulant methamphetamine (METH), the underlying mechanism is much less understood. The demonstration that successful resuscitation of an arrested heart depends on maintained functionality of the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of stable blood pressure, suggests that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse. We tested the hypothesis that cessation of brain stem cardiovascular regulation because of a loss of functionality in RVLM mediated by bioenergetics failure and oxidative stress underlies the cardiovascular collapse elicited by lethal doses of METH. Survival rate, cardiovascular responses and biochemical or morphological changes in RVLM induced by intravenous administration of METH in Sprague-Dawley rats were investigated. High doses of METH induced significant mortality within 20 min that paralleled concomitant the collapse of arterial pressure or heart rate and loss of functionality in RVLM. There were concurrent increases in the concentration of METH in serum and ventrolateral medulla, along with tissue anoxia, cessation of microvascular perfusion and necrotic cell death in RVLM. Furthermore, mitochondrial respiratory chain enzyme activity or electron transport capacity and ATP production in RVLM were reduced, and mitochondria-derived superoxide anion level was augmented. All those detrimental physiological and biochemical events were reversed on microinjection into RVLM of a mobile electron carrier in the mitochondrial respiratory chain, coenzyme Q10; a mitochondria-targeted antioxidant and superoxide anion scavenger, Mito-TEMPO; or an oxidative stress-induced necrotic cell death inhibitor, IM-54. We conclude that sustained anoxia and cessation of local blood flow that leads to bioenergetics failure and oxidative stress because of mitochondrial dysfunction, leading to acute necrotic cell death in RVLM underpins cardiovascular collapse elicited by lethal doses of METH.


The latent reservoir for HIV-1 in resting CD4+ T cells and other viral reservoirs during chronic infection: insights from treatment and treatment-interruption trials.
Although treatment of HIV-1 infection with highly active antiretroviral therapy can decrease virus in the plasma to undetectable levels, it cannot eradicate the infection due to the existence of viral reservoirs. These reservoirs are cell types or anatomic sites in which replication-competent virus persists without significant decay over time. This article reviews several proposed reservoirs for HIV-1 and their clinical significance. Recent advances allow formal genetic delineation of viral reservoirs and compartments. The best-understood reservoir is a small pool of resting memory CD4 T cells carrying a quiescent form of the HIV-1 genome integrated within active cellular genes. Turnover of these cells is extremely slow, consistent with their function in immunologic memory. Latently infected memory CD4 cells that become reactivated release replication-competent HIV-1 which can be detected in the plasma and which can restore high levels of viremia if treatment is stopped. This reservoir can store drug-resistant virus if it arises, thereby permanently limiting treatment options. Evidence for other cellular reservoirs, including monocytes and macrophages, and for anatomical reservoirs including the genital tract and the central nervous system, is also discussed. Recent advances in characterizing cellular and anatomic reservoirs and compartments influence approaches to antiretroviral treatment, the management of antiretroviral resistance, and potential eradication strategies. The study of long-lived viral reservoirs is critical to the understanding of chronic HIV-1 infection and to the ongoing search for a cure.


Sending signals dynamically.
Proteins mediate transmission of signals along intercellular and intracellular pathways and between the exterior and the interior of a cell. The dynamic properties of signaling proteins are crucial to their functions. We discuss emerging paradigms for the role of protein dynamics in signaling. A central tenet is that proteins fluctuate among many states on evolutionarily selected energy landscapes. Upstream signals remodel this landscape, causing signaling proteins to transmit information to downstream partners. New methods provide insight into the dynamic properties of signaling proteins at the atomic scale. The next stages in the signaling hierarchy-how multiple signals are integrated and how cellular signaling pathways are organized in space and time-present exciting challenges for the future, requiring bold multidisciplinary approaches.


Efficiency of ultrasonography in assessing cervical lymph node metastasis in oral carcinoma.
The study was conducted to assess the value of ultrasonography (USG) for lymph node metastasis in patients with carcinoma of oral cavity. A total of 20 cases were selected with primary tumor of oral cavity. Ninety-two lymph nodes were detected by ultrasound of 5 mm or more in diameter. The patients were examined preoperatively for palpable lymph nodes clinically and ultrasonographic examination of bilateral neck. Ultrasonographic parameters, such as size, shape, boundaries (well-delineated/ poorly delineated) and internal echoes for the lymph nodes were recorded. The histologic positive rate was 25%, 80% and 93% for nodes between 5 and 10 mm, 10 and 15 mm and for nodes 15 mm or more in size, respectively. Ultrasonographic findings showed a high significance as the size of nodes increases. The positive rate of 86% for the round nodes of 9 mm or more in size showed a high significance. The positive rate was 93% for well-delineated nodes and 68% for poorly delineated nodes. The most frequent echo pattern was homogenous followed by hypoechoic with positive rate for metastasis ranging from 83% to 88%. The diagnostic validity of USG as compared with histopathology showed sensitivity of 86% and specificity of 73% with overall efficiency of about 82% in detecting lymph node metastasis. USG is useful for preoperative evaluation of the neck, as the most reliable, inexpensive and easily available method. It is essential for diagnosis, staging and therapy choices.


SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis.
Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action. The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo. SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma.


Home visits by neighborhood Mentor Mothers provide timely recovery from childhood malnutrition in South Africa: results from a randomized controlled trial.
Child and infant malnourishment is a significant and growing problem in the developing world. Malnourished children are at high risk for negative health outcomes over their lifespans. Philani, a paraprofessional home visiting program, was developed to improve childhood nourishment. The objective of this study is to evaluate whether the Philani program can rehabilitate malnourished children in a timely manner. Mentor Mothers were trained to conduct home visits. Mentor Mothers went from house to house in assigned neighborhoods, weighed children age 5 and younger, and recruited mother-child dyads where there was an underweight child. Participating dyads were assigned in a 2:1 random sequence to the Philani intervention condition (n = 536) or a control condition (n = 252). Mentor Mothers visited dyads in the intervention condition for one year, supporting mothers' problem-solving around nutrition. All children were weighed by Mentor Mothers at baseline and three, six, nine and twelve month follow-ups. By three months, children in the intervention condition were five times more likely to rehabilitate (reach a healthy weight for their ages) than children in the control condition. Throughout the course of the study, 43% (n = 233 of 536) of children in the intervention condition were rehabilitated while 31% (n = 78 of 252) of children in the control condition were rehabilitated. Paraprofessional Mentor Mothers are an effective strategy for delivering home visiting programs by providing the knowledge and support necessary to change the behavior of families at risk.


Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial.
In the AVERROES study, apixaban, a novel factor Xa inhibitor, reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy. We aimed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack (TIA) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events. In AVERROES, 5599 patients (mean age 70 years) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81-324 mg per day). The mean follow-up was 1·1 years. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. Patients and investigators were masked to study treatment. In this prespecified subgroup analysis, we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA. AVERROES is registered at ClinicalTrials.gov, number NCT00496769. In patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (n=390, cumulative hazard 2·39% per year) compared with 33 in the aspirin group (n=374, 9·16% per year; hazard ratio [HR] 0·29, 95% CI 0·15-0·60). In those without previous stroke or TIA, 41 events occurred in the apixaban group (n=2417, 1·68% per year) compared with 80 in the aspirin group (n=2415, 3·06% per year; HR 0·51, 95% CI 0·35-0·74). The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17. Major bleeding was more frequent in patients with history of stroke or TIA than in patients without (HR 2·88, 95% CI 1·77-4·55) but risk of this event did not differ between treatment groups. In patients with atrial fibrillation, apixaban is similarly effective whether or not patients have had a previous stroke or TIA. Given that those with previous stroke or TIA have a higher risk of stroke, the absolute benefits might be greater in these patients. Bristol-Myers Squibb and Pfizer.


The doormat effect: when forgiving erodes self-respect and self-concept clarity.
We build on principles from interdependence theory and evolutionary psychology to propose that forgiving bolsters one's self-respect and self-concept clarity if the perpetrator has acted in a manner that signals that the victim will be safe and valued in a continued relationship with the perpetrator but that forgiving diminishes one's self-respect and self-concept clarity if the perpetrator has not. Study 1 employed a longitudinal design to demonstrate that the association of marital forgiveness with trajectories of self-respect over the first 5 years of marriage depends on the spouse's dispositional tendency to indicate that the partner will be safe and valued (i.e., agreeableness). Studies 2 and 3 employed experimental procedures to demonstrate that the effects of forgiveness on self-respect and self-concept clarity depend on the perpetrator's event-specific indication that the victim will be safe and valued (i.e., amends). Study 4 employed a longitudinal design to demonstrate that the association of forgiveness with subsequent self-respect and self-concept clarity similarly depends on the extent to which the perpetrator has made amends. These studies reveal that, under some circumstances, forgiveness negatively impacts the self.


RNA-dependent DNA polymerase activity of RNA tumor viruses. II. Directing influence of RNA in the reaction.
The role of ribonucleic acid (RNA) in deoxyribonucleic acid (DNA) synthesis with the purified DNA polymerase from the avian myeloblastosis virus has been studied. The polymerase catalyzes the synthesis of DNA in the presence of four deoxynucleoside triphosphates, Mg(2+), and a variety of RNA templates including those isolated from avian myeloblastosis, Rous sarcoma, and Rauscher leukemia viruses; phages f2, MS2, and Qbeta; and synthetic homopolymers such as polyadenylate.polyuridylic acid. The enzyme does not initiate the synthesis of new chains but incorporates deoxynucleotides at 3' hydroxyl ends of primer strands. The product is an RNA.DNA hybrid in which the two polynucleotide components are covalently linked. Free DNA has not been detected among the products formed with the purified enzyme in vitro. The DNA synthesized with avian myeloblastosis virus RNA after alkaline hydrolysis has a sedimentation coefficient of 6 to 7S.


Cellular pattern of insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the developing and mature ovarian follicle.
We have employed in situ hybridization histochemistry to map the cellular pattern of insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in developing rat ovaries from the time of birth through adulthood, and in response to hypophysectomy and gonadotropin replacement. From the early postnatal period, both IGF-I and IGF-I receptor messenger RNAs (mRNAs) were highly abundant and evenly distributed in granulosa cells of small, growing follicles. In large follicles, however, IGF-I gene expression was heterogeneous. IGF-I mRNA was most abundant in granulosa cells lining the antrum and surrounding the oocyte, but was low or undetectable in mural granulosa cells of Graafian follicles, and was also undetectable in luteinized granulosa cells of corpora lutea. IGF-I receptor mRNA was evenly distributed in developing and mature follicles and was highly abundant in the luteinized granulosa cells of corpora lutea. IGF-I receptor but not IGF-I mRNA was detected in growing oocytes. Hypophysectomy resulted in a decrease and treatment with PMSG resulted in an increase in follicular IGF-I receptor mRNA levels, whereas there was no change in IGF-I mRNA levels in the same protocol. In summary, high levels of both IGF-I and IGF-I receptor gene expression occur in the granulosa cells of actively growing follicles, suggesting that granulosa cell IGF-I may have a role in follicular or oocyte growth. IGF-I gene expression is lost concomitant with follicular enlargement and granulosa cell differentiation, whereas IGF-I receptor gene expression continues at high levels in luteinized granulosa cells, suggesting that IGF effects on differentiated granulosa cell function are due to circulating, not local, hormone. Finally, granulosa cell IGF-I receptor gene expression appears to be regulated by the gonadotropin present in pregnant mare serum.


Phenotypic heterogeneity in multiple myeloma families.
To describe a series of families with familial multiple myeloma (MM). Observations were used to generate hypotheses about the role of genetic factors, the mode of inheritance of these factors, and the association of other cancers with familial MM. This observational study consisted of 39 families with multiple cases of MM or related disorders from four collaborating research centers. Each center followed its usual family study method. Probands were interviewed, and, when possible, cancers were verified by medical records and pathology review. A working pedigree was compiled on each family. Seventeen families had affected members in two or more generations, and eight families had two or more affected members in a single generation. Four families had two or more members with plasma cell dyscrasias, with or without a single case of MM. In the remaining 10 families, a single MM case occurred with a family history of other cancers. Other cancers observed in family members included hematologic malignancies and solid tumors. In families with MM in multiple generations, there was a decrease in the age at MM diagnosis in successive generations. The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. Population-based epidemiologic studies are crucial, but because of the rarity of familial MM, a concerted case-finding approach may also be fruitful. Therefore, we propose an international consortium to study familial MM, and we invite all interested colleagues to participate.


Evaluation of the onset of protection induced by a modified-live virus vaccine in calves challenge inoculated with type 1b bovine viral diarrhea virus.
To evaluate onset of protection induced by modified-live virus (MLV) bovine viral diarrhea virus (BVDV) vaccine administered 7, 5, or 3 days before inoculation with type 1b BVDV (strain NY-1). Animals-40 calves. Calves were assigned to 4 groups: an unvaccinated control group or groups vaccinated with MLV vaccine containing BVDV types 1a and 2 at 7, 5, or 3 days, before inoculation with NY-1 BVDV. Blood samples were collected for leukocyte counts, serum virus neutralization, and virus isolation (VI); nasal swab specimens (NSSs) were obtained for VI, and rectal temperatures were monitored for 14 days after inoculation. No significant differences in leukocyte counts or rectal temperatures were detected after BVDV inoculation in vaccinated calves. Vaccinated calves had reduced viremia and viral shedding after inoculation, compared with results for unvaccinated calves. On day 5 after inoculation, a higher proportion of calves vaccinated 3 days before inoculation had positive VI from NSSs, compared with NSS VI results for calves vaccinated 5 and 7 days before inoculation. Unvaccinated calves had leukopenia on days 3, 5, and 6 and had higher rectal temperatures on days 7 and 8 after inoculation, compared with temperatures before inoculation. All unvaccinated calves had ≥ 1 positive VI result from NSSs 3 to 11 days after inoculation, and 4 became viremic. MLV BVDV vaccine prevented fever, viremia, and leukopenia in calves challenge inoculated with NY-1 BVDV. A high proportion of calves vaccinated 3 days before inoculation shed BVDV after inoculation.


Setting the top 10 priorities for obesity and weight-related research (POWeR): a stakeholder priority setting process.
To identify and prioritise the most impactful, unanswered questions for obesity and weight-related research. Prioritisation exercise of research questions using online surveys and an independently facilitated workshop. Online/virtual. We involved members of the public including people living with obesity, researchers, healthcare professionals and policy-makers in all stages of this study. Top 10 research questions to be prioritised in future obesity and weight-related research. Survey 1 produced 941 questions, from 278 respondents. Of these, 49 questions held satisfactory evidence in the scientific literature and 149 were out of scope. The remaining 743 questions were, where necessary, amalgamated and rephrased, into a list of 149 unique and unanswered questions. In the second survey, 405 respondents ranked the questions in order of importance. During the workshop, a subset of 38 survey respondents and stakeholders, agreed a final list of 10 priority research questions through small and large group consultation and consensus. The top 10 priority research questions covered: the role of the obesogenic environment; effective weight loss and maintenance strategies; prevention in children; effective prevention and treatment policies; the role of the food industry; access to and affordability of a healthy diet; sociocultural factors associated with weight; the biology of appetite and food intake; and long-term health modelling for obesity. This systematic and transparent process identified 149 unique and unanswered questions in the field of obesity and weight-related research culminating in a consensus among relevant stakeholders on 10 research priorities. Targeted research funding in these areas of top priority would lead to needed and impactful knowledge generation for the field of obesity and weight regulation and thereby improve population health.


Onset and transition of and recovery from adverse development: Study methodology.
Early intervention programs for first-episode psychosis have led to the awareness that the period before onset of a first episode is important in light of early intervention. This has induced a focus on the so-called 'at risk mental state' (ARMS). Individuals with ARMS are at increased risk for later psychotic disorder, but also for other psychiatric disorders as well as poor psychosocial functioning. Thus, adequate detection and treatment of ARMS is essential. Since 2018, screening for and treatment of ARMS is recommended standard care in the Netherlands. Implementation is still ongoing. We initiated a naturalistic long-term cohort study of ARMS individuals, the onset and transition of and recovery from adverse development (OnTheROAD) study, with the aim to monitor course and outcome of symptoms and psychosocial functioning over time, as well as patterns of comorbidity and associations with factors of risk and resilience. To this end, participants complete a broad battery of instruments at baseline and yearly follow-up assessments up to 3 years. Outcome is defined in terms of symptom severity level, functioning and quality of life. In particular, we aim to investigate the impact of negative symptoms as part of the ARMS concept. Results from this study can aid in refining the existing ARMS criteria, understanding the developmental course of ARMS and investigating the hypothesized pluripotentiality in outcome of ARMS. New knowledge may inform the further development of specialized early interventions. In this article, we describe the rationale, outline and set-up of OnTheROAD.


Who accepts responsibility for their transgressions?
After committing an offense, transgressors can optimize their chances of reconciling with the victim by accepting responsibility. However, transgressors may be motivated to avoid admitting fault because it can feel threatening to accept blame for harmful behavior. Who, then, is likely to accept responsibility for a transgression? We examined how implicit theories of personality--whether people see personality as malleable (incremental theory) or fixed (entity theory)--influence transgressors' likelihood of accepting responsibility. We argue that incremental theorists may feel less threatened by accepting responsibility because they are more likely to view the situation as an opportunity for them to grow as a person and develop their relationship with the victim. We found support for our predictions across four studies using a combination of real-world and hypothetical offenses, and correlational and experimental methods. These studies therefore identify an important individual difference factor that can lead to more effective responses from transgressors.


Health system and societal barriers for gestational diabetes mellitus (GDM) services - lessons from World Diabetes Foundation supported GDM projects.
Maternal mortality and morbidity remains high in many low- and middle-income countries (LMIC). Gestational Diabetes Mellitus (GDM) represents an underestimated and unrecognised impediment to optimal maternal health in LMIC; left untreated - it also has severe consequences for the offspring. A better understanding of the barriers hindering detection and treatment of GDM is needed. Based on experiences from World Diabetes Foundation (WDF) supported GDM projects this paper seeks to investigate societal and health system barriers to such efforts. Questionnaires were filled out by 10 WDF supported GDM project partners implementing projects in eight different LMIC. In addition, interviews were conducted with the project partners. The interviews were analysed using content analysis. Barriers to improving maternal health related to GDM nominated by project implementers included lack of trained health care providers - especially female doctors; high staff turnover; lack of standard protocols, consumables and equipment; financing of health services and treatment; lack of or poor referral systems, feedback mechanisms and follow-up systems; distance to health facility; perceptions of female body size and weight gain/loss in relation to pregnancy; practices related to pregnant women's diet; societal negligence of women's health; lack of decision-making power among women regarding their own health; stigmatisation; role of women in society and expectations that the pregnant woman move to her maternal home for delivery. A number of barriers within the health system and society exist. Programmes need to consider and address these barriers in order to improve GDM care and thereby maternal health in LMIC.


Favorable Outcome in Coccidioides Endophthalmitis-A Combined Medical and Surgical Treatment Approach.
To describe a case of Coccidioides endophthalmitis that resulted in a favorable visual outcome after a combined medical and surgical approach. A 33-year-old previously healthy woman was referred for evaluation of dyspnea and left-sided vision loss, which began 3 months before, after a trip to Nevada. She was found to have a pulmonary cavitary lesion and fluffy white material in the anterior chamber. An aqueous and vitreous paracentesis grew Coccidioides species. She was managed medically with a total of 7 weekly intravitreal injections of amphotericin B and intravenous liposomal amphotericin B followed by transition to oral posaconazole. Seven months after presentation, to ensure ocular sterilization and to clear the visual axis, she underwent temporary keratoprosthesis implantation, anterior segment reconstruction, removal of a cyclitic membrane and the crystalline lens, pars plana vitrectomy, placement of a pars plana Ahmed drainage device, and penetrating keratoplasty. After surgical intervention and with maintenance posaconazole therapy, the patient had resolution of her dyspnea and improved uncorrected (aphakic) vision with a clear corneal graft, quiet anterior chamber, and normal optic nerve and retina. A combined medical and surgical approach resulted in a favorable visual outcome and avoided the need for enucleation.


Soluble ligands of the alpha v beta 3 integrin mediate enhanced tyrosine phosphorylation of multiple proteins in adherent bovine pulmonary artery endothelial cells.
Binding of substrate-bound extracellular matrix proteins to cell surface integrins results in a variety of cellular responses including adhesion, cytoskeletal reorganization, and gene expression. We have previously shown that addition of soluble SC5b-9, the complement-vitronectin complex, resulted in an RGD-dependent increase in lung venular hydraulic conductivity (Ishikawa, S., Tsukada, H., and Bhattacharya, J. (1993) J. Clin. Invest. 91, 103-109). To identify specific integrin(s) and signal transduction pathways that are responsive to soluble vitronectin-containing ligands, we exposed confluent bovine pulmonary artery cells to purified soluble human mono- or multimeric vitronectin, or SC5b-9, and determined the extent of endothelial cell protein tyrosine phosphorylation. Monomeric vitronectin (Vn) did not induce enhanced protein tyrosine phosphorylation. However, multimeric Vn and SC5b-9 elicited time- and concentration-dependent increases in tyrosine phosphorylation of numerous proteins. Antiserum against vitronectin, RGD peptides, and monoclonal and polyclonal antibodies against the alpha v beta 3 integrin blocked the vitronectin- or SC5b-9-induced enhanced accumulation of tyrosine phosphoproteins, while antibodies against beta 1 integrins and the alpha v beta 5 integrin did not. Clustering of the alpha v beta 3 integrin using monoclonal antibody LM609 caused a pattern of enhanced tyrosine phosphorylation similar to that caused by multimeric Vn and SC5b-9, suggesting that aggregation of alpha v beta 3 was critical for signaling. Among the proteins that underwent enhanced tyrosine phosphorylation in response to vitronectin were the cytoskeletal proteins paxillin, cortactin, and ezrin, as well as the SH2 domain-containing protein Shc, and p125FAK. We conclude that ligation of the alpha v beta 3 integrin by soluble ligands promotes enhanced phosphorylation of several proteins implicated in tyrosine kinase signaling and suggest that this pathway may be important in inflammatory states which are accompanied by accumulation of SC5b-9.


Atypical presentation of entomophthoromycosis caused by Conidiobolus coronatus.
A male patient from Guinea-Bissau was admitted to Egas Moniz Hospital, Lisbon, complaining of fever and exhibiting a productive cough with mucopurulent discharge and weight loss. He had been using empirical medication with dexamethasone to treat his generalized facial swelling. At admission, he was cachectic and presented with soft facial edema, oropharyngeal thrush, and two fistulas of the palate. Acid-fast bacilli were detected in the sputum and were later identified as Mycobacterium tuberculosis. Cultures of the palatine exudate and biopsy resulted in the growth of Candida albicans. The patient was administered antituberculosis drugs and fluconazole, but his clinical situation deteriorated progressively. Extensive investigation of his clinical condition did not result in a conclusive diagnosis until he began to experience respiratory distress and subcutaneous nodules appeared on his face. Biopsies of the hypopharynx and nodules revealed the presence of Conidiobolus coronatus. After initiating combined antifungal and antibiotic therapy, the patient's clinical condition improved significantly. We report an unusual presentation of entomophthoromycosis and describe the clinical difficulties that delayed this diagnosis.


Skin vascular reactivity in healthy subjects: influence of hormonal status.
To investigate the influence of the hormonal status on skin vascular reactivity, 18 males, 18 women using oral contraceptives (oc), 17 premenopausal, and 18 postmenopausal women were studied. Finger skin temperature (FST, in degrees C) and laser Doppler flux (LDF, in perfusion units) were measured during heating (45 degrees C water bath) and cooling (15 degrees C) followed by a subsequent recovery period. Maximal heat-induced vasodilation was significantly higher in women using oc and in premenopausal women when compared with males. During cooling, FST and LDF were significantly higher in males compared with women using oc and premenopausal women, respectively. FST was also higher in postmenopausal women than in women using oc. During recovery, FST and LDF were significantly higher in males than in women using oc, and LDF was also higher in males than in premenopausal women. These findings are consistent with a less pronounced and less prolonged cold-induced vasoconstriction in males. Other hemodynamic (blood pressure or heart rate) or biological factors (age, amount of subcutaneous fat, hand volume, or body mass index) that possibly influence peripheral blood flow were found not to influence the results. The observed differences in vascular reactivity toward temperature changes between subjects with a different hormonal status suggest that sex hormones influence finger skin perfusion.


Validation of noninvasive quantification of bone marrow fat volume with microCT in aging rats.
Marrow fat infiltration is one of the hallmarks of age-related bone loss. This fat infiltration has been quantified by invasive and noninvasive methods. However, the validity of the noninvasive methods has not been correlated with a gold standard. In this study we aim to validate the usefulness of marrow fat quantification by correlating microCT (μCT) images with histology analysis. Fat volume (FV) and bone volume (BV) of distal femora of young (4 months) and old (27 months) Louvain/c (LOU) rats (n=22) were quantified by histology and compared with μCT images analyzed by an image analysis software (SliceOMatic). We found that for SliceOMatic/μCT the intra-rater reliability for duplicate measurements was 0.94 (p<0.001) and the inter-rater reliability for FV/BV ratio in young and old rats was 98% and 99% respectively. Both methods showed a significant increase (~2 fold) in the FV/BV ratio in the old rats as compared with their young counterparts (p<0.001). A significantly higher correlation (r2=0.85) in the old rats was found between our noninvasive method and histology. Furthermore, our noninvasive method showed good agreement with histology. In conclusion, noninvasive quantification of FV/BV ratio using an image analysis software is as reliable as histology for identifying age related marrow fat changes with high inter and intra-rater reliability. These findings provide a new noninvasive method for quantifying marrow fat, which is useful and can be tested not only in animals but also in human studies.


Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA).
To describe the relationship of retinal arteriolar and venular caliber with cardiovascular risk factors, including inflammatory biomarkers, in a multiethnic population of whites, blacks, Hispanics, and Chinese. A cross-sectional study comprising 5979 persons aged 45 to 84 years residing in six U.S. communities. Retinal vascular caliber was measured and summarized from digital retinal photographs. Standard cardiovascular risk factors, including biomarkers of inflammation (e.g., high-sensitivity C-reactive protein [hsCRP], interleukin [IL]-6, and plasma fibrinogen) and endothelial dysfunction (e.g., soluble intercellular adhesion molecule [sICAM]-1 [, plasminogen activator inhibitor [PAI]-1) were assessed. Mean retinal arteriolar caliber was 144.1+/-14.4 (SD) microm, and venular caliber 214.0+/-22.2 microm. In models controlling for age, gender, race-ethnicity, and center, smaller retinal arteriolar caliber was related to higher systolic and diastolic blood pressure, hypertension status, current alcohol consumption, greater body mass index, and higher levels of total homocysteine; larger retinal arteriolar caliber was related to diabetes, current cigarette smoking, and higher levels of plasma fibrinogen; and larger retinal venular caliber was related to diabetes, current cigarette smoking, greater body mass index and waist-hip ratio, higher levels of serum glucose, plasma triglyceride, plasma LDL-cholesterol, hsCRP, plasma fibrinogen, IL6, sICAM-1, and PAI-1 and lower levels of HDL-cholesterol. In multivariate analyses, blacks and Hispanics had larger retinal arteriolar and venular calibers than did whites and Chinese. Retinal arteriolar and venular caliber is associated with a range of cardiovascular risk factors, including hypertension, diabetes, measures of obesity, and dyslipidemia. Venular caliber is also associated with systemic inflammation.


Functional near infrared spectroscopy using spatially resolved data to account for tissue scattering: A numerical study and arm-cuff experiment.
Functional Near-Infrared Spectroscopy (fNIRS) aims to recover changes in tissue optical parameters relating to tissue hemodynamics, to infer functional information in biological tissue. A widely-used application of fNIRS relies on continuous wave (CW) methodology that utilizes multiple distance measurements on human head for study of brain health. The typical method used is spatially resolved spectroscopy (SRS), which is shown to recover tissue oxygenation index (TOI) based on gradient of light intensity measured between two detectors. However, this methodology does not account for tissue scattering which is often assumed. A new parameter recovery algorithm is developed, which directly recovers both the scattering parameter and scaled chromophore concentrations and hence TOI from the measured gradient of light-attenuation at multiple wavelengths. It is shown through simulations that in comparison to conventional SRS which estimates cerebral TOI values with an error of ±12.3%, the proposed method provides more accurate estimate of TOI exhibiting an error of ±5.7% without any prior assumptions of tissue scatter, and can be easily implemented within CW fNIRS systems. Using an arm-cuff experiment, the obtained TOI using the proposed method is shown to provide a higher and more realistic value as compared to utilizing any prior assumptions of tissue scatter.


Treating diabetic peripheral neuropathic pain.
Diabetic peripheral neuropathic pain affects the functionality, mood, and sleep patterns of approximately 10 to 20 percent of patients with diabetes mellitus. Treatment goals include restoring function and improving pain control. Patients can realistically expect a 30 to 50 percent reduction in discomfort with improved functionality. The main classes of agents used to treat diabetic peripheral neuropathic pain include tricyclic antidepressants, anticonvulsants, serotonin-norepinephrine reuptake inhibitors, opiates and opiate-like substances, and topical medications. Physicians should ask patients whether they have tried complementary and alternative medicine therapies for their pain. Only two medications are approved specifically for the treatment of diabetic peripheral neuropathic pain: pregabalin and duloxetine. However, evidence supports the use of other therapies, and unless there are contraindications, tricyclic antidepressants are the first-line treatment. Because patients often have multiple comorbidities, physicians must consider potential adverse effects and possible drug interactions before prescribing a medication.


Noise minimization and equalization for Stokes polarimeters in the presence of signal-dependent Poisson shot noise.
We address the optimization of Stokes polarimeters in the presence of signal-dependent shot noise, which is the dominant type of noise in certain imaging systems. We show that in some precise sense, the polarimeters optimal for additive noise are also optimal for such noise and propose polarimeter architectures in which noise variances are equalized and independent of the input polarization state.


Contrast-enhanced ultrasound in the diagnosis of gallbladder diseases: a multi-center experience.
To assess the usefulness of contrast-enhanced ultrasound (CEUS) in differentiating malignant from benign gallbladder (GB) diseases. This study had institutional review board approval. 192 patients with GB diseases from 9 university hospitals were studied. After intravenous bonus injection of a phospholipid-stabilized shell microbubble contrast agent, lesions were scanned with low acoustic power CEUS. A multiple logistic regression analysis was performed to identify diagnostic clues from 17 independent variables that enabled differentiation between malignant and benign GB diseases. Receiver operating characteristic (ROC) curve analysis was performed. Among the 17 independent variables, multiple logistic regression analysis showed that the following 4 independent variables were associated with the benign nature of the GB diseases, including the patient age, intralesional blood vessel depicted on CEUS, contrast washout time, and wall intactness depicted on CEUS (all P<0.05). ROC analysis showed that the patient age, intralesional vessels on CEUS, and the intactness of the GB wall depicted on CEUS yielded an area under the ROC curve (Az) greater than 0.8 in each and Az for the combination of the 4 significant independent variables was 0.915 [95% confidence interval (CI): 0.857-0.974]. The corresponding Az, sensitivity, and specificity for the age were 0.805 (95% CI: 0.746-0.863), 92.2%%, and 59.6%; for the intralesional vessels on CEUS were 0.813 (95% CI: 0.751-0.875), 59.8%, and 98.0%; and for the GB wall intactness were 0.857 (95% CI: 0.786-0.928), 78.4%, and 92.9%. The cut-off values for benign GB diseases were patient age <53.5 yrs, dotted intralesional vessels on CEUS and intact GB wall on CEUS. CEUS is valuable in differentiating malignant from benign GB diseases. Branched or linear intralesional vessels and destruction of GB wall on CEUS are the CEUS features highly suggestive of GB malignancy and the patient age >53.5 yrs is also a clue for GB malignancy.


Stroke Associated with COVID-19 Vaccines.
Development of safe and effective vaccines against coronavirus disease 2019 (COVID-19) remains the cornerstone of controlling this pandemic. However, there are increasing reports of various types of stroke including ischemic stroke, and hemorrhagic stroke, as well as cerebral venous sinus thrombosis (CVST) after COVID-19 vaccination. This paper aims to review reports of stroke associated with COVID-19 vaccines and provide a coherent clinical picture of this condition. A literature review was performed with a focus on data from recent studies. Most of such patients are women under 60 years of age and who had received ChAdOx1 nCoV-19 vaccine. Most studies reported CVST with or without secondary ischemic or hemorrhagic stroke, and some with Vaccine-induced Thrombotic Thrombocytopenia (VITT). The most common clinical symptom of CVST seen after COVID-19 vaccination was headache. The clinical course of CVST after COVID-19 vaccination may be more severe than CVST not associated with COVID vaccination. Management of CVST following COVID-19 vaccination is challenging and may differ from the standard treatment of CVST. Low molecular weight heparin is commonly used in the treatment of CVST; however, it may worsen outcomes in CVST associated with VITT. Furthermore, administration of intravenous immunoglobulin and high-dose glucocorticoids have been recommended with various success rates. These contradictory observations are a source of confusion in clinical decision-making and warrant further study and development of clinical guidelines. Clinicians should be aware of clinical presentation, diagnosis, and management of stroke associated with COVID-19 vaccination.


SU-E-J-112: A Splatting Method to Generate DRRs for Deformed CT Volume.
To develop an efficient algorithm for generating high-quality digitally reconstructed radiographs (DRRs) for regularly and irregularly sampled volumes based on a splatting method with dynamic elliptical Gaussian kernels, and to evaluate this method using ray tracing. The traditional ray tracing method, which takes every intersected voxel into account, produces high quality DRRs but is very time consuming. Additionally, it is not suitable for handling irregularly-sampled volumes since it always requires image re-sampling, which leads to inaccuracy. We present a splatting approach to compute the 'footprint function', facilitating efficient perspective projection of elliptical Gaussian kernels at very low cost. This reported framework allows dealing with both regularly and irregularly sampled volumes effectively and efficiently. An XCAT digital phantom was used to generate 3D chest volumes at different respiratory phases, and CT projections are generated using ray tracing and the splatting method, respectively. Normalized cross correlation (NCC) is applied to evaluate the DRR similarity of two methods. Respiratory Phases one and four are used as volume datasets from the 4D XCAT digital phantom as they represent the lung at end inhale and end exhale, respectively. The dataset of Phase one is the basic regularly-sampled volume while the dataset of Phase four is deformed from that of Phase one, and resampled to a regularly sampled dataset for the ray tracing method. NCC between splatting and ray tracing DRRs are 0.9980 and 0.9977 for Phase one and Phase four, respectively. The calculation speed of the splatting method is 3 times faster than that of ray tracing. Our splatting approach can generate high-quality DRRs efficiently, and is a good alternative for current DRR generation techniques for deformed volume datasets. This research is supported by CPRIT Individual Investigator Award RP110329.


Hot-Melt 3D Extrusion for the Fabrication of Customizable Modified-Release Solid Dosage Forms.
In this work, modified-release solid dosage forms were fabricated by adjusting geometrical properties of solid dosage forms through hot-melt 3D extrusion (3D HME). Using a 3D printer with air pressure driving HME system, solid dosage forms containing ibuprofen (IBF), polyvinyl pyrrolidone (PVP), and polyethylene glycol (PEG) were printed by simultaneous HME and 3D deposition. Printed solid dosage forms were evaluated for their physicochemical properties, dissolution rates, and floatable behavior. Results revealed that IBF content in the solid dosage form could be individualized by adjusting the volume of solid dosage form. IBF was dispersed as amorphous state with enhanced solubility and dissolution rate in a polymer solid dosage form matrix. Due to absence of a disintegrant, sustained release of IBF from printed solid dosage forms was observed in phosphate buffer at pH 6.8. The dissolution rate of IBF was dependent on geometric properties of the solid dosage form. The dissolution rate of IBF could be modified by merging two different geometries into one solid dosage form. In this study, the 3D HME process showed high reproducibility and accuracy for preparing dosage forms. API dosage and release profile were found to be customizable by modifying or combining 3D modeling.


Epidemiology of tuberculosis in big cities of the European Union and European Economic Area countries.
This cross-sectional survey aimed to examine the epidemiology of tuberculosis (TB) in European Union (EU) and European Economic Area (EEA) cities with populations greater than 500,000. National TB programme managers were asked to provide data on big city population size, total number of notified TB cases in big cities and national notification rate for 2009. A rate ratio was calculated using the big city TB notification rate as a numerator and country TB notification rate, excluding big city TB cases and population, as a denominator. Twenty of the 30 EU/EEA countries had at least one big city. Pooled rate ratios were 2.5, 1.0, and 0.7 in low-, intermediate- and high-incidence countries respectively. In 15 big cities, all in low-incidence countries, rate ratios were twice the national notification rate. These data illustrate the TB epidemiology transition, a situation whereby TB disease concentrates in big cities as national incidence falls, most likely as a result of the higher concentration of risk groups found there. This situation requires targeted interventions and we recommend that big city TB data, including information about patients' risk factors, are collected and analysed systematically, and that successful interventions are shared.


Coevolution of generalist feeding ecologies and gyrencephalic mushroom bodies in insects.
Here we demonstrate the independent acquisition of strikingly similar brain architectures across divergent insect taxa and even across phyla under similar adaptive pressures. Convoluted cortical gyri-like structures characterize the mushroom body calyces in the brains of certain species of insects; we have investigated in detail the cellular and ecological correlates of this morphology in the Scarabaeidae (scarab beetles). "Gyrencephalic" mushroom bodies with increased surface area and volume of calycal synaptic neuropils and increased intrinsic neuron number characterize only those species belonging to generalist plant-feeding subfamilies, whereas significantly smaller "lissencephalic" mushroom bodies are found in more specialist dung-feeding scarab beetles. Such changes are not unique to scarabs or herbivores, because the mushroom bodies of predatory beetles display similar morphological disparities in generalists vs. specialists. We also show that gyrencephalic mushroom bodies in generalist scarabs are not associated with an increase in the size of their primary input neuropil, the antennal lobe, or in the number of antennal lobe glomeruli but rather with an apparent increase in the density of calycal microglomeruli and the acquisition of calycal subpartitions. These differences suggest changes in calyx circuitry facilitating the increased demands on processing capability and flexibility imposed by the evolution of a generalist feeding ecology.


Insulin-like peptides in the mosquito Anopheles stephensi: identification and expression in response to diet and infection with Plasmodium falciparum.
Insulin-like peptides (ILPs) regulate a multitude of biological processes, including metabolism and immunity to infection, and share similar structural motifs across widely divergent taxa. Insulin/insulin-like growth factor signaling (IIS) pathway elements are similarly conserved. We have shown that IIS regulates reproduction, innate immunity, and lifespan in female Anopheles stephensi, a major mosquito vector of human malaria. To further explore IIS regulation of these processes, we identified genes encoding five ILPs in this species and characterized their expression in tissues. Antisera to ILP homologs in Anopheles gambiae were used to identify cellular sources in An. stephensi females by immunocytochemistry. We analyzed tissue-specific ILP transcript expression in young and older females, in response to different feeding regimens, and in response to infection with Plasmodiumfalciparum with quantitative reverse transcriptase-PCR assays. While some ILP transcript changes were evident in older females and in response to blood feeding, significant changes were particularly notable in response to hormonal concentrations of ingested human insulin and to P. falciparum infection. These changes suggest that ILP secretion and action may be similarly responsive in Plasmodium-infected females and potentially alter metabolism and innate immunity.


VOPO4 nanosheets as anode materials for lithium-ion batteries.
VOPO4 nanosheets are successfully synthesized using a hydrothermal method followed by calcination. The XRD results reveal that obtained products are crystallized in the orthorhombic VOPO4 phase. SEM and TEM images demonstrate that VOPO4 products possess unique nanosheet morphology. Electrochemical tests show that the VOPO4 nanosheets exhibit an excellent electrochemical performance as anode materials. They can deliver an initial discharge capacity of 1356 mA h g(-1) at 0.1 C, and possess a favorable capacity at rates of 0.2, 1, and 2 C. The synthesized VOPO4 can be used as a good anode material; furthermore, the nanosheet structure can effectively improve the electrochemical performance of this material.


Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques.
Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab-infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection.


Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats.
Aberrant energy metabolism is one characteristic of diabetes mellitus (DM). Two types of DM have been identified, type 1 and type 2. Most of type 2 DM patients eventually become insulin dependent because insulin secretion by the islets of Langerhans becomes exhausted. In the present study, we show that resveratrol (3,5,4'-trihydroxylstilbene) possesses hypoglycemic and hypolipidemic effects in streptozotocin-induced DM (STZ-DM) rats. In resveratrol-treated STZ-DM rats, the plasma glucose concentration on day 14 was reduced by 25.3 +/- 4.2%, and the triglyceride concentration was reduced by 50.2 +/- 3.2% compared with the vehicle-treated rats. In STZ-nicotinamide DM rats, the plasma glucose concentration on day 14 was reduced by 20.3 +/- 4.2%, and the triglyceride concentration was reduced by 33.3 +/- 2.2% compared with the vehicle-treated rats. Resveratrol administration ameliorates common DM symptoms, such as body weight loss, polyphagia, and polydipsia. In STZ-nicotinamide DM rats, resveratrol administration significantly decreased insulin secretion and delayed the onset of insulin resistance. Further studies showed that glucose uptake by hepatocytes, adipocytes, and skeletal muscle and hepatic glycogen synthesis were all stimulated by resveratrol treatment. Because the stimulation of glucose uptake was not attenuated in the presence of an optimal amount of insulin in insulin-responsive cells, the antihyperglycemic effect of resveratrol appeared to act through a mechanism(s) different from that of insulin.


Genome-wide analysis of copy number variation in type 1 diabetes.
Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl) cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.


Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement.
Autosomal-dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. In this study, we performed genetic analysis of a unique form of SCA (SCA36) that is accompanied by motor neuron involvement. Genome-wide linkage analysis and subsequent fine mapping for three unrelated Japanese families in a cohort of SCA cases, in whom molecular diagnosis had never been performed, mapped the disease locus to the region of a 1.8 Mb stretch (LOD score of 4.60) on 20p13 (D20S906-D20S193) harboring 37 genes with definitive open reading frames. We sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56 and an unregistered missense variant (Phe265Leu) in C20orf194, but we found no mutations in PDYN and TGM6. The expansion showed complete segregation with the SCA phenotype in family studies, whereas Phe265Leu in C20orf194 did not. Screening of the expansions in the SCA cohort cases revealed four additional occurrences, but none were revealed in the cohort of 27 Alzheimer disease cases, 154 amyotrophic lateral sclerosis cases, or 300 controls. In total, nine unrelated cases were found in 251 cohort SCA patients (3.6%). A founder haplotype was confirmed in these cases. RNA foci formation was detected in lymphoblastoid cells from affected subjects by fluorescence in situ hybridization. Double staining and gel-shift assay showed that (GGCCUG)n binds the RNA-binding protein SRSF2 but that (CUG)(6) does not. In addition, transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients. Our finding suggests that SCA36 is caused by hexanucleotide repeat expansions through RNA gain of function.


Personality and outcome in individuals with treatment-resistant depression-Exploring differential treatment effects in the Tavistock Adult Depression Study (TADS).
Although research over the past decades has investigated the impact of the personality dimensions of dependency and self-criticism on treatment outcome, little is known of how these personality features influence responsiveness to treatment in patients with severe, chronic forms of depression. The present study uses data from the Tavistock Adult Depression Study, a randomized controlled trial investigating the effectiveness of long-term psychoanalytic psychotherapy (LTPP) compared with treatment as usual (TAU) for individuals diagnosed with treatment-resistant depression. Patients were rated with the Anaclitic-Introjective Depression Assessment Q-sort, which distinguishes between two more maladaptive (Submissive and Dismissive) and two less maladaptive (Needy and Self-Critical) subdimensions of dependent or anaclitic and self-critical or introjective depression. Multilevel modeling was used to compare individuals' growth curves of depression severity as measured by the Hamilton Rating Scale for Depression over the 18-month treatment period and 2-year follow-up. Rates of clinically significant change were also determined. As expected, depressed patients with more maladaptive dependent and self-critical features did not benefit from LTPP or TAU. Patients with less maladaptive self-critical features benefited from both LTPP and TAU, while those with less maladaptive dependent features showed considerable gains from LTPP but not from TAU, with medium to large effect sizes. Findings of this study are consistent with existing research suggesting the need to modify and tailor treatments in accordance with individuals' pretreatment personality features. Given the time and cost-intensive nature of longer-term treatment, this may be particularly important in patients with treatment-resistant depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Exploring the complexity of intellectual disability in fetal alcohol spectrum disorders.
Brain development in mammals is long lasting. It begins early during embryonic growth and is finalized in early adulthood. This progression represents a delicate choreography of molecular, cellular, and physiological processes initiated and directed by the fetal genotype in close interaction with environment. Not surprisingly, most aberrations in brain functioning including intellectual disability (ID) are attributed to either gene(s), or environment or the interaction of the two. The ensuing complexity has made the assessment of this choreography, ever challenging. A model to assess this complexity has used a mouse model (C57BL/6J or B6) that is subjected to prenatal alcohol exposure. The resulting pups show learning and memory deficits similar to patients with fetal alcohol spectrum disorder (FASD), which is associated with life-long changes in gene expression. Interestingly, this change in gene expression underlies epigenetic processes including DNA methylation and miRNAs. This paradigm is applicable to ethanol exposure at different developmental times (binge at trimesters 1, 2, and 3 as well as continuous preference drinking (70%) of 10% alcohol by B6 females during pregnancy). The exposure leads to life-long changes in neural epigenetic marks, gene expression, and a variety of defects in neurodevelopment and CNS function. We argue that this cascade may be reversed postnatally via drugs, chemicals, and environment including maternal care. Such conclusions are supported by two sets of results. First, antipsychotic drugs that are used to treat ID including psychosis function via changes in DNA methylation, a major epigenetic mark. Second, post-natal environment may improve (with enriched environments) or worsen (with negative and maternal separation stress) the cognitive ability of pups that were prenatally exposed to ethanol as well as their matched controls. In this review, we will discuss operational epigenetic mechanisms involved in the development of intellectual ability/disability in response to alcohol during prenatal or post-natal development. In doing so, we will explore the potential of epigenetic manipulation in the treatment of FASD and related disorders implicated in ID.


Tales from the crypts: regulatory peptides and cytokines in gastrointestinal homeostasis and disease.
The gastrointestinal (GI) tract is composed of a diverse set of organs that together receive extracorporeal nutrition and convert it to energy substrates and cellular building blocks. In the process, it must sort through all that we ingest and discriminate what is useable from what is not, and having done that, it discards what is "junk." To accomplish these many and varied tasks, the GI tract relies on endogenous enteric hormones produced by enteroendocrine cells and the enteric nervous system. In many instances, the mediators of these tasks are small peptides that home to the CNS and accessory gut organs to coordinate oral intake with digestive secretions. As the contents of ingested material can contain harmful agents, the gut is armed with an extensive immune system. A breach of the epithelial barrier of the GI tract can result in local and eventually systemic disease if the gut does not mount an aggressive immune response.


The potential role of amifostine in conjunction with cisplatin in the treatment of locally advanced carcinoma of the cervix.
The treatment of locally advanced carcinoma of the cervix with radiation therapy as a single modality is inadequate, specifically for stage III and IVA disease. While chemotherapy as single-modality therapy is ineffective in advanced cervical cancer, there is some evidence of efficacy when used in combination with radiation therapy. A recently conducted phase II trial from the Albert Einstein College of Medicine used standard whole pelvic radiation therapy with concurrent cisplatin 20 mg/m(2)/d X 5 days for four courses in women with stage IB to IVA cervical cancer. Toxicities, mainly hematologic and soft tissue, were acceptable in this trial. There was only a modest impact on disease-free survival among women with stage III disease. A subsequent phase I trial conducted by the New York Gynecologic Oncology Group tested the addition of amifostine to the combination of cisplatin plus radiation therapy using the Albert Einstein College of Medicine regimen. Amifostine at doses escalated from 340 to 910 mg/m(2) was administered immediately before cisplatin. The dose-limiting toxicity was hypotension. Amifostine should be tested in future clinical trials either as a cytoprotective agent in patients receiving cisplatin plus radiation therapy or, alternatively, to assess dose intensification of cisplatin in combination with radiation therapy.


Coding and Classifying Knowledge Exchange on Social Media: a Comparative Analysis of the #Twitterstorians and AskHistorians Communities.
As social media become a staple for knowledge discovery and sharing, questions arise about how self-organizing communities manage learning outside the domain of organized, authority-led institutions. Yet examination of such communities is challenged by the quantity of posts and variety of media now used for learning. This paper addresses the challenges of identifying (1) what information, communication, and discursive practices support successful online communities, (2) whether such practices are similar on Twitter and Reddit, and (3) whether machine learning classifiers can be successfully used to analyze larger datasets of learning exchanges. This paper builds on earlier work that used manual coding of learning and exchange in Reddit 'Ask' communities to derive a coding schema we refer to as 'learning in the wild'. This schema of eight categories: explanation with disagreement, agreement, or neutral presentation; socializing with negative, or positive intent; information seeking; providing resources; and comments about forum rules and norms. To compare across media, results from coding Reddit's AskHistorians are compared to results from coding a sample of #Twitterstorians tweets (n = 594). High agreement between coders affirmed the applicability of the coding schema to this different medium. LIWC lexicon-based text analysis was used to build machine learning classifiers and apply these to code a larger dataset of tweets (n = 69,101). This research shows that the 'learning in the wild' coding schema holds across at least two different platforms, and is partially scalable to study larger online learning communities.


Endocrine differences among colour morphs in a lizard with alternative behavioural strategies.
Alternative behavioural strategies of colour morphs are expected to associate with endocrine differences and to correspond to differences in physical performance (e.g. movement speed, bite force in lizards); yet the nature of correlated physiological and performance traits in colour polymorphic species varies widely. Colour morphs of male tawny dragon lizards Ctenophorus decresii have previously been found to differ in aggressive and anti-predator behaviours. We tested whether known behavioural differences correspond to differences in circulating baseline and post-capture stress levels of androgen and corticosterone, as well as bite force (an indicator of aggressive performance) and field body temperature. Immediately after capture, the aggressive orange morph had higher circulating androgen than the grey morph or the yellow morph. Furthermore, the orange morph maintained high androgen following acute stress (30min of capture); whereas androgen increased in the grey and yellow morphs. This may reflect the previously defined behavioural differences among morphs as the aggressive response of the yellow morph is conditional on the colour of the competitor and the grey morph shows consistently low aggression. In contrast, all morphs showed an increase in corticosterone concentration after capture stress and morphs did not differ in levels of corticosterone stress magnitude (CSM). Morphs did not differ in size- and temperature-corrected bite force but did in body temperature at capture. Differences in circulating androgen and body temperature are consistent with morph-specific behavioural strategies in C. decresii but our results indicate a complex relationship between hormones, behaviour, temperature and bite force within and between colour morphs.


Parental age effects on odor sensitivity in healthy subjects and schizophrenia patients.
A schizophrenia phenotype for paternal and maternal age effects on illness risk could benefit etiological research. As odor sensitivity is associated with variability in symptoms and cognition in schizophrenia, we examined if it was related to parental ages in patients and healthy controls. We tested Leukocyte Telomere Length (LTL) as an explanatory factor, as LTL is associated with paternal age and schizophrenia risk. Seventy-five DSM-IV patients and 46 controls were assessed for detection of PEA, WAIS-III for cognition, and LTL, assessed by qPCR. In healthy controls, but not schizophrenia patients, decreasing sensitivity was monotonically related to advancing parental ages, particularly in sons. The relationships between parental aging and odor sensitivity differed significantly for patients and controls (Fisher's R to Z: χ(2) = 6.95, P = 0.009). The groups also differed in the association of odor sensitivity with cognition; lesser sensitivity robustly predicted cognitive impairments in patients (<0.001), but these were unassociated in controls. LTL was unrelated to odor sensitivity and did not explain the association of lesser sensitivity with cognitive deficits.Parental aging predicted less sensitive detection in healthy subjects but not in schizophrenia patients. In patients, decreased odor sensitivity strongly predicted cognitive deficits, whereas more sensitive acuity was associated with older parents. These data support separate risk pathways for schizophrenia. A parental age-related pathway may produce psychosis without impairing cognition and odor sensitivity. Diminished odor sensitivity may furthermore be useful as a biomarker for research and treatment studies in schizophrenia. © 2015 Wiley Periodicals, Inc.


Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells.
We previously reported the phosphoinositide 3-kinase-dependent activation of the 5'-AMP-activated kinase (AMPK) by peroxynitrite (ONOO-) and hypoxia-reoxygenation in cultured endothelial cells. Here we show the molecular mechanism of activation of this pathway. Exposure of bovine aortic endothelial cells to ONOO- significantly increased the phosphorylation of both Thr172 of AMPK and Ser1179 of endothelial nitric-oxide synthase, a known downstream enzyme of AMPK. In addition, activation of AMPK by ONOO- was accompanied by increased phosphorylation of protein kinase Czeta (PKCzeta) (Thr410/403) and translocation of cytosolic PKCzeta into the membrane. Further, inhibition of PKCzeta abrogated ONOO- -induced AMPK-Thr172 phosphorylation as that of endothelial nitric-oxide synthase. Furthermore, overexpression of a constitutively active PKCzeta mutant enhanced the phosphorylation of AMPK-Thr172, suggesting that PKCzeta is upstream of AMPK activation. In contrast, ONOO- activated PKCzeta in LKB1-deficient HeLa-S3 but affected neither AMPK-Thr172 nor AMPK activity. These data suggest that LKB1 is required for PKCzeta-enhanced AMPK activation. In vitro, recombinant PKCzeta phosphorylated LKB1 at Ser428, resulting in phosphorylation of AMPK at Thr172. Further, direct mutation of Ser428 of LKB1 into alanine, like the kinase-inactive LKB1 mutant, abolished ONOO- -induced AMPK activation. In several cell types originating from human, rat, and mouse, inhibition of PKCzeta significantly attenuated the phosphorylation of both LKB1-Ser428 and AMPK-Thr172 that were enhanced by ONOO-. Taken together, we conclude that PKCzeta can regulate AMPK activity by increasing the Ser428 phosphorylation of LKB1, resulting in association of LKB1 with AMPK and consequent AMPK Thr172 phosphorylation by LKB1.


Characteristics of rational harmonic mode‑locked short‑cavity fiber ring laser using a bismuth‑oxide-based erbium‑doped fiber and a bismuth‑oxide‑based highly nonlinear fiber.
We demonstrate a rational harmonic mode-locked fiber ring laser employing a 151-cm-long bismuth-oxide-based erbium-doped fiber (Bi-EDF) and a 250-cm-long bismuth-oxide-based highly nonlinear fiber (Bi-HNLF). Continuous wavelength tuning covering both the conventional wavelength band and the longer wavelength band can be achieved by utilizing the wide gain bandwidth of the Bi-EDF. The pulse amplitude can also be equalized by adjusting the modulation parameters of the intracavity modulator. Ultra-high nonlinearity of the Bi-HNLF collaborates with spectral filtering by an optical bandpass filter to suppress the supermode noise quite effectively. The total cavity length is as short as 10 m. Stable and amplitude equalized pulses up to 40 GHz can be successfully generated over the entire wavelength tuning range.


Comparison and correlation of neisseria meningitidis serogroup B immunologic assay results and human antibody responses following three doses of the Norwegian meningococcal outer membrane vesicle vaccine MenBvac.
The prediction of efficacy of Neisseria meningitidis serogroup B (MenB) vaccines is currently hindered due to the lack of an appropriate correlate of protection. For outer membrane vesicle (OMV) vaccines, immunogenicity has primarily been determined by the serum bactericidal antibody (SBA) assay and OMV enzyme-linked immunosorbent assay (ELISA). However, the opsonophagocytic assay (OPA), surface labeling assay, whole blood assay (WBA), and salivary antibody ELISA have been developed although correlation with protection is presently undetermined. Therefore, the aim of the study was to investigate further the usefulness of, and relationships between, MenB immunologic assays. A phase II trial of the OMV vaccine, MenBvac, with proven efficacy was initiated to compare immunologic assays incorporating the vaccine and six heterologous strains. Correlations were achieved between the SBA assay, OMV ELISA, and OPA using human polymorphonuclear leukocytes and human complement but not between an OPA using HL60 phagocytic cells and baby rabbit complement. Correlations between the surface labeling assay, the SBA assay, and the OMV ELISA were promising, although target strain dependent. Correlations between the salivary antibody ELISA and other assays were poor. Correlations to the WBA were prevented since many samples had results greater than the range of the assay. The study confirmed the immunogenicity and benefit of a third dose of MenBvac against the homologous vaccine strain using a variety of immunologic assays. These results emphasize the need for standardized methodologies that would allow a more robust comparison of assays between laboratories and promote their further evaluation as correlates of protection against MenB disease.


Supportive Care in Older Adults with Cancer: Across the Continuum.
Supportive care is an essential component of anticancer treatment regardless of age or treatment intent. As the number of older adults with cancer increases, and supportive care strategies enable more patients to undergo treatment, greater numbers of older patients will become cancer survivors. These patients may have lingering adverse effects from treatment and will need continued supportive care interventions. Older adults with cancer benefit from geriatric assessment (GA)-guided supportive care interventions. This can occur at any stage across the cancer treatment continuum. As a GA commonly uncovers issues potentially unrelated to anticancer treatment, it could be argued that the assessment is essentially a supportive care strategy. Key aspects of a GA include identification of comorbidities, assessing for polypharmacy, screening for cognitive impairment and delirium, assessing functional status, and screening for psychosocial issues. Treatment-related issues of particular importance in older adults include recognition of increased bone marrow toxicity, management of nausea and vomiting, identification of anemia, and prevention of neurotoxicity. The role of physical therapy and cancer rehabilitation as a supportive care strategy in older adults is important regardless of treatment stage or intent.


Postoperative Nomogram for Relapse-Free Survival in Patients with High Grade Upper Tract Urothelial Carcinoma.
We developed a prognostic nomogram for patients with high grade urothelial carcinoma of the upper urinary tract after extirpative surgery. Clinical data were available for 2,926 patients diagnosed with high grade urothelial carcinoma of the upper urinary tract who underwent extirpative surgery. Cox proportional hazard regression models identified independent prognosticators of relapse in the development cohort (838). A backward step-down selection process was applied to achieve the most informative nomogram with the least number of variables. The L2-regularized logistic regression was applied to generate the novel nomogram. Harrell's concordance indices were calculated to estimate the discriminative accuracy of the model. Internal validation processes were performed using bootstrapping, random sampling, tenfold cross-validation, LOOCV, Brier score, information score and F1 score. External validation was performed on an external cohort (2,088). Decision tree analysis was used to develop a risk classification model. Kaplan-Meier curves were applied to estimate the relapse rate for each category. Overall 35.3% and 30.7% of patients experienced relapse in the development and external validation cohort. The final nomogram included age, pT stage, pN stage and architecture. It achieved a discriminative accuracy of 0.71 and 0.76, and the AUC was 0.78 and 0.77 in the development and external validation cohort, respectively. Rigorous testing showed constant results. The 5-year relapse-free survival rates were 88.6%, 68.1%, 40.2% and 12.5% for the patients with low risk, intermediate risk, high risk and very high risk disease, respectively. The current nomogram, consisting of only 4 variables, shows high prognostic accuracy and risk stratification for patients with high grade urothelial carcinoma of the upper urinary tract following extirpative surgery, thereby adding meaningful information for clinical decision making.