Identification and Detection of a Virus Associated with Strawberry Pallidosis Disease.
The etiology of pallidosis, a disease of strawberry identified more than 45 years ago, remains unknown. We report a putative agent of the disease, a virus belonging to the Crinivirus genus of the Closterovirideae family. A sensitive reverse transcription-polymerase chain reaction (RTPCR) test has been developed. Polyclonal antibodies that can be used to detect the virus in petiole tissue blots were developed using a recombinant virus coat protein. The nucleotide sequences of regions of the viral genome that encode the heat shock protein 70 homolog and the major coat protein were obtained. Alignments of the major coat protein show that the virus isolated from strawberry plants positive for pallidosis is most closely related to Cucumber yellows virus (syn. Beet pseudo-yellows virus) and Cucurbit yellow stunt disorder virus, members of the Crinivirus genus.


Memory of recent oxygen experience switches pheromone valence in Caenorhabditis elegans.
Animals adjust their behavioral priorities according to momentary needs and prior experience. We show that Caenorhabditis elegans changes how it processes sensory information according to the oxygen environment it experienced recently. C. elegans acclimated to 7% O2 are aroused by CO2 and repelled by pheromones that attract animals acclimated to 21% O2 This behavioral plasticity arises from prolonged activity differences in a circuit that continuously signals O2 levels. A sustained change in the activity of O2-sensing neurons reprograms the properties of their postsynaptic partners, the RMG hub interneurons. RMG is gap-junctionally coupled to the ASK and ADL pheromone sensors that respectively drive pheromone attraction and repulsion. Prior O2 experience has opposite effects on the pheromone responsiveness of these neurons. These circuit changes provide a physiological correlate of altered pheromone valence. Our results suggest C. elegans stores a memory of recent O2 experience in the RMG circuit and illustrate how a circuit is flexibly sculpted to guide behavioral decisions in a context-dependent manner.


Evaluating the Effect of a Mechanical Adjunct to Improve the Installation of Child Restraint Systems to Vehicles.
We explored if an alternative CRS design that utilized a mechanical adjunct to amplify the force applied to the adult seat belt (intervention CRS) results in more accurate and secure attachment between the CRS and the vehicle compared to similar CRS models that use LATCH or the existing adult seat belt. We conducted three separate studies to address this question and additionally explored: (1) the contribution of prior CRS installation experience (Study 1), (2) the value-added of CRS labeling (Study 2), and (3) paper-based vs. video instructions (Study 3). In Studies 1 and 2 we assessed a forward facing combination CRS design (intervention CRS) compared to a commercially available LATCH equipped model (control CRS) and in Study 3 we conducted a similar study using a convertible model of both the intervention and control CRS. Participants installed both CRS in a contemporary minivan and could choose which type of attachment to use for the control CRS (LATCH or seat belt); order of installation was counter-balanced. Evaluators systematically examined installations for accuracy and security. Study 1: A greater proportion of participants in both the experienced and inexperienced groups was able to securely install the intervention CRS compared to the control CRS: (45% vs. 16%, p =.0001 for experienced) and (37% vs. 6%, p =.003 for inexperienced). No differences between the CRS were observed for accuracy of installation in either user group. Study 2: A greater proportion of participants were able to securely install the enhanced intervention CRS compared to the control CRS: (62% vs. 9%, p =.001). The intervention CRS demonstrated reduced installation accuracy: (30% vs. 61%, p =.001). Study 3: A greater proportion of participants was able to securely install the intervention CRS compared to the control CRS: 79% vs. 66% p =.03, but this effect was smaller than in the previous studies. Participants were less likely to achieve an accurate installation with the intervention CRS compared to the control CRS: 54% vs. 79%, p =.004. Common accuracy errors in each study included twisting or misrouting the seatbelt when installing the intervention CRS. Our results suggest that novel CRS designs that utilize mechanical advantage to facilitate attachment of the CRS to the vehicle result in a tighter installation compared to LATCH equipped models, but an increase in accuracy errors occurred.


Micropapular Cutaneous Sarcoidosis Reviewed.
Micropapular cutaneous sarcoidosis (MPCS) is a rare variant of sarcoidosis. Herein we review the literature and include a recent case of MPCS discussing pathogenesis, diagnosis, treatment, and prognosis. A review was conducted using the terms "micropapular sarcoidosis" and "micropapular sarcoid." A recent case of a 50-year-old male patient with biopsy-identified MPCS was also included in the review. In total, 12 cases with an aggregate of 18 patients were included in the review. Presentation among all patients was consistent, with scattered, occasionally pruritic, faintly erythematous shiny white papules. Skin biopsy demonstrated noncaseating granulomas. Systemic prednisone, oxytetracycline, and hydroxychloroquine, as well as topical betamethasone, were used for therapy. In our review there does not seem to be a clear link as to the definite cause of the MPCS. While the relationships to tuberculosis and autoimmunity seem to be often emphasized, there was no clear association with either etiology.


Pressure-induced expression changes in segmental flow regions of the human trabecular meshwork.
Elevated intraocular pressure (IOP) is thought to create distortion or stretching of the juxtacanalicular and Schlemm's canal cells and their extracellular matrix (ECM) leading to a cascade of events that restore IOP to normal levels, a process termed IOP homeostasis. The ECM of the trabecular meshwork (TM) is intricately involved in the regulation of outflow resistance and IOP homeostasis, as matrix metalloproteinase (MMP)-initiated ECM turnover in the TM is necessary to maintain outflow facility. Previous studies have shown ECM gene expression and mRNA splice form differences in TM cells in response to sustained stretch, implicating their involvement in the dynamic process of IOP homeostasis. The observation that outflow is segmental around the circumference of the eye adds another layer of complexity to understanding the molecular events necessary to maintaining proper outflow facility. The aim of this work was to identify molecular expression differences between segmental flow regions of the TM from anterior segments perfused at either physiological or elevated pressure. Human anterior segments were perfused in an ex vivo model system, TM tissues were extracted and quantitative PCR arrays were performed. Comparisons were made between high flow and low flow regions of the TM from anterior segments perfused either at normal (8.8 mmHg) or at elevated (17.6 mmHg) perfusion pressure for 48 h. The results are presented here as independent sets: 1) fold change gene expression between segmental flow regions at a single perfusion pressure, and 2) fold change gene expression in response to elevated perfusion pressure in a single flow region. Multiple genes from the following functional families were found to be differentially expressed in segmental regions and in response to elevated pressure: collagens, ECM glycoproteins including matricellular proteins, ECM receptors such as integrins and adhesion molecules and ECM regulators, such as matrix metalloproteinases. In general, under normal perfusion pressure, more ECM genes were enriched in the high flow regions than in the low flow regions of the TM, whereas more ECM genes were found to be enriched in low flow regions of the TM in response to elevated perfusion pressure. Thus it appears that a limited subset of ECM genes is differentially regulated in both high and low flow regions and in response to elevated pressure. Some of these same ECM genes have previously been shown to be involved in the pressure response of stretched TM cells supporting their central role in IOP homeostasis. In general, different ECM gene family members are called upon to produce the response to elevated pressure in different segmental regions of the TM.


The value of an embedded qualitative study in a trial of a second antidepressant for people who had not responded to one antidepressant: understanding the perspectives of patients and general practitioners.
Depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. The number of prescriptions for antidepressants has risen dramatically in recent years yet up to 50% of patients who are treated for depression with antidepressants do not report feeling better as a result of treatment, and do not show the desired improvement on depression measures. We report a qualitative study embedded in a trial of second antidepressant for people who had not responded to one antidepressant, exploring the acceptability of a combination of antidepressants from the perspectives of both patients and practitioners, together with experiences of participating in a clinical trial. A qualitative study embedded in a randomized controlled trial investigating the effectiveness and cost-effectiveness of combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants versus SNRI or SSRI therapy alone (the MIR trial). 59 interviews were conducted with people who declined to participate in the trial, people who completed the study and people who withdrew from the intervention, and 16 general practitioners. Across the data-sets, four main themes were identified: the hard work of managing depression, uncertainties over the value of a second antidepressant, help-seeking at a point of crisis, and attainment and maintenance of a hard-won equilibrium. Exploring reasons for declining to participate in a trial of a second antidepressant in people who had not responded to one antidepressant suggests that people who are already taking one antidepressant may be reluctant to take a second, being wary of possible side-effects, but also being unconvinced of the logic behind such a combination. In addition, people describe being in a state of equilibrium and reluctant to make a change, reflecting that this equilibrium is 'hard-won' and they are unwilling to risk disturbing this. This makes some people reluctant to enrol in a clinical trial. Understanding a patient's view on medication is important for GPs when discussing antidepressants. MIR Trial Registration: ISRCTN 06653773 .


ROCK inhibition enhances the recovery and growth of cryopreserved human embryonic stem cells and human induced pluripotent stem cells.
Poor recovery of cryopreserved human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells is a significant impediment to progress with pluripotent stem cells. In this study, we demonstrate that Y-27632, a specific inhibitor of Rho kinase (ROCK) activity, significantly enhances recovery of hES cells from cryopreserved stocks when cultured with or without a growth inactivated feeder layer. Furthermore, treatment with the ROCK inhibitor for several days increased the number of colonies and colony size of hES cells compared to shorter exposures. Remarkably, hES cells that had formed relatively few colonies 5 days after thawing exhibited rapid growth upon addition of Y-27632. Additionally, we determined that Y-27632 significantly improves the recovery of cryopreserved human iPS cells and their growth upon subculture. Thus, Y-27632 provides a means to "kick-start" slow-growing human pluripotent stem cells, especially after being thawed from frozen stocks. Together, these results argue that Y-27632 is a useful tool in overcoming obstacles to studies involving the cultivation of both hES cells and human iPS cells.


Southeast Asian ovalocytosis and pregnancy in a malaria-endemic region of Papua New Guinea.
The band 3 deletion for southeast Asian ovalocytosis (SAO) occurs commonly in southeast Asia and the western Pacific. Southeast Asian ovalocytosis is associated with protection against cerebral malaria in children and therefore could reduce sequestration of erythrocytes parasitized by Plasmodium falciparum in the brain microvasculature. Sequestration of parasitized erythrocytes in the placenta accounts for much of the pathology of malaria during pregnancy. Therefore, we investigated the effect of SAO on malaria during pregnancy in the malaria-hyperendemic north coastal region of Papua New Guinea. The frequency of SAO in 927 women attending hospital for delivery was 8.7% (95% confidence interval = 6.9-10.5). Markers of fertility, the frequency of miscarriages and stillbirths, maternal anemia, placental and peripheral malaria at delivery, and birth weight were similar in women with and without SAO. In summary, although we can not exclude an interaction between SAO and malaria during pregnancy, we found no evidence that it provided a clinical benefit in this population.


Goal setting in cardiac rehabilitation: implications for clinical practice.
Effective goal setting is a vital component of cardiac rehabilitation (CR) programs. The objectives of this study were to investigate the types of goals set by patients attending a CR program in a tertiary teaching hospital and the compatibility of the goals set with the patient's risk factor profile. A descriptive, cross sectional, retrospective audit of the medical records of patients who attended the CR program in a tertiary teaching hospital in Sydney NSW between January 2007 and December 2009 was undertaken. The medical records of 355 patients who attended CR within the stipulated time frame were audited. Short and long term goals were set by 104 and 50 patients, respectively. Four themes identified in the analysis of the goal data were reducing behavioural risk factors for further cardiovascular events, improvements in physical symptoms, enhancing mental well being and return to normal life. The majority of the goals related to physical activity (82%). Collaborative goal setting and the need to establish goals that are attainable and correspond with the patient's health behaviours and clinical measures that require modification is vital.


Cerebral blood flow alteration in neuroprotection following cerebral ischaemia.
The best neuroprotectant for acute ischaemic stroke would always be the rapid return of oxygen and glucose to physiological levels. This is currently provided by thrombolysis which restores blood flow to the ischaemic region. The attempt to confer neuroprotection by targeting the brain parenchyma has shown promise in experimental stroke models, but has unequivocally failed to translate to the clinic. Neuroprotective therapy primarily targets the biochemical cascade that produces cell death following cerebral ischaemia. However, these agents may also alter signal transduction that controls cerebral blood flow, for example glutamate, which may affect the outcome after ischaemia. In these cases, neuroprotection may potentially be due to the improved access to oxygen and glucose rather than biochemical prevention of cell death. Improvement in cerebral blood flow is an important but often overlooked effect of neuroprotective therapy, analogous to the protective effects of drug-induced hypothermia. This short review will discuss cerebral blood flow alteration and protection of the brain in the context of ischaemic preconditioning, oxygen sensing and thrombolysis. Future neuroprotection studies in cerebral ischaemia require stringent monitoring of cerebral blood flow, plus other physiological parameters. This will increase the chances that any protection observed may be able to translate to human therapy.


Juvenile obesity enhances emotional memory and amygdala plasticity through glucocorticoids.
In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic-pituitary-adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor-malaise and tone-shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD-induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function.


A divalent metal-dependent self-cleaving DNAzyme with a tyrosine side chain.
The enzymatic incorporation of a phenol-modified 2'-deoxyuridine triphosphate gave rise to a modified DNA library that was subsequently used in an in vitro selection for ribophosphodiester-cleaving DNAzymes in the presence of divalent zinc and magnesium cations. After 11 rounds of selection, cloning and sequencing resulted in 14 distinct sequences, the most active of which was Dz11-17PheO. Dz11-17PheO self-cleaved an embedded ribocytidine with an observed rate constant of 0.20 ± 0.02 min(-1) in the presence of 10 mM Mg(2+) and 1 mM Zn(2+) at room temperature. The activity was inhibited at low concentrations of Hg(2+) cations and somewhat higher concentrations of Eu(3+) cations.


Postprandial changes of amino acid and acylcarnitine concentrations in dried blood samples.
Blood sampling for newborn screening cannot be standardized as for example blood collection in adults after an overnight fast. Therefore the influence of postprandial changes and individual variation is valuable information for the assessment of sensitivity and specificity of newborn screening for certain disorders. We have analyzed 92 pairs of dried blood samples taken pre- and one hour postprandially, respectively. We have determined the mean increase in metabolite concentration and calculated its significance. Individual variation after an overnight fast in healthy adults (n = 3) was between 12 and 32% (SD). Postprandial increases of acylcarnitines were mostly not significant and not exceeding 10%. Postprandial increase of amino acids was highly significant for most proteinogenic amino acids, but not for all. With the collected data we were able to estimate that mainly decreased levels of methionine and, to a lesser extent, of free carnitine could be "masked" by postprandial increases of the respective metabolites, and could therefore lead to false negative results for the detection of disorders of cobalamin metabolism and carnitine transporter deficiency.


Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response.
Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-γ and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-γ inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression.


Mental health users' experiences of being interviewed by another user in a research project. A qualitative study.
Although user involvement in research is an area of high priority there is a lack of knowledge about how users of the mental health system perceive participation in studies carried out by other users. The aim of the study was to describe how users experience participation in research interviews performed by other users. A varied sample of 17 mental health users with experience of being interviewed in a research project by another user was thematically interviewed in this qualitative study. Data was subject to content analysis. Being interviewed by another user was a special experience including both negative and positive aspects, and took place in an atmosphere of comradeship. However, being interviewed by another user could generate feelings of insecurity. This finding indicates requirements from the informants how to perform user-involved research in the future. In planning for user-involved research education, it is necessary to consider training and issues related to secure ethical principals concerning the informants.


Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.
There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.


Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions.
The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with α-secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid β (Aβ) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPα and increased levels of sAPPβ and endogenous Aβ peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.


Novel red phosphors KBaEu(XO4)3 (X = Mo, W) show high color purity and high thermostability from a disordered chained structure.
Two novel red phosphors KBaEu(XO4)3 (X = Mo, W) have been synthesized by high-temperature solid-state reactions and the crystal structures were determined for the first time. Single-crystal X-ray diffraction data reveal that their space groups are C2/c. The crystalline structure is constituted of K/BaO8 distorted square antiprisms and distorted EuO8 polyhedra which form chains lying along the c-axis and two kinds of distorted XO4 tetrahedra. This high disorder of K/Ba which might lower the crystal field symmetry around Eu3+ results in the high purity of red emission around 615 nm originating from 5D0 → 7F2 transition under near-ultraviolet (NUV) excitation. With increasing temperature, the luminescence of KBaEu(XO4)3 (X = Mo, W) phosphors decreases almost linearly with subtle alteration for the CIE coordinate. As the temperature reaches 550 K, the red emission intensity decreases to 37.3% and 50.7% of that at 300 K for KBaEu(MoO4)3 and KBaEu(WO4)3, respectively. The analysis of the decay curves of the 5D0 → 7F2 emission at variable temperatures indicates the weak cross relaxation and non-radiative energy transfer between Eu3+ ions. These results demonstrate that the investigated phosphors are attractive for application in high power NUV excited white LEDs.


Global emergence of Alphaviruses that cause arthritis in humans.
Arthropod-borne viruses (arboviruses) may cause severe emerging and re-emerging infectious diseases, which pose a significant threat to human and animal health in the world today. These infectious diseases range from mild febrile illnesses, arthritis, and encephalitis to haemorrhagic fevers. It is postulated that certain environmental factors, vector competence, and host susceptibility have a major impact on the ecology of arboviral diseases. Presently, there is a great interest in the emergence of Alphaviruses because these viruses, including Chikungunya virus, O'nyong'nyong virus, Sindbis virus, Ross River virus, and Mayaro virus, have caused outbreaks in Africa, Asia, Australia, Europe, and America. Some of these viruses are more common in the tropics, whereas others are also found in temperate regions, but the actual factors driving Alphavirus emergence and re-emergence remain unresolved. Furthermore, little is known about the transmission dynamics, pathophysiology, genetic diversity, and evolution of circulating viral strains. In addition, the clinical presentation of Alphaviruses may be similar to other diseases such as dengue, malaria, and typhoid, hence leading to misdiagnosis. However, the typical presence of arthritis may distinguish between Alphaviruses and other differential diagnoses. The absence of validated diagnostic kits for Alphaviruses makes even routine surveillance less feasible. For that purpose, this review describes the occurrence, genetic diversity, clinical characteristics, and the mechanisms involving Alphaviruses causing arthritis in humans. This information may serve as a basis for better awareness and detection of Alphavirus-caused diseases during outbreaks and in establishing appropriate prevention and control measures.


Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression.
Subcutaneous implantation of demineralized bone matrix initiates a sequence of developmental events, which culminate in endochondral bone formation. During early stages of development of matrix-induced implants, ED1, Ia-positive monocytes-macrophages were observed, suggesting that in the initial phases of the endochondral bone formation cascade, the bone-inductive protein osteogenin and related bone morphogenetic proteins (BMPs) might serve as potent chemoattractants to recruit circulating monocytes. In this investigation, we demonstrate that at concentrations of 10-100 fg/ml (0.3-3 fM), native bovine osteogenin and recombinant human BMP-2B (rhBMP-2B) induce the directed migration of human blood monocytes in vitro. This chemotactic response was associated with expression of BMP binding sites (receptors) on monocytes. About 750 receptors per cell were detected with an apparent dissociation constant of 200 pM. Both osteogenin and rhBMP-2B at higher concentrations (0.1-30 ng/ml) stimulated mRNA expression for an additional regulatory molecule, type beta 1 transforming growth factor (TGF-beta 1) in human monocytes. TGF-beta 1, in turn, is known to induce a cascade of events leading to matrix generation. Monocytes stimulated by TGF-beta are known to secrete a number of chemotactic and mitogenic cytokines that recruit endothelial and mesenchymal cells and promote their synthesis of collagen and associated matrix constituents. TGF-beta 1 in concert with these other cytokines and matrix components regulates chemotaxis, mesenchymal proliferation, differentiation, angiogenesis, and controlled synthesis of extracellular matrix. Our results demonstrate that osteogenin and related BMPs through their profound effects on monocyte recruitment and cytokine synthesis may promote additional successive steps in the endochondral bone formation cascade.


Development and implementation of PROgmatic: A clinical trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes.
Background Many clinical trials are conducted as explanatory trials, but the applicability of results from explanatory trials to clinical practice may be questioned. Pragmatic trials elucidate both benefits and harms of an intervention under conditions close to daily clinical practice. We have planned a pragmatic multi-centre trial in patients with Graves' hyperthyroidism. However, trial management is a complicated task in pragmatic trials, due to limited interaction between participants and trial personnel. Purpose The aim of this project was to develop and implement PROgmatic, a fully integrated trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes (PROs). Methods Necessary tasks and logistical challenges that should be handled by PROgmatic were identified, and the system was designed and developed to handle these tasks. A combination of generic applications and custom coding was applied to develop an integrated system that met the required needs. PROgmatic features include secure web-based data entry; electronic case report forms (eCRFs); central participant registration and randomisation; automated emails linking to electronic PROs; automated reminders to participants; automated notifications to trial personnel regarding booking of trial visits, safety and compliance alerts; and monitoring of trial progress. PROgmatic underwent rigorous pilot testing, including data verification and validation, before it was released for trial management. Results PROgmatic was successfully implemented in the GRAves' Selenium Supplementation (GRASS) trial (ClinicalTrials.gov: NCT01611896) December 2012. The feedback from trial personnel on usability and utility has been positive, and PROgmatic has handled all intended tasks properly. Limitations Implementation of PROgmatic in future studies requires adaptation of the custom coding. Not all email systems accept emails with active links, and participants who use these systems therefore need to complete paper surveys. Conclusions PROgmatic facilitated the complex task of conducting a pragmatic multi-centre trial. The automated electronic capture of PRO data is time saving and reduces the risk of erroneous data entry. Email notifications to trial personnel combined with serially activated eCRFs that logically lead patient flow through the trial have helped making the pragmatic trial feasible. PROgmatic provides a template for other pragmatic multi-centre trials with patient-reported measures as high-priority outcomes.


Advances in telemetric continuous intraocular pressure assessment.
With an ageing population showing an increasing prevalence of glaucoma, there is a pressing demand for continuous intraocular pressure (IOP) measurements which could surpass clinic-based measurements such as routine applanation tonometry. Glaucoma patients have fluctuations in IOP, and it has been proposed that these fluctuations are relevant to glaucoma progression. In addition, interindividual and intraindividual variation in corneal thickness and rigidity can lead to significant and poorly quantitated errors in applanation-based methods of estimating IOP. Microelectrical mechanical systems and complementary metal oxide semiconductor-based technology has enabled the development of smart miniaturised devices by augmenting the computational ability of microelectronics with capabilities of microsensors and microactuators. This review addresses various sensor technologies and both invasive and non-invasive approaches to the measurement of IOP. Advances in wireless communication (telemetry) between the implanted sensors and the external readout device are reviewed. In addition, biocompatibility of implantable sensors is discussed.


Brain Activity Underlying Muscle Relaxation.
Fine motor control of not only muscle contraction but also muscle relaxation is required for appropriate movements in both daily life and sports. Movement disorders such as Parkinson's disease and dystonia are often characterized by deficits of muscle relaxation. Neuroimaging and neurophysiological studies suggest that muscle relaxation is an active process requiring cortical activation, and not just the cessation of contraction. In this article, we review the neural mechanisms of muscle relaxation, primarily utilizing research involving transcranial magnetic stimulation (TMS). Several studies utilizing single-pulse TMS have demonstrated that, during the relaxation phase of a muscle, the excitability of the corticospinal tract controlling that particular muscle is more suppressed than in the resting condition. Other studies, utilizing paired-pulse TMS, have shown that the intracortical inhibition is activated just before muscle relaxation. Moreover, muscle relaxation of one body part suppresses cortical activities controlling other body parts in different limbs. Therefore, the cortical activity might not only be a trigger for muscle relaxation of the target muscles but could also bring about an inhibitory effect on other muscles. This spread of inhibition can hinder the appropriate contraction of muscles involved in multi-limb movements such as those used in sports and the play of musical instruments. This may also be the reason why muscle relaxation is so difficult for beginners, infants, elderly, and the cognitively impaired.


The Psychology of Entrenched Privilege: High Socioeconomic Status Individuals From Affluent Backgrounds Are Uniquely High in Entitlement.
As rates of intergenerational social mobility decline, it is increasingly important to understand the psychological consequences of entrenched socioeconomic privilege. Here, we explore whether current and childhood socioeconomic status (SES) are interactively related to entitlement, such that among currently high SES individuals, those from affluent backgrounds are likely to feel uniquely high levels of entitlement, whereas currently low SES individuals feel low entitlement regardless of their backgrounds. A meta-analysis of four exploratory studies (total N = 3,105) found that currently high SES individuals who were also raised in high SES households were especially inclined to report feeling entitled, a pattern that was robust across three indicators of SES: income, education, and subjective SES. Results of a preregistered, confirmatory study (N = 1,058) replicated this interactive pattern for education and subjective SES, though not for income. Our findings highlight the importance of considering current and childhood SES jointly to understand the psychological consequences of SES.


Identification of transcripts with enriched expression in the developing and adult pancreas.
Despite recent advances, the transcriptional hierarchy driving pancreas organogenesis remains largely unknown, in part due to the paucity of comprehensive analyses. To address this deficit we generated ten SAGE libraries from the developing murine pancreas spanning Theiler stages 17-26, making use of available Pdx1 enhanced green fluorescent protein (EGFP) and Neurog3 EGFP reporter strains, as well as tissue from adult islets and ducts. We used a specificity metric to identify 2,536 tags with pancreas-enriched expression compared to 195 other mouse SAGE libraries. We subsequently grouped co-expressed transcripts with differential expression during pancreas development using K-means clustering. We validated the clusters first using quantitative real time PCR and then by analyzing the Theiler stage 22 pancreas in situ hybridization staining patterns of over 600 of the identified genes using the GenePaint database. These were then categorized into one of the five expression domains within the developing pancreas. Based on these results we identified a cascade of transcriptional regulators expressed in the endocrine pancreas lineage and, from this, we developed a predictive regulatory network describing beta-cell development. Taken together, this work provides evidence that the SAGE libraries generated here are a valuable resource for continuing to elucidate the molecular mechanisms regulating pancreas development. Furthermore, our studies provide a comprehensive analysis of pancreas development, and insights into the regulatory networks driving this process are revealed.


Sixty years trying to define the malaria burden in Africa: have we made any progress?
Controversy surrounds the precise numbers of malaria deaths and clinical episodes in Africa. This would not have surprised malariologists working in Africa 60 years ago as they began to unravel the enigma that is 'malaria'. Malaria is a complex disease manifesting as a multitude of symptoms, degrees of severity and indirect morbid consequences. Clinical immunity develops quickly and the presence of infection cannot always be used to distinguish between malaria and other illnesses. During the 1950s and 1960s parasite prevalence was used in preference to statistics on malaria mortality and morbidity. An argument is made for a resurrection of this measure of the quantity of malaria across Africa as a more reliable means to understand the impact of control.


'Normal' serum sodium concentration among inpatients over 65 admitted to hospital: an observational study.
The usual reference range of serum sodium (typically 135-145 mmol/l) is derived from healthy populations but may not apply to hospital patients. To describe the range of serum sodium in inpatients and outpatients of both sexes at different ages. To ascertain correlates of serum sodium among older inpatients. To describe the association between sodium and mortality. We used routine hospital data on serum sodium in inpatients admitted between 1 January 2011 and 31 December 2014 and patients attending outpatient or community clinics with no record of admission to the same hospitals in the same period. We investigated the distribution of sodium values within these groups and explored the relationship between serum sodium and death using logistic regression. Levels among hospital inpatients were significantly lower than in outpatients of the same age. Emergency admissions had lower levels and those admitted from care homes higher levels, risk of inhospital death began to rise at 140 mmol/L, well within the 'normal' range. Patients with a serum sodium concentration of 145 mmol/L on admission have a risk of inhospital death 3.7 times higher than that of a patient with a concentration of 140 mmol/L. The range for serum sodium concentration on admission in inpatients is broader and lower than the commonly accepted reference range. The risk of mortality increases at sodium concentration >139 mmol/L, well within reference range currently considered normal.


Synthetic collective intelligence.
Intelligent systems have emerged in our biosphere in different contexts and achieving different levels of complexity. The requirement of communication in a social context has been in all cases a determinant. The human brain, probably co-evolving with language, is an exceedingly successful example. Similarly, social insects complex collective decisions emerge from information exchanges between many agents. The difference is that such processing is obtained out of a limited individual cognitive power. Computational models and embodied versions using non-living systems, particularly involving robot swarms, have been used to explore the potentiality of collective intelligence. Here we suggest a novel approach to the problem grounded in the genetic engineering of unicellular systems, which can be modified in order to interact, store memories or adapt to external stimuli in collective ways. What we label as Synthetic Swarm Intelligence defines a parallel approach to the evolution of computation and swarm intelligence and allows to explore potential embodied scenarios for decision making at the microscale. Here, we consider several relevant examples of collective intelligence and their synthetic organism counterparts.


Brazil's conditional cash transfer program associated with declines in infant mortality rates.
Conditional cash transfer programs are innovative social safety-net programs that aim to relieve poverty. They provide a regular source of income to poor families and are "conditional" in that they require poor families to invest in the health and education of their children through greater use of educational and preventive health services. Brazil's Bolsa Família conditional cash transfer program, created in 2003, is the world's largest program of its kind. During the first five years of the program, it was associated with a significant 9.3 percent reduction in overall infant mortality rates, with greater declines in postneonatal mortality rates than in mortality rates at an earlier age and in municipalities with many users of Brazil's Family Health Program than in those with lower use rates. There were also larger effects in municipalities with higher infant mortality rates at baseline. Programs like Bolsa Família can improve child health and reduce long-standing health inequalities. Policy makers should review the adequacy of basic health services to ensure that the services can respond to the increased demand created by such programs. Programs should also target vulnerable groups at greatest risk and include careful monitoring and evaluation.


Advanced mesospheric temperature mapper for high-latitude airglow studies.
Over the past 60 years, ground-based remote sensing measurements of the Earth's mesospheric temperature have been performed using the nighttime hydroxyl (OH) emission, which originates at an altitude of ∼87 km. Several types of instruments have been employed to date: spectrometers, Fabry-Perot or Michelson interferometers, scanning-radiometers, and more recently temperature mappers. Most of them measure the mesospheric temperature in a few sample directions and/or with a limited temporal resolution, restricting their research capabilities to the investigation of larger-scale perturbations such as inertial waves, tides, or planetary waves. The Advanced Mesospheric Temperature Mapper (AMTM) is a novel infrared digital imaging system that measures selected emission lines in the mesospheric OH (3,1) band (at ∼1.5 μm) to create intensity and temperature maps of the mesosphere around 87 km. The data are obtained with an unprecedented spatial (∼0.5 km) and temporal (typically 30″) resolution over a large 120° field of view, allowing detailed measurements of wave propagation and dissipation at the ∼87 km level, even in the presence of strong aurora or under full moon conditions. This paper describes the AMTM characteristics, compares measured temperatures with values obtained by a collocated Na lidar instrument, and presents several examples of temperature maps and nightly keogram representations to illustrate the excellent capabilities of this new instrument.


Hidden Variation in Microsatellite Loci: Utility and Implications for Forensic DNA Analysis.
Short tandem repeat (STR) analysis has been the standard in forensic DNA examinations for almost 15 years. The purpose of this article is to provide some perspective on the biological nature of STR alleles themselves, examine underlying distributions of alleles in the STR loci that are routinely used, and to discuss features of these alleles that are not observable with the currently employed methods. Many of the internationally standardized STR loci contain variations of their interrupted repeat structures, either due to the compound or complex nature of the locus or due to nucleotide variations within the simple repeat motif, which inevitably leads them to become more stratified at the population level. Current STR typing procedures utilizing PCR amplification followed by fragment analysis via capillary or gel electrophoresis does not provide the resolution to discern these polymorphisms. Thus, current designation of alleles is operationally and not biologically defined. Although in the comparison of an evidentiary STR profile to that of a potential contributor, the biological nature of the allele may not be of consequence. When comparisons require assumptions of relatedness between individuals, the biological nature of shared alleles becomes an underlying focus. Herein we will discuss the nature of these additional allelic polymorphisms, what is known of their distribution among the STR loci utilized in forensic testing and within populations, and the advantages this level of allelic discrimination has in forensic and relationship testing.


Bax regulates neuronal Ca2+ homeostasis.
Excessive Ca(2+) entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation.


A biomechanical comparison of the traditional squat, powerlifting squat, and box squat.
The purpose of this study was to compare the biomechanics of the traditional squat with 2 popular exercise variations commonly referred to as the powerlifting squat and box squat. Twelve male powerlifters performed the exercises with 30, 50, and 70% of their measured 1 repetition maximum (1RM), with instruction to lift the loads as fast as possible. Inverse dynamics and spatial tracking of the external resistance were used to quantify biomechanical variables. A range of significant kinematic and kinetic differences (p < 0.05) emerged between the exercises. The traditional squat was performed with a narrow stance, whereas the powerlifting squat and box squat were performed with similar wide stances (48.3 ± 3.8, 89.6 ± 4.9, 92.1 ± 5.1 cm, respectively). During the eccentric phase of the traditional squat, the knee traveled past the toes resulting in anterior displacement of the system center of mass (COM). In contrast, during the powerlifting squat and box squat, a more vertical shin position was maintained, resulting in posterior displacements of the system COM. These differences in linear displacements had a significant effect (p < 0.05) on a number of peak joint moments, with the greatest effects measured at the spine and ankle. For both joints, the largest peak moment was produced during the traditional squat, followed by the powerlifting squat, then box squat. Significant differences (p < 0.05) were also noted at the hip joint where the largest moment in all 3 planes were produced during the powerlifting squat. Coaches and athletes should be aware of the biomechanical differences between the squatting variations and select according to the kinematic and kinetic profile that best match the training goals.


Molybdenum-Doped PdPt@Pt Core-Shell Octahedra Supported by Ionic Block Copolymer-Functionalized Graphene as a Highly Active and Durable Oxygen Reduction Electrocatalyst.
Development of highly active and durable electrocatalysts that can effectively electrocatalyze oxygen reduction reactions (ORR) still remains one important challenge for high-performance electrochemical conversion and storage applications such as fuel cells and metal-air batteries. Herein, we propose the combination of molybdenum-doped PdPt@Pt core-shell octahedra and the pyrene-functionalized poly(dimethylaminoethyl methacrylate)-b-poly[(ethylene glycol) methyl ether methacrylate] ionic block copolymer-functionalized reduced graphene oxide (Mo-PdPt@Pt/IG) to effectively augment the interfacial cohesion of both components using a tunable ex situ mixing strategy. The rationally designed Mo-PdPt@Pt core-shell octahedra have unique compositional benefits, including segregation of Mo atoms on the vertexes and edges of the octahedron and 2-3 shell layers of Pt atoms on a PdPt alloy core, which can provide highly active sites to the catalyst for ORR along with enhanced electrochemical stability. In addition, the ionic block copolymer functionalized graphene can facilitate intermolecular charge transfer and good stability of metal NPs, which arises from the ionic block copolymer interfacial layer. When the beneficial features of the Mo-PdPt@Pt and IG are combined, the Mo-PdPt@Pt/IG exhibits substantially enhanced activity and durability for ORR relative to those of commercial Pt/C. Notably, the Mo-PdPt@Pt/IG shows mass activity 31-fold higher than that of Pt/C and substantially maintains high activities after 10 000 cycles of intensive durability testing. The current study highlights the crucial strategies in designing the highly active and durable Pt-based octahedra and effective combination with functional graphene supports toward the synergetic effects on ORR.


Lewy bodies of Parkinson's disease contain neurofilament antigens.
The Lewy body, a histological hallmark of Parkinson's disease, is a filamentous inclusion residing most prominently in pigmented neurons of the brainstem. Immunocytochemical reactions of Lewy bodies were examined with antisera to several filamentous proteins of the nervous system and positive reactions were found with those against neurofilaments. An abnormal organization of the neuronal cytoskeleton may be a pathological feature of Parkinson's disease.


A new approach to integrate GPU-based Monte Carlo simulation into inverse treatment plan optimization for proton therapy.
Monte Carlo (MC)-based spot dose calculation is highly desired for inverse treatment planning in proton therapy because of its accuracy. Recent studies on biological optimization have also indicated the use of MC methods to compute relevant quantities of interest, e.g. linear energy transfer. Although GPU-based MC engines have been developed to address inverse optimization problems, their efficiency still needs to be improved. Also, the use of a large number of GPUs in MC calculation is not favorable for clinical applications. The previously proposed adaptive particle sampling (APS) method can improve the efficiency of MC-based inverse optimization by using the computationally expensive MC simulation more effectively. This method is more efficient than the conventional approach that performs spot dose calculation and optimization in two sequential steps. In this paper, we propose a computational library to perform MC-based spot dose calculation on GPU with the APS scheme. The implemented APS method performs a non-uniform sampling of the particles from pencil beam spots during the optimization process, favoring those from the high intensity spots. The library also conducts two computationally intensive matrix-vector operations frequently used when solving an optimization problem. This library design allows a streamlined integration of the MC-based spot dose calculation into an existing proton therapy inverse planning process. We tested the developed library in a typical inverse optimization system with four patient cases. The library achieved the targeted functions by supporting inverse planning in various proton therapy schemes, e.g. single field uniform dose, 3D intensity modulated proton therapy, and distal edge tracking. The efficiency was 41.6 ± 15.3% higher than the use of a GPU-based MC package in a conventional calculation scheme. The total computation time ranged between 2 and 50 min on a single GPU card depending on the problem size.


Association between antibiotic prescribing and visit duration in adults with upper respiratory tract infections.
Upper respiratory tract infections (URTIs) are the most common reason for individuals to seek health care in the United States. Inappropriate antibiotic use exposes patients unnecessarily to potential adverse events and increases the prevalence of antibiotic-resistant bacteria. One of the reasons physicians may prescribe an antibiotic inappropriately is to save time. The aim of this study was to determine whether there is an association between antibiotic use and a shorter visit duration in adults with URTIs. Visits to office-based primary care physicians made by adults aged 18 to 60 years from 1995 through 2000 were extracted from the National Ambulatory Medical Care Survey. Visits that resulted in a primary diagnosis of acute URTI; acute nasopharyngitis; acute bronchitis; sinusitis; streptococcal sore throat, acute pharyngitis, or acute tonsillitis; or otitis media were included in the study. Visits associated with >1 diagnosis were included in a separate category Visit duration was defined as the face-to-face time between the patient and physician. There were 3764 visits that met the criteria for inclusion in this study, representing an estimated 27 million annual visits to office-based primary care physicians by adults with URTIs. Antibiotics were prescribed in 67% of visits. The mean visit duration associated with prescription of an antibiotic was 14.2 minutes, compared with 15.2 minutes without prescription of an antibiotic (P = 0.007). In multivariable modeling, independent predictors of visit duration were calendar year (additional 0.3 minute per year; 95% CI, 0.1 to 0.6), internal medicine specialty (additional 2.2 minutes vs family practice; 95% CI, 1.3 to 3.1), covisit with a nurse-practitioner or physician assistant (6.6 minutes shorter; 95% CI, -2.7 to -10.6), and Midwestern location of practice (1.1 minutes shorter vs Northeast; 95% CI, -0.1 to -2.2). Antibiotic use was marginally associated with a shorter visit duration (0.7 minute shorter; 95% CI, 0.0 to -1.3; P = NS). In the present study, antibiotic use was marginally associated with a shorter visit duration for adults with URTIs. Any potential efficiencies gained by physicians through prescribing antibiotics for adults with URTIs are likely to be outweighed by increases in antimicrobial resistance and exposure of patients to unneeded medication.


A case study of coupling upflow anaerobic sludge blanket (UASB) and ANITA™ Mox process to treat high-strength landfill leachate.
A pilot study was conducted to study the treatability of high-strength landfill leachate by a combined process including upflow anaerobic sludge blanket (UASB), carbon removal (C-stage) moving bed biofilm reactor (MBBR) and ANITA™ Mox process. The major innovation on this pilot study is the patent-pending process invented by Veolia that integrates the above three unit processes with an effluent recycle stream, which not only maintains the low hydraulic retention time to enhance the treatment performance but also reduces inhibiting effect from chemicals present in the high-strength leachate. This pilot study has demonstrated that the combined process was capable of treating high-strength leachate with efficient chemical oxygen demand (COD) and nitrogen removals. The COD removal efficiency by the UASB was 93% (from 45,000 to 3,000 mg/L) at a loading rate of 10 kg/(m(3)·d). The C-stage MBBR removed an additional 500 to 1,000 mg/L of COD at a surface removal rate (SRR) of 5 g/(m(2)·d) and precipitated 400 mg/L of calcium. The total inorganic nitrogen removal efficiency by the ANITA Mox reactor was about 70% at SRR of 1.0 g/(m(2)·d).


Transcription activation of a UV-inducible Clostridium perfringens bacteriocin gene by a novel sigma factor.
Expression of the plasmid-encoded Clostridium perfringens gene for bacteriocin BCN5 was shown to depend in vivo and in vitro on the activity of UviA protein. UviA, also plasmid-encoded, proved to be an RNA polymerase sigma factor and was also partly autoregulatory. The uviA gene has two promoters; one provided a UviA-independent, basal level of gene expression while the stronger, UviA-dependent promoter was only utilized after the cell experienced DNA damage. As a result, BCN5 synthesis is induced by treatment with UV light or mitomycin C. UviA is related to a special class of sigma factors found to date only in Clostridium species and responsible for activating transcription of toxin genes in Clostridium difficile, Clostridium tetani, and Clostridium botulinum.


GEViTRec: Data Reconnaissance Through Recommendation Using a Domain-Specific Visualization Prevalence Design Space.
Genomic Epidemiology (genEpi) is a branch of public health that uses many different data types including tabular, network, genomic, and geographic, to identify and contain outbreaks of deadly diseases. Due to the volume and variety of data, it is challenging for genEpi domain experts to conduct data reconnaissance; that is, have an overview of the data they have and make assessments toward its quality, completeness, and suitability. We present an algorithm for data reconnaissance through automatic visualization recommendation, GEViTRec. Our approach handles a broad variety of dataset types and automatically generates visually coherent combinations of charts, in contrast to existing systems that primarily focus on singleton visual encodings of tabular datasets. We automatically detect linkages across multiple input datasets by analyzing non-numeric attribute fields, creating a data source graph within which we analyze and rank paths. For each high-ranking path, we specify chart combinations with positional and color alignments between shared fields, using a gradual binding approach to transform initial partial specifications of singleton charts to complete specifications that are aligned and oriented consistently. A novel aspect of our approach is its combination of domain-agnostic elements with domain-specific information that is captured through a domain-specific visualization prevalence design space. Our implementation is applied to both synthetic data and real Ebola outbreak data. We compare GEViTRec's output to what previous visualization recommendation systems would generate, and to manually crafted visualizations used by practitioners. We conducted formative evaluations with ten genEpi experts to assess the relevance and interpretability of our results. Code, Data, and Study Materials Availability: https://github.com/amcrisan/GEVitRec.


Probabilistic risk assessment of Chinese residents' exposure to fluoride in improved drinking water in endemic fluorosis areas.
Studies have yet to evaluate the effects of water improvement on fluoride concentrations in drinking water and the corresponding health risks to Chinese residents in endemic fluorosis areas (EFAs) at a national level. This paper summarized available data in the published literature (2008-2016) on water fluoride from the EFAs in China before and after water quality was improved. Based on these obtained data, health risk assessment of Chinese residents' exposure to fluoride in improved drinking water was performed by means of a probabilistic approach. The uncertainties in the risk estimates were quantified using Monte Carlo simulation and sensitivity analysis. Our results showed that in general, the average fluoride levels (0.10-2.24 mg/L) in the improved drinking water in the EFAs of China were lower than the pre-intervention levels (0.30-15.24 mg/L). The highest fluoride levels were detected in North and Southwest China. The mean non-carcinogenic risks associated with consumption of the improved drinking water for Chinese residents were mostly accepted (hazard quotient < 1), but the non-carcinogenic risk of children in most of the EFAs at the 95th percentile exceeded the safe level of 1, indicating the potential non-cancer-causing health effects on this fluoride-exposed population. Sensitivity analyses indicated that fluoride concentration in drinking water, ingestion rate of water, and the exposure time in the shower were the most relevant variables in the model, therefore, efforts should focus mainly on the definition of their probability distributions for a more accurate risk assessment.


SkelGen: a general tool for structure-based de novo ligand design.
The recent lapse in productivity in the pharmaceutical industry has facilitated the emergence of experimental and in silico structure-based design methodologies, based on identification of biologically active low molecular weight fragments that can be exploited to produce potential drug candidates with diverse chemistries. SkelGen, an in silico example of this methodology, is reviewed. The ability of this algorithm to identify chemically diverse low molecular weight fragments that would potentially bind to DNA gyrase is recounted, as is the first purely de novo structure-based design of five compounds that show at least micromolar activity against the estrogen receptor. The ability of the algorithm to incorporate partial protein flexibility during its design of compounds to the estrogen receptor is discussed, and an opinion as to the near and long-term futures for de novo design algorithms is expressed.


Fiber-based cryogenic and time-resolved spectroscopy of PbS quantum dots.
PbS quantum dots are promising active emitters for use with high-quality Si nanophotonic devices in the telecommunications-band. Measurements of low quantum dot densities are limited both because of low fluorescence levels and the challenges of single photon detection at these wavelengths. Here, we report on methods using a fiber taper waveguide to efficiently extract PbS quantum dot photoluminescence. Temperature dependent ensemble measurements reveal an increase in emitted photons concomitant with an increase in excited-state lifetime from 58.9 ns at 293 K to 657 ns at 40 K. Measurements are also performed on quantum dots on high-Q (>10(5)) microdisks using cavity-resonant, pulsed excitation.


Sacral neuromodulation for refractory urge incontinence is less effective following spinal surgery.
Patients with neurogenic disorders and voiding dysfunction have been reported to respond poorly to sacral neuromodulation. We report on our experience in treating voiding symptoms with sacral neuromodulation after spinal surgery. The medical charts of patients evaluated for sacral neuromodulation from 2000-2008 were retrospectively reviewed. Indications, need for explantation, and clinical success (>50% symptom improvement) were recorded. The cohort of patients who had undergone prior spinal surgery was compared to patients with no history of spinal surgery or neurological disease. Thirty-two patients with a history of spinal surgery and 136 with no history of neurologic disease underwent sacral neuromodulation testing. Twenty men and women (62.5%) from the spinal surgery group ultimately underwent permanent implantation. Seventeen of the 32 patients were diagnosed with urge incontinence, of whom 52.9% reported a successful outcome at a mean of 2.3 years of follow-up, compared to an 80.3% success rate in patients with no history of spinal surgery (p=0.018). Sixteen of 32 carried a diagnosis of urgency/frequency with 62.5% success at last follow-up, compared 73.9% (p=0.35) of those without a history of spinal surgery or neurological disease. Thirteen of 32 patients diagnosed with urinary retention experienced a 61.5% long-term success rate, compared with 63.6% for those without spinal surgery and urinary retention. Six of 20 (30.0%) in the spinal surgery group were explanted at a mean time of 2.9 years, compared with 27 of 102 (26.5%) of the non-neurologic patients. Clinical success can be achieved using sacral neuromodulation in patients with voiding dysfunction and a history of spinal surgery; however, those with urge incontinence are less likely to report significant improvement.


Cell and Microvesicle Urine microRNA Deep Sequencing Profiles from Healthy Individuals: Observations with Potential Impact on Biomarker Studies.
Urine is a potential source of biomarkers for diseases of the kidneys and urinary tract. RNA, including microRNA, is present in the urine enclosed in detached cells or in extracellular vesicles (EVs) or bound and protected by extracellular proteins. Detection of cell- and disease-specific microRNA in urine may aid early diagnosis of organ-specific pathology. In this study, we applied barcoded deep sequencing to profile microRNAs in urine of healthy volunteers, and characterized the effects of sex, urine fraction (cells vs. EVs) and repeated voids by the same individuals. Compared to urine-cell-derived small RNA libraries, urine-EV-derived libraries were relatively enriched with miRNA, and accordingly had lesser content of other small RNA such as rRNA, tRNA and sn/snoRNA. Unsupervised clustering of specimens in relation to miRNA expression levels showed prominent bundling by specimen type (urine cells or EVs) and by sex, as well as a tendency of repeated (first and second void) samples to neighbor closely. Likewise, miRNA profile correlations between void repeats, as well as fraction counterparts (cells and EVs from the same specimen) were distinctly higher than correlations between miRNA profiles overall. Differential miRNA expression by sex was similar in cells and EVs. miRNA profiling of both urine EVs and sediment cells can convey biologically important differences between individuals. However, to be useful as urine biomarkers, careful consideration is needed for biofluid fractionation and sex-specific analysis, while the time of voiding appears to be less important.


Highly conductive carbon nanotube matrix accelerates developmental chloride extrusion in central nervous system neurons by increased expression of chloride transporter KCC2.
Exceptional mechanical and electrical properties of carbon nanotubes (CNT) have attracted neuroscientists and neural tissue engineers aiming to develop novel devices that interface with nervous tissues. In the central nervous system (CNS), the perinatal chloride shift represents a dynamic change that forms the basis for physiological actions of γ-aminobutyric acid (GABA) as an inhibitory neurotransmitter, a process of fundamental relevance for normal functioning of the CNS. Low intra-neuronal chloride concentrations are maintained by a chloride-extruding transporter, potassium chloride cotransporter 2 (KCC2). KCC2's increasing developmental expression underlies the chloride shift. In neural injury, repressed KCC2 expression plays a co-contributory role by corrupting inhibitory neurotransmission. Mechanisms of Kcc2 up-regulation are thus pertinent because of their medical relevance, yet they remain elusive. Here, it is shown that primary CNS neurons originating from the cerebral cortex, cultured on highly-conductive few-walled-CNT (fwCNT) have a strikingly accelerated chloride shift caused by increased KCC2 expression. KCC2 upregulation is dependent on neuronal voltage-gated calcium channels (VGCC) and, furthermore, on calcium/calmodulin-dependent kinase II, which is linked to VGCC-mediated calcium-influx. It is also demonstrated that accelerated Kcc2 transcription in brain-slices prepared from genetically-engineered reporter mice, in which Kcc2 promoter drives luciferase, when the cerebral cortex of these mice is exposed to fwCNT-coated devices. Based on these findings, whether fwCNT can enhance neural engineering devices for the benefit of neural injury conditions associated with elevated neuronal intracellular chloride concentration-such as pain, epilepsy, traumatic neural injury and ischemia-can now be addressed. Taken together, our novel insights illustrate how fwCNTs can promote low neuronal chloride in individual neurons and thus inhibitory transmission in neural circuits.


Can a road safety measure be both effective and ineffective at the same time? A game-theoretic model of the effects of daytime running lights.
Studies that have evaluated the effects on accidents of daytime running lights for cars have consistently found that cars using daytime running lights are involved in fewer multi-party accidents in daylight than cars not using daytime running lights. However, studies evaluating the effects of mandatory use of daytime running lights have not always found an accident reduction. Although findings are mixed, there is a tendency for the aggregate effects of daytime running lights (i.e. the effects of an increasing share of traffic using daytime running lights) to be smaller than the intrinsic effects (i.e. the difference in accident involvement between cars using and not using daytime running lights). This paper presents a game-theoretic model to explain these apparently inconsistent findings. The game-theoretic model is based on so called Schelling-diagrams, originally introduced by Nobel laureate in economics Schelling. The effects of daytime running lights are modelled by means of Schelling-diagrams. It is shown that it is by no means impossible for cars using daytime running lights to always be safer than cars not using daytime running lights, while the total number of accidents remains constant even if the percentage of cars using daytime running lights increases from, say, 10% to 90%.


Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease.
The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG.


Safety testing and operational procedures for self-developed radiofrequency coils.
The development of novel radiofrequency (RF) coils for human ultrahigh-field (≥7 T), non-proton and body applications is an active field of research in many MR groups. Any RF coil must meet the strict requirements for safe application on humans with respect to mechanical and electrical safety, as well as the specific absorption rate (SAR) limits. For this purpose, regulations such as the International Electrotechnical Commission (IEC) standard for medical electrical equipment, vendor-suggested test specifications for third party coils and custom-developed test procedures exist. However, for higher frequencies and shorter wavelengths in ultrahigh-field MR, the RF fields may become extremely inhomogeneous in biological tissue and the risk of localized areas with elevated power deposition increases, which is usually not considered by existing safety testing and operational procedures. In addition, important aspects, such as risk analysis and comprehensive electrical performance and safety tests, are often neglected. In this article, we describe the guidelines used in our institution for electrical and mechanical safety tests, SAR simulation and verification, risk analysis and operational procedures, including coil documentation, user training and regular quality assurance testing, which help to recognize and eliminate safety issues during coil design and operation. Although the procedure is generally applicable to all field strengths, specific requirements with regard to SAR-related safety and electrical performance at ultrahigh-field are considered. The protocol describes an internal procedure and does not reflect consensus among a large number of research groups, but rather aims to stimulate further discussion related to minimum coil safety standards. Furthermore, it may help other research groups to establish their own procedures. Copyright © 2015 John Wiley & Sons, Ltd.


Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene.
We have used the public sequencing and annotation of the mouse genome to delimit the previously resolved type 1 diabetes (T1D) insulin-dependent diabetes (Idd)18 interval to a region on chromosome 3 that includes the immunologically relevant candidate gene, Vav3. To test the candidacy of Vav3, we developed a novel congenic strain that enabled the resolution of Idd18 to a 604-kb interval, designated Idd18.1, which contains only two annotated genes: the complete sequence of Vav3 and the last exon of the gene encoding NETRIN G1, Ntng1. Targeted sequencing of Idd18.1 in the NOD mouse strain revealed that allelic variation between NOD and C57BL/6J (B6) occurs in noncoding regions with 138 single nucleotide polymorphisms concentrated in the introns between exons 20 and 27 and immediately after the 3' untranslated region. We observed differential expression of VAV3 RNA transcripts in thymocytes when comparing congenic mouse strains with B6 or NOD alleles at Idd18.1. The T1D protection associated with B6 alleles of Idd18.1/Vav3 requires the presence of B6 protective alleles at Idd3, which are correlated with increased IL-2 production and regulatory T cell function. In the absence of B6 protective alleles at Idd3, we detected a second T1D protective B6 locus, Idd18.3, which is closely linked to, but distinct from, Idd18.1. Therefore, genetic mapping, sequencing, and gene expression evidence indicate that alteration of VAV3 expression is an etiological factor in the development of autoimmune beta-cell destruction in NOD mice. This study also demonstrates that a congenic strain mapping approach can isolate closely linked susceptibility genes.


RPGR-associated retinal degeneration in human X-linked RP and a murine model.
We investigated the retinal disease due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in human patients and in an Rpgr conditional knockout (cko) mouse model. XLRP patients with RPGR-ORF15 mutations (n = 35, ages at first visit 5-72 years) had clinical examinations, and rod and cone perimetry. Rpgr-cko mice, in which the proximal promoter and first exon were deleted ubiquitously, were back-crossed onto a BALB/c background, and studied with optical coherence tomography and electroretinography (ERG). Retinal histopathology was performed on a subset. Different patterns of rod and cone dysfunction were present in patients. Frequently, there were midperipheral losses with residual rod and cone function in central and peripheral retina. Longitudinal data indicated that central rod loss preceded peripheral rod losses. Central cone-only vision with no peripheral function was a late stage. Less commonly, patients had central rod and cone dysfunction, but preserved, albeit abnormal, midperipheral rod and cone vision. Rpgr-cko mice had progressive retinal degeneration detectable in the first months of life. ERGs indicated relatively equal rod and cone disease. At late stages, there was greater inferior versus superior retinal degeneration. RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy.


Quantifying the Benefit of Prehospital Rapid Treatment in Acute Stroke: Benchmark for Future Innovative Clinical Trials.
In acute ischemic stroke, time from onset to tissue-type plasminogen activator treatment (OTT) is a major determinant of outcome. To reduce OTT, clinical trials have been undertaken evaluating prehospital cerebral imaging with mobile computed tomographic scanners. Furthermore, blood biomarkers may allow rapid differentiation between ischemic stroke and intracerebral hemorrhage before hospital admission. How such treatment strategies translate into clinical benefit has not been specifically evaluated. We constructed decision models to estimate the net clinical benefit yielded by shorter OTT. In different scenarios, we estimated the proportion of patients with favorable outcome and the average quality of life. An OTT reduction of 60 minutes increases the probability of favorable outcome by 6.6% in a mixed stroke population. For comparison, the average effect of tissue-type plasminogen activator itself is 7.0%. Prehospital mobile computed tomography gaining 25 to 40 minutes increases the probability of favorable outcome by 3.0% to 4.6%. The additional benefit of prehospital computed tomography to deliver patients with large vessel occlusion directly to endovascular treatment centers increases the probability of favorable outcome by another 0.2% to 1.0%. A blood test discriminating ischemic stroke and intracerebral hemorrhage may beneficially substitute brain scan before tissue-type plasminogen activator if >32 to 40 minutes are gained and if sensitivity for intracerebral hemorrhage is >75% to 80%. Reducing the OTT has robust beneficial effects for acute stroke patients. Prehospital tissue-type plasminogen activator treatment without brain imaging may become conceivable under several preconditions, including a point-of-care test with >75% to 80% sensitivity to detect intracerebral hemorrhage and a time gain of >32 to 40 minutes. Ethical implications remain to be addressed.


Broad-scale latitudinal patterns of genetic diversity among native European and introduced house sparrow (Passer domesticus) populations.
Introduced species offer unique opportunities to study evolution in new environments, and some provide opportunities for understanding the mechanisms underlying macroecological patterns. We sought to determine how introduction history impacted genetic diversity and differentiation of the house sparrow (Passer domesticus), one of the most broadly distributed bird species. We screened eight microsatellite loci in 316 individuals from 16 locations in the native and introduced ranges. Significant population structure occurred between native than introduced house sparrows. Introduced house sparrows were distinguished into one North American group and a highly differentiated Kenyan group. Genetic differentiation estimates identified a high magnitude of differentiation between Kenya and all other populations, but demonstrated that European and North American samples were differentiated too. Our results support previous claims that introduced North American populations likely had few source populations, and indicate house sparrows established populations after introduction. Genetic diversity also differed among native, introduced North American, and Kenyan populations with Kenyan birds being least diverse. In some cases, house sparrow populations appeared to maintain or recover genetic diversity relatively rapidly after range expansion (<50 years; Mexico and Panama), but in others (Kenya) the effect of introduction persisted over the same period. In both native and introduced populations, genetic diversity exhibited large-scale geographic patterns, increasing towards the equator. Such patterns of genetic diversity are concordant with two previously described models of genetic diversity, the latitudinal model and the species diversity model.


In-depth characterization of the cerebrospinal fluid (CSF) proteome displayed through the CSF proteome resource (CSF-PR).
In this study, the human cerebrospinal fluid (CSF) proteome was mapped using three different strategies prior to Orbitrap LC-MS/MS analysis: SDS-PAGE and mixed mode reversed phase-anion exchange for mapping the global CSF proteome, and hydrazide-based glycopeptide capture for mapping glycopeptides. A maximal protein set of 3081 proteins (28,811 peptide sequences) was identified, of which 520 were identified as glycoproteins from the glycopeptide enrichment strategy, including 1121 glycopeptides and their glycosylation sites. To our knowledge, this is the largest number of identified proteins and glycopeptides reported for CSF, including 417 glycosylation sites not previously reported. From parallel plasma samples, we identified 1050 proteins (9739 peptide sequences). An overlap of 877 proteins was found between the two body fluids, whereas 2204 proteins were identified only in CSF and 173 only in plasma. All mapping results are freely available via the new CSF Proteome Resource (http://probe.uib.no/csf-pr), which can be used to navigate the CSF proteome and help guide the selection of signature peptides in targeted quantitative proteomics.


Identification of a small molecule splicing inhibitor targeting UHM domains.
Splicing factor mutations are frequent in myeloid neoplasms, blood cancers, and solid tumors. Cancer cells harboring these mutations present a particular vulnerability to drugs that target splicing factors such as SF3b155 or CAPERα. Still, the arsenal of chemical probes that target the spliceosome is very limited. U2AF homology motifs (UHMs) are common protein interaction domains among splicing factors. They present a hydrophobic pocket ideally suited to anchor small molecules with the aim to inhibit protein-protein interaction. Here, we combined a virtual screening of a small molecules database and an in vitro competition assay and identified a small molecule, we named UHMCP1 that prevents the SF3b155/U2AF65 interaction. NMR analyses and molecular dynamics simulations confirmed the binding of this molecule in the hydrophobic pocket of the U2AF65 UHM domain. We further provide evidence that UHMCP1 impacts RNA splicing and cell viability and is therefore an interesting novel compound targeting an UHM domain with potential anticancer properties.


The self-organization of speech sounds.
The speech code is a vehicle of language: it defines a set of forms used by a community to carry information. Such a code is necessary to support the linguistic interactions that allow humans to communicate. How then may a speech code be formed prior to the existence of linguistic interactions? Moreover, the human speech code is discrete and compositional, shared by all the individuals of a community but different across communities, and phoneme inventories are characterized by statistical regularities. How can a speech code with these properties form? We try to approach these questions in the paper, using the "methodology of the artificial". We build a society of artificial agents, and detail a mechanism that shows the formation of a discrete speech code without pre-supposing the existence of linguistic capacities or of coordinated interactions. The mechanism is based on a low-level model of sensory-motor interactions. We show that the integration of certain very simple and non-language-specific neural devices leads to the formation of a speech code that has properties similar to the human speech code. This result relies on the self-organizing properties of a generic coupling between perception and production within agents, and on the interactions between agents. The artificial system helps us to develop better intuitions on how speech might have appeared, by showing how self-organization might have helped natural selection to find speech.


Enhanced bedside mortality prediction combining point-of-care lactate and the quick Sequential Organ Failure Assessment (qSOFA) score in patients hospitalised with suspected infection in southeast Asia: a cohort study.
Simple, bedside prediction of infection-related mortality in low-resource settings is crucial for triage and resource-utilisation decisions. We aimed to evaluate mortality prediction by combining point-of-care venous lactate with the quick Sequential Organ Failure Assessment (qSOFA) score in adult patients admitted to hospital with suspected infection in southeast Asia. We performed a cohort study by prospectively enrolling patients aged 18 years or older who had been admitted to hospital within the previous 24 h for suspected infection (with at least three documented systemic manifestations of infection according to the 2012 Surviving Sepsis Campaign) at Sunpasitthiprasong Hospital in Ubon Ratchathani, Thailand (derivation cohort). Venous lactate concentration was determined by a point-of-care device and multiple scores were developed. We then evaluated candidate 28-day mortality prediction models combining qSOFA and the lactate scores. A final model was compared with the qSOFA score, a lactate score, and a modified Sequential Organ Failure Assessment (SOFA) score for mortality discrimination using the area under the receiver operating characteristic curve (AUROC). Mortality discrimination of the qSOFA-lactate score was then verified in an external, prospectively enrolled, multinational cohort in southeast Asia. Between March 1, 2013, and Jan 26, 2017, 5001 patients were enrolled in the derivation cohort; 4980 had point-of-care lactate data available and were eligible for analysis, and 816 died within 28 days of enrolment. The discrimination for 28-day mortality prediction of a qSOFA-lactate score combining the qSOFA score and a lactate score was superior to that of the qSOFA score alone (AUROC 0·78 [95% CI 0·76-0·80] vs 0·68 [0·67-0·70]; p<0·0001) and similar to a modified SOFA score (0·77 [0·75-0·78]; p=0·088). A lactate score alone had superior discrimination compared with the qSOFA score (AUROC 0·76 [95% CI 0·74-0·78]; p<0·0001). 815 patients were enrolled in the external validation cohort and 792 had point-of-care lactate data and were included in the analysis; the qSOFA-lactate score (AUROC 0·77 [95% CI 0·73-0·82]) showed significantly improved 28-day mortality discrimination compared with the qSOFA score alone (0·69 [0·63-0·74]; p<0·0001). In southeast Asia, rapid, bedside assessments based on point-of-care lactate concentration combined with the qSOFA score can identify patients at risk of sepsis-related mortality with greater accuracy than the qSOFA score alone, and with similar accuracy to a modified SOFA score. National Institutes of Health, Wellcome Trust.


Photovoice: A Research Method and Intervention to Engage Older Adults.
The purpose of the current article is to describe the use of photovoice with individuals from vulnerable population groups. Ten African American men and women ages 66 to 72 with heart failure from three different low income public housing facilities were recruited for participation in a qualitative photovoice project. Participants were given 5 weeks to take photographs of images that represented facilitators of and barriers to engaging in self-care behaviors. Each week, participants met as a group to discuss the photographs and their meanings to other participants. The photovoice method was empowering to participants, easy to use, and shown to be appropriate within African American older adults with heart failure. The photovoice method assisted in providing the opportunity for this vulnerable population to share their personal beliefs and perspectives. Use of this method assisted in identification of themes that represented facilitators of and barriers to engaging in self-care and was effective in meeting the specific aims of the research project. Findings from the current study support photovoice as a valuable method to use with vulnerable individuals with chronic conditions. [Journal of Gerontological Nursing, 44(7), 43-49.].


Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice.
DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.


Association of family income supplements in adolescence with development of psychiatric and substance use disorders in adulthood among an American Indian population.
In a natural experiment in which some families received income supplements, prevalence of adolescent behavioral symptoms decreased significantly. These adolescents are now young adults. To examine the effects of income supplements in adolescence and adulthood on the prevalence of adult psychiatric disorders. Quasi-experimental, longitudinal. A representative sample of children aged 9, 11, or 13 years in 1993 (349 [25%] of whom are American Indian) were assessed for psychiatric and substance use disorders through age 21 years (1993-2006). Of the 1420 who participated in 1993, 1185 were interviewed as adults. From 1996, when a casino opened on the Indian reservation, every American Indian but no non-Indians received an annual income supplement that increased from $500 to around $9000. Prevalence of adult psychiatric disorders and substance use disorders based on the Diagnostic and Statistical Manual of Mental Disorders in 3 age cohorts, adjusted for age, sex, length of time in the family home, and number of Indian parents. As adults, significantly fewer Indians than non-Indians had a psychiatric disorder (106 Indians [weighted 30.2%] vs 337 non-Indians [weighted 36.0%]; odds ratio [OR], 0.46; 95% confidence interval [CI], 0.30-0.72; P = .001), particularly alcohol and cannabis abuse, dependence, or both. The youngest age-cohort of Indian youth had the longest exposure to the family income. Interactions between race/ethnicity and age cohort were significant. Planned comparisons showed that fewer of the youngest Indian age-cohort had any psychiatric disorder (31.4%) than the Indian middle cohort (41.7%; OR, 0.43; 95% CI, 0.24-0.78; P = .005) or oldest cohort (41.3%; OR, 0.69; 95% CI, 0.51-0.94; P = .01) or the youngest non-Indian cohort (37.1%; OR, 0.66; 95% CI, 0.48-0.90; P = .008). Study hypotheses were not upheld for nicotine or other drugs, or emotional or behavioral disorders. The income supplement received in adulthood had no impact on adult psychopathology. Lower prevalence of psychopathology in American Indian youth following a family income supplement, compared with the nonexposed, non-Indian population, persisted into adulthood.


Trends, rhythms, and aberrations in global climate 65 Ma to present.
Since 65 million years ago (Ma), Earth's climate has undergone a significant and complex evolution, the finer details of which are now coming to light through investigations of deep-sea sediment cores. This evolution includes gradual trends of warming and cooling driven by tectonic processes on time scales of 10(5) to 10(7) years, rhythmic or periodic cycles driven by orbital processes with 10(4)- to 10(6)-year cyclicity, and rare rapid aberrant shifts and extreme climate transients with durations of 10(3) to 10(5) years. Here, recent progress in defining the evolution of global climate over the Cenozoic Era is reviewed. We focus primarily on the periodic and anomalous components of variability over the early portion of this era, as constrained by the latest generation of deep-sea isotope records. We also consider how this improved perspective has led to the recognition of previously unforeseen mechanisms for altering climate.