Measurements and simulations of microscopic damage to DNA in water by 30 keV electrons: A general approach applicable to other radiation sources and biological targets.
The determination of the microscopic dose-damage relationship for DNA in an aqueous environment is of a fundamental interest for dosimetry and applications in radiation therapy and protection. We combine geant4 particle-scattering simulations in water with calculations concerning the movement of biomolecules to obtain the energy deposit in the biologically relevant nanoscopic volume. We juxtaposition these results to the experimentally determined damage to obtain the dose-damage relationship at a molecular level. This approach is tested for an experimentally challenging system concerning the direct irradiation of plasmid DNA (pUC19) in water with electrons as primary particles. Here a microscopic target model for the plasmid DNA based on the relation of lineal energy and radiation quality is used to calculate the effective target volume. It was found that on average fewer than two ionizations within a 7.5-nm radius around the sugar-phosphate backbone are sufficient to cause a single strand break, with a corresponding median lethal energy deposit being E_{1/2}=6±4 eV. The presented method is applicable for ionizing radiation (e.g., γ rays, x rays, and electrons) and a variety of targets, such as DNA, proteins, or cells.


A profile of patients treated at a national leprosy outpatient referral clinic in Rio de Janeiro, Brazil, 1986-2007.
To analyze a profile of patients treated at a national leprosy outpatient referral clinic in metropolitan Rio de Janeiro, Brazil, over a period of more than two decades, and the subgroup of nationally registered leprosy cases from the same residential area, as well as all registered cases statewide. An observational, descriptive analysis was carried out for patients treated from 1986 to 2007 at the Souza Araújo Outpatient Clinic (Ambulatório Souza Araújo, ASA), a national referral center for the diagnosis and treatment of leprosy at the Oswaldo Cruz Foundation (Fiocruz) that serves clients from the city of Rio de Janeiro and other municipalities in the metropolitan area of Rio de Janeiro State. Demographic and clinical data for the subgroup of leprosy cases registered with Brazil's National Disease Notification System (Sistema Nacional de Informação de Agravos de Notificação, SINAN) between 2001 and 2007 and residing in the same municipalities as the ASA patients, and for all registered cases statewide, were also analyzed. Among the ASA patients, there was a decrease in average family income (from 3.9 to 2.7 times the minimum salary between the periods 1998-2002 and 2003-2007); the proportion of multibacillary (MB) patients (from 52.7% to 46.9%); and the proportion of patients younger than 15 years old (from 12.8% to 8.7%). Among the MB patients, the average initial and final bacilloscopic indices were significantly higher in 2003-2007. Compared with the SINAN cases, more ASA cases involved disability and were younger than 15 years old. Patients living with leprosy in the metropolitan area of the state of Rio de Janeiro belong to the most deprived social strata and have not benefited from the overall improvement in socioeconomic conditions in Brazil.


Challenges and future directions for representations of functional brain organization.
A key principle of brain organization is the functional integration of brain regions into interconnected networks. Functional MRI scans acquired at rest offer insights into functional integration via patterns of coherent fluctuations in spontaneous activity, known as functional connectivity. These patterns have been studied intensively and have been linked to cognition and disease. However, the field is fractionated. Diverging analysis approaches have segregated the community into research silos, limiting the replication and clinical translation of findings. A primary source of this fractionation is the diversity of approaches used to reduce complex brain data into a lower-dimensional set of features for analysis and interpretation, which we refer to as brain representations. In this Primer, we provide an overview of different brain representations, lay out the challenges that have led to the fractionation of the field and that continue to form obstacles for convergence, and propose concrete guidelines to unite the field.


Urban growth, climate change, and freshwater availability.
Nearly 3 billion additional urban dwellers are forecasted by 2050, an unprecedented wave of urban growth. While cities struggle to provide water to these new residents, they will also face equally unprecedented hydrologic changes due to global climate change. Here we use a detailed hydrologic model, demographic projections, and climate change scenarios to estimate per-capita water availability for major cities in the developing world, where urban growth is the fastest. We estimate the amount of water physically available near cities and do not account for problems with adequate water delivery or quality. Modeled results show that currently 150 million people live in cities with perennial water shortage, defined as having less than 100 L per person per day of sustainable surface and groundwater flow within their urban extent. By 2050, demographic growth will increase this figure to almost 1 billion people. Climate change will cause water shortage for an additional 100 million urbanites. Freshwater ecosystems in river basins with large populations of urbanites with insufficient water will likely experience flows insufficient to maintain ecological process. Freshwater fish populations will likely be impacted, an issue of special importance in regions such as India's Western Ghats, where there is both rapid urbanization and high levels of fish endemism. Cities in certain regions will struggle to find enough water for the needs of their residents and will need significant investment if they are to secure adequate water supplies and safeguard functioning freshwater ecosystems for future generations.


Myelin water imaging reflects clinical variability in multiple sclerosis.
Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p=0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p<0.001) and patients (59%, p<0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p=0.008, R=0.58). Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS.


Investigation of nanosized crystalline form to improve the oral bioavailability of poorly water soluble cilostazol.
The aim of this study was to develop cilostazol (CLT) nanocrystals intended to improve its dissolution rate and enhance its bioavailability. In this study, CLT nanosuspension was prepared by the anti-solvent and high-pressure homogenization method. The effects of the production parameters, such as the stabilizer concentration, pressure and number of cycles, were investigated. Characterization of the product was performed by scanning electron microscopy (SEM), Nitrogen adsorption, differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), X-ray Photoelectron Spectroscopy (XPS), particle size analysis and dissolution testing. Additionally, the comparison studies of oral bioavailability in beagle dogs of three type tables were performed. The images of SEM showed a spherical smooth CLT powder, and Nitrogen adsorption test revealed spray dried powder were porous with high BET surface area compared with that of raw CLT. DSC and XRPD results demonstrated that the combination of preferred polymorph B and C of CLT were prepared successfully, the saturation solubility of the nanosized crystalline powder is about 5 fold greater than that of raw CLT, and the dissolution rate was enhanced 4 fold than that of raw CLT. The Cmax and AUC0-48h of CLT nanosized crystalline tablets were 2.1 fold and 1.9 fold, and 3.0 fold and 2.3 fold compared with those of the nanosized tablets and commercial tablets, respectively. The anti-solvent-high-pressure homogenization technique was employed successfully to produce cilostazol nanosuspensions. The bioavailability of CLT tablets prepared using spray dried nanosized crystalline powder after oral administration to dogs was markedly increased compared with that produced by nanosized tablets and commercial tablets, because of its greater dissolution rate owing to its transition of the crystalline state to form C and form B, reduced particle size and porous structure with increased surface area.


Effects of MACPF/CDC proteins on lipid membranes.
Recent work on the MACPF/CDC superfamily of pore-forming proteins has focused on the structural analysis of monomers and pore-forming oligomeric complexes. We set the family of proteins in context and highlight aspects of their function which the direct and exclusive equation of oligomers with pores fails to explain. Starting with a description of the distribution of MACPF/CDC proteins across the domains of life, we proceed to show how their evolutionary relationships can be understood on the basis of their structural homology and re-evaluate models for pore formation by perforin, in particular. We furthermore highlight data showing the role of incomplete oligomeric rings (arcs) in pore formation and how this can explain small pores generated by oligomers of proteins belonging to the family. We set this in the context of cell biological and biophysical data on the proteins' function and discuss how this helps in the development of an understanding of how they act in processes such as apicomplexan parasites gliding through cells and exiting from cells.


Molecular Detection of Antibiotic-Resistant Genes in Pseudomonas aeruginosa from Nonclinical Environment: Public Health Implications in Mthatha, Eastern Cape Province, South Africa.
Evaluation of resistant profiles and detection of antimicrobial-resistant genes of bacterial pathogens in the nonclinical milieu is imperative to assess the probable risk of dissemination of resistant genes in the environment. This paper sought to identify antibiotic-resistant genes in Pseudomonas aeruginosa from nonclinical sources in Mthatha, Eastern Cape, and evaluate its public health implications. Samples collected from abattoir wastewater and aquatic environment were processed by membrane filtration and cultured on CHROMagarTM Pseudomonas medium. Species identification was performed by autoSCAN-4 (Dade Behring Inc., IL). Molecular characterization of the isolates was confirmed using real-time polymerase chain reaction (rPCR) and selected isolates were further screened for the possibility of harboring antimicrobial resistance genes. Fifty-one Pseudomonas species were recovered from abattoir wastewater and surface water samples, out of which thirty-six strains were Pseudomonas aeruginosa (70.6%). The P. aeruginosa isolates demonstrated resistance to aztreonam (86.1%), ceftazidime (63.9%), piperacillin (58.3%), cefepime (55.6%), imipenem (50%), piperacillin/tazobactam (47.2%), meropenem (41.7%), and levofloxacin (30.6%). Twenty out of thirty-six P. aeruginosa displayed multidrug resistance profiles and were classified as multidrug-resistant (MDR) (55.6%). Most of the bacterial isolates exhibited a high Multiple Antibiotic Resistance (MAR) Index ranging from 0.08 to 0.69 with a mean MAR index of 0.38. In the rPCR analysis of fifteen P. aeruginosa isolates, 14 isolates (93.3%) were detected harboring bla SHV, six isolates (40%) harbored bla TEM, and three isolates (20%) harbored bla CTX-M, being the least occurring ESBL. Results of the current study revealed that P. aeruginosa isolates recovered from nonclinical milieu are resistant to frontline clinically relevant antipseudomonal drugs. This is concerning as it poses a risk to the environment and constitutes a public health threat. Given the public health relevance, the paper recommends monitoring of multidrug-resistant pathogens in effluent environments.


Role of pacemaking current in cardiac nodes: insights from a comparative study of sinoatrial node and atrioventricular node.
Cardiac pacemaking in the sinoatrial (SA) node and atrioventricular (AV) node is generated by an interplay of many ionic currents, one of which is the funny pacemaker current (If). To understand the functional role of If in two different pacemakers, comparative studies of spontaneous activity and expression of the HCN channel in mouse SA node and AV node were performed. The intrinsic cycle length (CL) is 179+/-2.7 ms (n=5) in SA node and 258+/-18.7 ms (n=5) in AV node. Blocking of If current by 1 micromol/L ZD7288 increased the CL to 258+/-18.7 ms (n=5) and 447+/-92.4 ms (n=5) in SA node and AV node, respectively. However, the major HCN channel, HCN4 expressed at low level in the AV node compared to the SA node. To clarify the discrepancy between the functional importance of If and expression level of HCN4 channel, a SA node cell model was used. Increasing the If conductance resulted in decreasing in the CL in the model, which explains the high pacemaking rate and high expression of HCN channel in the SA node. Resistance to the blocking of If in the SA node might result from compensating effects from other currents (especially voltage sensitive currents) involved in pacemaking. The computer simulation shows that the difference in the intrinsic CL could explain the difference in response to If blocking in these two cardiac nodes.


Sweat, Skepticism, and Uncharted Territory: A Qualitative Study of Opinions on Data Sharing Among Public Health Researchers and Research Participants in Mumbai, India.
Efforts to internalize data sharing in research practice have been driven largely by developing international norms that have not incorporated opinions from researchers in low- and middle-income countries. We sought to identify the issues around ethical data sharing in the context of research involving women and children in urban India. We interviewed researchers, managers, and research participants associated with a Mumbai non-governmental organization, as well as researchers from other organizations and members of ethics committees. We conducted 22 individual semi-structured interviews and involved 44 research participants in focus group discussions. We used framework analysis to examine ideas about data and data sharing in general; its potential benefits or harms, barriers, obligations, and governance; and the requirements for consent. Both researchers and participants were generally in favor of data sharing, although limited experience amplified their reservations. We identified three themes: concerns that the work of data producers may not receive appropriate acknowledgment, skepticism about the process of sharing, and the fact that the terrain of data sharing was essentially uncharted and confusing. To increase data sharing in India, we need to provide guidelines, protocols, and examples of good practice in terms of consent, data preparation, screening of applications, and what individuals and organizations can expect in terms of validation, acknowledgment, and authorship.


An interactive application for malaria elimination transmission and costing in the Asia-Pacific.
Leaders in the Asia-Pacific have endorsed an ambitious target to eliminate malaria in the region by 2030. The emergence and spread of artemisinin drug resistance in the Greater Mekong Subregion makes elimination urgent and strategic for the global goal of malaria eradication. Mathematical modelling is a useful tool for assessing and comparing different elimination strategies and scenarios to inform policymakers. Mathematical models are especially relevant in this context because of the wide heterogeneity of regional, country and local settings, which means that different strategies are needed to eliminate malaria. However, models and their predictions can be seen as highly technical, limiting their use for decision making. Simplified applications of models are needed to allow policy makers to benefit from these valuable tools. This paper describes a method for communicating complex model results with a user-friendly and intuitive framework. Using open-source technologies, we designed and developed an interactive application to disseminate the modelling results for malaria elimination. The design was iteratively improved while the application was being piloted and extensively tested by a diverse range of researchers and decision makers. This application allows several target audiences to explore, navigate and visualise complex datasets and models generated in the context of malaria elimination. It allows widespread access, use of and interpretation of models, generated at great effort and expense as well as enabling them to remain relevant for a longer period of time. It has long been acknowledged that scientific results need to be repackaged for larger audiences. We demonstrate that modellers can include applications as part of the dissemination strategy of their findings. We highlight that there is a need for additional research in order to provide guidelines and direction for designing and developing effective applications for disseminating models.


Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans.
Central sensitization (CS) refers to an increase in the excitability of spinal dorsal horn neurons that results from, and far outlasts the initiating nociceptive input. Here, functional magnetic resonance imaging was used to examine whether supraspinal activity might contribute to the maintenance of CS in humans. A crossover parametric design was used to distinguish and control for brain activity that is related to the consequence of increased pain experienced during CS. When the intensity of pain during CS and normal states were matched, only activity within the brainstem, including the mesencephalic pontine reticular formation, and the anterior thalami remained increased during CS. Further analyses revealed that activity in the isolated brainstem area correlated positively with the force of noxious stimulation only during CS, whereas activity in the isolated thalamic area was not modulated parametrically in either CS or normal states. Additionally, the mean activity in the isolated brainstem area was increased only during CS, whereas the mean activity in the isolated thalamic area was increased in both states, albeit less so in the normal state. Together, these findings suggest a specific role of the brainstem for the maintenance of CS in humans. Regarding brain areas related to the consequence of increased pain perception during CS, we found that only cortical activity, mainly in the primary somatosensory area, was significantly correlated with intensity of pain that was attributable to both the force of noxious stimulation used and state in which noxious stimulation was applied.


Conditions for the generation of beta oscillations in the subthalamic nucleus-globus pallidus network.
The advance of Parkinson's disease is associated with the existence of abnormal oscillations within the basal ganglia with frequencies in the beta band (13-30 Hz). While the origin of these oscillations remains unknown, there is some evidence suggesting that oscillations observed in the basal ganglia arise due to interactions of two nuclei: the subthalamic nucleus (STN) and the globus pallidus pars externa (GPe). To investigate this hypothesis, we develop a computational model of the STN-GPe network based upon anatomical and electrophysiological studies. Significantly, our study shows that for certain parameter regimes, the model intrinsically oscillates in the beta range. Through an analytical study of the model, we identify a simple set of necessary conditions on model parameters that guarantees the existence of beta oscillations. These conditions for generation of oscillations are described by a set of simple inequalities and can be summarized as follows: (1) The excitatory connections from STN to GPe and the inhibitory connections from GPe to STN need to be sufficiently strong. (2) The time required by neurons to react to their inputs needs to be short relative to synaptic transmission delays. (3) The excitatory input from the cortex to STN needs to be high relative to the inhibition from striatum to GPe. We confirmed the validity of these conditions via numerical simulation. These conditions describe changes in parameters that are consistent with those expected as a result of the development of Parkinson's disease, and predict manipulations that could inhibit the pathological oscillations.


Differential modulation of word recognition by semantic and spatial orienting of attention.
In the present study, we investigated the ability to orient attention to abstract associative features of complex stimuli, more specifically, to the semantic categories of visual word stimuli. We compared the behavioral and electrophysiological effects of semantic orienting with those elicited by spatial orienting to word stimuli. Two parallel, cued lexical-decision tasks, with semantic- or spatial-orienting cues, were used. Results showed that both semantic and spatial orienting facilitated behavioral performance. The event-related potential analysis revealed different and non-overlapping patterns of modulation of word processing by semantic and spatial orienting. Modulation by semantic orienting started later, affecting only the potentials linked to conceptual or semantic processing (N300 and N400). The pattern of N300/N400 modulation in the semantic-orienting condition was similar to that observed in semantic-priming tasks, and was compatible with the operation of controlled semantic processes. Spatial orienting significantly enhanced the amplitude of the early visual potential P1 as well as the language-related N400 potential. These findings showed that the similar end-result of behavioral facilitation by semantic and spatial orienting is achieved through largely distinct mechanisms acting upon separate levels of stimulus analysis.


Item-specific encoding produces an additional benefit of directed forgetting: evidence from intrusion errors.
List-method directed forgetting involves encoding 2 lists, between which half of the participants are told to forget List 1. When participants are free to study however they want, directed forgetting impairs List 1 recall and enhances List 2 recall in the forget group compared with a control remember group. In a large-scale experiment, the current work demonstrated that when item-specific encoding instructions were enforced during learning, directed forgetting impaired List 1 recall, but it did not enhance List 2 recall. This pattern was found regardless of whether encoding was incidental or intentional. Whenever directed forgetting did not enhance List 2 recall, it nevertheless reduced cross-list intrusions. These results indicate that directed forgetting can help differentiate memories from one another, thereby reducing intrusions from irrelevant competing memories.


Past rewards capture spatial attention and action choices.
The desire to increase rewards and minimize punishing events is a powerful driver in behaviour. Here, we assess how the value of a location affects subsequent deployment of goal-directed attention as well as involuntary capture of attention on a trial-to-trial basis. By tracking eye position, we investigated whether the ability of an irrelevant, salient visual stimulus to capture gaze (stimulus-driven attention) is modulated by that location's previous value. We found that distractors draw attention to them significantly more if they appear at a location previously associated with a reward, even when gazing towards them now leads to punishments. Within the same experiment, it was possible to demonstrate that a location associated with a reward can also bias subsequent goal-directed attention (indexed by action choices) towards it. Moreover, individuals who were vulnerable to being distracted by previous reward history, as indexed by oculomotor capture, were also more likely to direct their actions to those locations when they had a free choice. Even when the number of initial responses was made to be rewarded and punished stimuli were equalized, the effects of previous reward history on both distractibility and action choices remained. Finally, a covert attention task requiring button-press responses rather than overt gaze shifts demonstrated the same pattern of findings. Thus, past rewards can act to modulate both subsequent stimulus-driven as well as goal-directed attention. These findings reveal that there can be surprising short-term costs of using reward cues to regulate behaviour. They show that current valence information, if maintained inappropriately, can have negative subsequent effects, with attention and action choices being vulnerable to capture and bias, mechanisms that are of potential importance in understanding distractibility and abnormal action choices.


Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells.
The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change.


Pandemic influenza A (H1N1) 2009 vaccination in children: a UK perspective.
Pandemic H1N1 influenza infection was common in the UK in 2009 and children were particularly vulnerable. Most cases were mild or subclinical, but there was significant mortality, predominantly in those with pre-existing disease. Despite the rapid development of monovalent pandemic vaccines, and the fast-tracked approval process, these products were not available for large-scale use until the end of the second wave of infection. Vaccine uptake was relatively low, both among children and health-care workers. The monovalent pandemic vaccines and the 2010/2011 trivalent seasonal influenza vaccines were immunogenic and effective, and they probably reduced the impact of the third wave of infection. Vaccines containing novel adjuvants enabled antigen sparing, but safety concerns could limit the future use of these adjuvanted influenza vaccines in children. Public perceptions that the threat of the pandemic was exaggerated by the authorities, and concerns about vaccine safety, might prompt an inadequate response to the next influenza pandemic, potentially compromising public health.


No association of multiple type 2 diabetes loci with type 1 diabetes.
We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; p (combined) = 1.0 x 10(-4)). No SNPs showed evidence of interaction with any covariate (p > 0.05). We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.


Mechanisms underlying inflammation in neurodegeneration.
Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfunction and death. Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease.


Starting small and early for research funding.
Many new nursing leaders assuming deanships or assistant or interim deanships have limited education, experience, or background to prepare them for the job. To assist new deans and those aspiring to be deans, the authors of this department, 2 deans, offer survival tips based on their personal experiences and insights. They address common issues, challenges, and opportunities that face academic executive teams, such as negotiating an executive contract, obtaining faculty lines, building effective work teams, managing difficult employees, and creating nimble organizational structure to respond to changing consumer, healthcare delivery, and community needs. The authors welcome counterpoint discussions with readers.


N-acetyltransferase 2 and bladder cancer: an overview and consideration of the evidence for gene-environment interaction.
Genetic polymorphism of the carcinogen metabolizing enzyme N-acetyl transferase 2 (NAT2) may influence susceptibility to bladder cancers related to smoking or to occupational exposure to arylamine carcinogens. This article reviews the results of 21 published case-control studies of NAT2 polymorphism and bladder-cancer risk, with a total of 2700 cases and 3426 controls. The published evidence suggests that NAT2 slow acetylator phenotype or genotype may be associated with a small increase in bladder cancer risk. However, given the possibility of selective publication of results from studies that found an excess risk, the current evidence is not sufficient to conclude that there is a real increase in risk. Only five of the 21 studies reported results separately for the effect of NAT2 on bladder cancer risk in smokers and non-smokers. Although the results suggest that the effect may be greater in smokers than in non-smokers, the possibility of publication bias makes these results difficult to interpret. There was insufficient evidence to assess the joint effect of NAT2 and occupational exposure to arylamines on bladder cancer risk. Even if estimates of the effect of NAT2 from published data are correct, studies with around 3000-5000 cases will be needed to confirm them.


Geographical and climatic limits of needle types of one- and two-needled pinyon pines.
AIM: The geographical extent and climatic tolerances of one- and two-needled pinyon pines (Pinus subsect. Cembroides) are the focus of questions in taxonomy, palaeoclimatology and modelling of future distributions. The identification of these pines, traditionally classified by one- versus two-needled fascicles, is complicated by populations with both one- and two-needled fascicles on the same tree, and the description of two more recently described one-needled varieties: the fallax-type and californiarum-type. Because previous studies have suggested correlations between needle anatomy and climate, including anatomical plasticity reflecting annual precipitation, we approached this study at the level of the anatomy of individual pine needles rather than species. LOCATION: Western North America. METHODS: We synthesized available and new data from field and herbarium collections of needles to compile maps of their current distributions across western North America. Annual frequencies of needle types were compared with local precipitation histories for some stands. Historical North American climates were modelled on a c. 1-km grid using monthly temperature and precipitation values. A geospatial model (ClimLim), which analyses the effect of climate-modulated physiological and ecosystem processes, was used to rank the importance of seasonal climate variables in limiting the distributions of anatomical needle types. RESULTS: The pinyon needles were classified into four distinct types based upon the number of needles per fascicle, needle thickness and the number of stomatal rows and resin canals. The individual needles fit well into four categories of needle types, whereas some trees exhibit a mixture of two needle types. Trees from central Arizona containing a mixture of Pinus edulis and fallax-type needles increased their percentage of fallax-type needles following dry years. All four needle types occupy broader geographical regions with distinctive precipitation regimes. Pinus monophylla and californiarum-type needles occur in regions with high winter precipitation. Pinus edulis and fallax-type needles are found in regions with high monsoon precipitation. Areas supporting californiarum-type and fallax-type needle distributions are additionally characterized by a more extreme May-June drought. MAIN CONCLUSIONS: These pinyon needle types seem to reflect the amount and seasonality of precipitation. The single needle fascicle characterizing the fallax type may be an adaptation to early summer or periodic drought, while the single needle of Pinus monophylla may be an adaptation to summer-autumn drought. Although the needles fit into four distinct categories, the parent trees are sometimes less easily classified, especially near their ancestral Pleistocene ranges in the Mojave and northern Sonoran deserts. The abundance of trees with both one- and two-needled fascicles in the zones between P. monophylla, P. edulis and fallax-type populations suggest that needle fascicle number is an unreliable characteristic for species classification. Disregarding needle fascicle number, the fallax-type needles are nearly identical to P. edulis, supporting Little's (1968) initial classification of these trees as P. edulis var. fallax, while the californiarum-type needles have a distinctive morphology supporting Bailey's (1987) classification of this tree as Pinus californiarum.


Mental health care for irregular migrants in Europe: barriers and how they are overcome.
Irregular migrants (IMs) are exposed to a wide range of risk factors for developing mental health problems. However, little is known about whether and how they receive mental health care across European countries. The aims of this study were (1) to identify barriers to mental health care for IMs, and (2) to explore ways by which these barriers are overcome in practice. Data from semi-structured interviews with 25 experts in the field of mental health care for IMs in the capital cities of 14 European countries were analysed using thematic analysis. Experts reported a range of barriers to mental health care for IMs. These include the absence of legal entitlements to health care in some countries or a lack of awareness of such entitlements, administrative obstacles, a shortage of culturally sensitive care, the complexity of the social needs of IMs, and their fear of being reported and deported. These barriers can be partly overcome by networks of committed professionals and supportive services. NGOs have become important initial points of contact for IMs, providing mental health care themselves or referring IMs to other suitable services. However, these services are often confronted with the ethical dilemma of either acting according to the legislation and institutional rules or providing care for humanitarian reasons, which involves the risk of acting illegally and providing care without authorisation. Even in countries where access to health care is legally possible for IMs, various other barriers remain. Some of these are common to all migrants, whilst others are specific for IMs. Attempts at improving mental health care for IMs should consider barriers beyond legal entitlement, including communicating information about entitlement to mental health care professionals and patients, providing culturally sensitive care and ensuring sufficient resources.


Biochemical characterization of TASSELSEED 2, an essential plant short-chain dehydrogenase/reductase with broad spectrum activities.
The development of unisexual flowers in maize and other plants proceeds through selective elimination of floral organs in an initially bisexual floral meristem. The essential character of the tasselseed 2 gene (TS2) in this cell-death pathway has been established previously. Molecular cloning of TS2 reveals membership to the evolutionarily conserved superfamily of short-chain dehydrogenases/reductases, but its substrate specificity remained unknown. Recombinant TS2 protein was produced in Escherichia coli, and purified to apparent homogeneity. Analytical ultracentrifugation and gel filtration experiments show that TS2 is a tetrameric enzyme. Thermal denaturation followed by circular dichroism spectroscopy reveals that TS2 binds NAD(H) and NAD(P)(H). Substrate screening demonstrates that TS2 converts steroids with specificities found at positions 3 and 17, and several dicarbonyl and quinone compounds, thus establishing TS2 as a plant 3beta/17beta-hydroxysteroid dehydrogenase and carbonyl/quinone reductase. Taken together, the genetic data and the substrate specificities determined suggest that TS2 converts specific plant compounds and acts as a prereceptor control mechanism, in a manner similar to that of mammalian hydroxysteroid dehydrogenases.


Human antimicrobial peptides LL-37 and human β-defensin-2 reduce viral replication in keratinocytes infected with varicella zoster virus.
There is mounting evidence that antimicrobial peptides have an important role in cutaneous defence, but the expression of these antimicrobial peptides in atopic eczema (AE) is still unclear. There are several families of antimicrobial peptides, including cathelicidins and human β-defensins. Patients with AE are more susceptible to severe cutaneous viral infections, including varicella zoster virus (VZV). To characterize the functional activity of the antimicrobial peptides LL-37 (human cathelicidin) and human β-defensin (hBD)-2 keratinocytes were infected with VZV, in a skin-infection model. Flow-cytometry analysis was used to investigate LL-37 expression in normal human keratinocytes, and quantitative PCR was used to determine viral loads in infected HaCaT keratinocytes and B cells, with and without exogenous LL-37 and hBD-2. LL-37 expression was present in keratinocytes, and both exogenous LL-37 and hBD-2 significantly reduced VZV load in infected keratinocytes and B cells. Specific antibodies blocked the antiviral action exhibited by these antimicrobial peptides. Pre-incubation of VZV with LL-37, but not hBD-2, further reduced VZV load. Both LL-37 and hBD-2 have an antiviral effect on VZV replication in the keratinocyte HaCaT cell line and in B cells, but their mechanism of action is different. Evidence of the relationship between antimicrobial peptide expression and higher susceptibility to infections in AE skin is still emerging. Developing novel antiviral therapies based on antimicrobial peptides may provide improved treatment options for patients with AE.


Long-term memories bias sensitivity and target selection in complex scenes.
In everyday situations, we often rely on our memories to find what we are looking for in our cluttered environment. Recently, we developed a new experimental paradigm to investigate how long-term memory (LTM) can guide attention and showed how the pre-exposure to a complex scene in which a target location had been learned facilitated the detection of the transient appearance of the target at the remembered location [Summerfield, J. J., Rao, A., Garside, N., & Nobre, A. C. Biasing perception by spatial long-term memory. The Journal of Neuroscience, 31, 14952-14960, 2011; Summerfield, J. J., Lepsien, J., Gitelman, D. R., Mesulam, M. M., & Nobre, A. C. Orienting attention based on long-term memory experience. Neuron, 49, 905-916, 2006]. This study extends these findings by investigating whether and how LTM can enhance perceptual sensitivity to identify targets occurring within their complex scene context. Behavioral measures showed superior perceptual sensitivity (d') for targets located in remembered spatial contexts. We used the N2pc ERP to test whether LTM modulated the process of selecting the target from its scene context. Surprisingly, in contrast to effects of visual spatial cues or implicit contextual cueing, LTM for target locations significantly attenuated the N2pc potential. We propose that the mechanism by which these explicitly available LTMs facilitate perceptual identification of targets may differ from mechanisms triggered by other types of top-down sources of information.


Crystal structure of the human cytosolic sialidase Neu2. Evidence for the dynamic nature of substrate recognition.
Gangliosides play key roles in cell differentiation, cell-cell interactions, and transmembrane signaling. Sialidases hydrolyze sialic acids to produce asialo compounds, which is the first step of degradation processes of glycoproteins and gangliosides. Sialidase involvement has been implicated in some lysosomal storage disorders such as sialidosis and galactosialidosis. Neu2 is a recently identified human cytosolic sialidase. Here we report the first high resolution x-ray structures of mammalian sialidase, human Neu2, in its apo form and in complex with an inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). The structure shows the canonical six-blade beta-propeller observed in viral and bacterial sialidases with its active site in a shallow crevice. In the complex structure, the inhibitor lies in the catalytic crevice surrounded by ten amino acids. In particular, the arginine triad, conserved among sialidases, aids in the proper positioning of the carboxylate group of DANA within the active site region. The tyrosine residue, Tyr(334), conserved among mammalian and bacterial sialidases as well as in viral neuraminidases, facilitates the enzymatic reaction by stabilizing a putative carbonium ion in the transition state. The loops containing Glu(111) and the catalytic aspartate Asp(46) are disordered in the apo form but upon binding of DANA become ordered to adopt two short alpha-helices to cover the inhibitor, illustrating the dynamic nature of substrate recognition. The N-acetyl and glycerol moieties of DANA are recognized by Neu2 residues not shared by bacterial sialidases and viral neuraminidases, which can be regarded as a key structural difference for potential drug design against bacteria, influenza, and other viruses.


Image Reconstruction Analysis for Positron Emission Tomography With Heterostructured Scintillators.
The concept of structure engineering has been proposed for exploring the next generation of radiation detectors with improved performance. A TOF-PET geometry with heterostructured scintillators with a pixel size of 3.0 × 3.1 × 15 mm3 was simulated using Monte Carlo. The heterostructures consisted of alternating layers of BGO as a dense material with high stopping power and plastic (EJ232) as a fast light emitter. The detector time resolution was calculated as a function of the deposited and shared energy in both materials on an event-by-event basis. While sensitivity was reduced to 32% for 100-μm thick plastic layers and 52% for 50 μm, the coincidence time resolution (CTR) distribution improved to 204 ± 49 and 220 ± 41 ps, respectively, compared to 276 ps that we considered for bulk BGO. The complex distribution of timing resolutions was accounted for in the reconstruction. We divided the events into three groups based on their CTR and modeled them with different Gaussian TOF kernels. On an NEMA IQ phantom, the heterostructures had better contrast recovery in early iterations. On the other hand, BGO achieved a better contrast-to-noise ratio (CNR) after the 15th iteration due to the higher sensitivity. The developed simulation and reconstruction methods constitute new tools for evaluating different detector designs with complex time responses.


Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?
This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.


[Suicide in the elderly from a gender perspective].
This study examines the relationship between suicide and aging from a gender perspective, examining the socially imposed boundaries of masculinity and femininity in the lives of elderly people who committed suicide. It is a qualitative study in which 50 psychosocial autopsies conducted with elderly relatives were selected from 10 cities in the North, South, Northeast and Midwest of Brazil. In this article we have identified situations of gender vulnerabilities in the lives of 13 people who committed suicide: 10 men and 3 women selected for their exemplary character. Two main categories were listed: the first refers to femininity including the "gender destiny" experienced by elderly women who commit suicide when they can no longer care for themselves or work. The second concerns the hegemonic masculinity in crisis, in which old men die after changing from the role of providers due to retirement or illness. It should be stressed that gender norms, codes of honor, power inequalities and stereotypes affect both women and men in terms of susceptibility to suicidal behavior.


Explanatory models concerning the effects of small-area characteristics on individual health.
Material and social living conditions at the small-area level are assumed to have an effect on individual health. We review existing explanatory models concerning the effects of small-area characteristics on health and describe the gaps future research should try to fill. Systematic literature search for, and analysis of, studies that propose an explanatory model of the relationship between small-area characteristics and health. Fourteen studies met our inclusion criteria. Using various theoretical approaches, almost all of the models are based on a three-tier structure linking social inequalities (posited at the macro-level), small-area characteristics (posited at the meso-level) and individual health (micro-level). No study explicitly defines the geographical borders of the small-area context. The health impact of the small-area characteristics is explained by specific pathways involving mediating factors (psychological, behavioural, biological). These pathways tend to be seen as uni-directional; often, causality is implied. They may be modified by individual factors. A number of issues need more attention in research on explanatory models concerning small-area effects on health. Among them are the (geographical) definition of the small-area context; the systematic description of pathways comprising small-area contextual as well as compositional factors; questions of direction of association and causality; and the integration of a time dimension.


Hepatitis B and C co-infection are independent predictors of progressive kidney disease in HIV-positive, antiretroviral-treated adults.
Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-positive individuals. Hepatitis C (HCV) co-infection has been associated with increased risk of CKD, but prior studies lack information on potential mechanisms. We evaluated the association between HCV or hepatitis B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR <60 mL/min/1.73 m(2) or 25% decline with a baseline <60). Generalized Estimating Equations were used to model the odds of progressive CKD. At baseline, 13.8% and 3.3% of participants were co-infected with HCV and HBV, respectively. Median eGFR was 111, and 3.7% developed progressive CKD. After adjustment, the odds of progressive CKD were increased in participants with HCV (OR 1.72, 95% CI 1.07-2.76) or HBV (OR 2.26, 95% CI 1.15-4.44). Participants with undetectable or low HCV-RNA had similar odds of progressive CKD as HCV seronegative participants, while participants with HCV-RNA >800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60-5.90). Interleukin-6, hyaluronic acid, and the FIB-4 hepatic fibrosis index were higher among participants who developed progressive CKD, but were no longer associated with progressive CKD after adjustment. Future studies should validate the relationship between HCV viremia and CKD. ClinicalTrials.gov NCT00027352; NCT00004978.


Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.


Structural and biophysical characterization of the EphB4*ephrinB2 protein-protein interaction and receptor specificity.
Increasing evidence implicates the interaction of the EphB4 receptor with its preferred ligand, ephrinB2, in pathological forms of angiogenesis and in tumorigenesis. To identify the molecular determinants of the unique specificity of EphB4 for ephrinB2, we determined the crystal structure of the ligand binding domain of EphB4 in complex with the extracellular domain of ephrinB2. This structural analysis suggested that one amino acid, Leu-95, plays a particularly important role in defining the structural features that confer the ligand selectivity of EphB4. Indeed, all other Eph receptors, which promiscuously bind many ephrins, have a conserved arginine at the position corresponding to Leu-95 of EphB4. We have also found that amino acid changes in the EphB4 ligand binding cavity, designed based on comparison with the crystal structure of the more promiscuous EphB2 receptor, yield EphB4 variants with altered binding affinity for ephrinB2 and an antagonistic peptide. Isothermal titration calorimetry experiments with an EphB4 Leu-95 to arginine mutant confirmed the importance of this amino acid in conferring high affinity binding to both ephrinB2 and the antagonistic peptide ligand. Isothermal titration calorimetry measurements also revealed an interesting thermodynamic discrepancy between ephrinB2 binding, which is an entropically driven process, and peptide binding, which is an enthalpically driven process. These results provide critical information on the EphB4*ephrinB2 protein interfaces and their mode of interaction, which will facilitate development of small molecule compounds inhibiting the EphB4*ephrinB2 interaction as novel cancer therapeutics.


Database of patients' experiences (DIPEx): a multi-media approach to sharing experiences and information.
The Database of Individual Patients' Experience of illness (DIPEx) is a multimedia website and CD-ROM that links patients' experiences with evidence-based information about treatments and the illness itself and with a range of other resources that may be useful, including support groups and links to other websites. DIPEx aims to identify the questions that matter to people when they are ill and it has potential for informing patients, educating healthcare professionals, and providing a patient-centred perspective to researchers and those who manage health services.


Capturing the antigen landscape: HLA-E, CD1 and MR1.
T cell receptor (TCR) recognition of antigens presented by relatively non-polymorphic MHC-like molecules is emerging as a significant contributor to health and disease. These evolutionarily ancient pathways have been inappropriately labelled 'non-conventional' because their roles were discovered after viral-specific peptide presentation by polymorphic MHC class I molecules. We suggest that these pathways are complementary to mainstream peptide presentation. HLA-E, CD1 and MR1 can present diverse self and foreign antigens to TCRs and therefore contribute to tissue homeostasis, pathogen defence, inflammation and immune responses to cancer. Despite presenting different classes of antigens, they share many features and are under common selective pressures. Through understanding their roles in disease, therapeutic manipulation for disease prevention and treatment should become possible.


Conducting a Multilingual Study Researching Traumatised Refugees Utilizing a Patient-Reported Outcome System.
Approximately 300,000 asylum-seeking children arrived in Europe in 2015. The chance of experiencing a traumatic event is very high for fleeing children. Since the origin of the refugees is widespread, the languages spoken are diverse. Multilingual electronic patient-reported outcome systems (ePROs) can be used to gather medical data in a foreign language and display the results in the health professionals' language, which helps overcoming the language barrier. Utilizing such a system, a two-phase study aiming to screen refugee minors for potential mental health issues has started. Potential eligible participants are examined using questionnaires with good psychometric properties and cross-cultural applicability. To date, 75 minors and 21 of their relatives participated in the study, being German and Arabic the most desired languages for the electronic survey. Developing a system that provides multilingual questionnaires entails several drawbacks like a cumbersome translation process and dealing with writing directions. The proposed translation process and the ePRO can be re-used in similar studies.


ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.
Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.


A novel activity of the Dickkopf-1 amino terminal domain promotes axial and heart development independently of canonical Wnt inhibition.
The secreted Dickkopf-1 (Dkk1) protein mediates numerous cell fate decisions and morphogenetic processes. Its carboxyl terminal cysteine-rich region (termed C1) binds LRP5/6 and inhibits canonical Wnt signaling. Paradoxically, the isolated C1 domain of Dkk1 as well as Wnt antagonists that act by sequestering Wnts, such as Frz-B, WIF-1 and Crescent, are poor mimics of the inductive and patterning activities of Dkk1 critical for heart and axial development. To understand the basis for the unique properties of Dkk1, we investigated the function of its amino terminal cysteine-rich region (N1). N1 does not bind LRP or Kremen nor inhibit Wnt signaling and has had no known function. We show that it can synergize with BMP antagonism to induce prechordal and axial mesoderm when expressed as an independent protein in Xenopus embryos. Moreover, we show that it can function in trans to complement the activity of C1 protein to mediate two embryologic functions of Dkk1: induction of chordal and prechordal mesoderm and specification of heart tissue from non-cardiogenic mesoderm. Remarkably, N1 also synergizes with WIF-1 and Crescent, indicating that N1 signals independently of C1 and its interactions with LRP. Since cleavage of Dkk1 is not detected, these results define N1 as a novel signaling domain within the intact protein that is responsible for the potent effects of Dkk1 on the induction and patterning of the body axis and heart. We conclude that this new activity is also likely to synergize with canonical Wnt inhibitory in the numerous developmental and disease processes that involve Dkk1.


Baseline polysaccharide-specific antibodies may not consistently inhibit booster antibody responses in infants to a serogroup C meningococcal protein-polysaccharide conjugate vaccine.
Negative correlations between baseline antibody concentrations and increases in antibody concentrations (after booster doses of vaccines) have been reported previously. Such correlation coefficients are widely reported by statisticians to be subject to mathematical coupling. Negative correlations may be attributable partly or wholly to the combination of mathematical coupling and measurement error (or other short term fluctuations in measurements) and therefore not clinically interpretable. In this study we re-analysed the serum antibody responses from five clinical trials of serogroup C meningococcal conjugate vaccine (MenCV) given to infants for priming followed by boosting with MenCV or a meningococcal A/C polysaccharide vaccine (MenA/C) at 12 months of age. Using Pearson's correlation method to assess the effect of pre-booster MenC-IgG concentration on the relative increase in MenC-IgG concentration post-booster, a significant negative correlation was observed for all the groups, indicating that high pre-booster antibody was associated with a smaller rise in antibody post-booster. We tested two additional statistical methods that account for mathematical coupling. Using Blomqvist method of adjustment to assess the plausible extent of bias, correlation coefficients were still negative providing error variance was low. The other method, a multilevel modelling specification of Oldham's method appeared not to be appropriate. In contrast, using Pearson's correlation method a consistent negative correlation between carrier protein-specific baseline antibody concentration and the increase in MenC-specific antibody concentration was only observed following booster immunisation with the protein-polysaccharide conjugate vaccine but not following the MenA/C plain polysaccharide vaccine. These findings suggest that analysis of the inhibitory effect of baseline antibody on the response to booster immunisation is challenging and should account for the possibility of mathematical coupling and measurement error. That an inhibitory effect of baseline antibody cannot be assumed a priori is supported by observations in animal models, which show that baseline antibody can both suppress or enhance the antibody response to a specific antigen.


Comparison of changes in autonomic and respiratory parameters of girls after yoga and games at a community home.
The heart rate, breathing rate, and skin resistance were recorded for 20 community home girls (Home group) and for 20 age-matched girls from a regular school (School group). The former group had a significantly higher rate of breathing and a more irregular breath pattern known to correlate with high fear and anxiety, than the School group. Skin resistance was significantly lower in the School group, which may suggest greater arousal, 28 girls of the Home group formed 14 pairs, matched for age and duration of stay in the home. Subjects of a pair were randomly assigned to either yoga or games groups. For the former emphasis was on relaxation and awareness, whereas for the latter increasing physical activity was emphasized. At the end of an hour daily for six months both groups showed a significant decrease in the resting heart rate relative to initial values (Wilcoxon paired-sample rest), and the yoga group showed a significant decrease in breath rate, which appeared more regular but no significant increase in the skin resistance. These results suggest that a yoga program which includes relaxation, awareness, and graded physical activity is a useful addition to the routine of community home children.


Long-term survival and outcome in children admitted to kilifi district hospital with convulsive status epilepticus.
Objectives. The incidence of convulsive status epilepticus (CSE) is high in Africa but the long-term outcome is unknown. We examined the neurocognitive outcome and survival of children treated for CSE in a Kenyan hospital 3 to 4 years after discharge. Methods. The frequency and nature of neurological deficits among this group of children were determined and compared to a control group. The children were screened with the Ten Questions Questionnaire for neurodevelopmental impairment if alive and those that screened positive were invited for further assessment to determine the pattern and extent of their impairment. A verbal autopsy was performed to determine the cause of death in those that died. Results. In the 119 cases followed-up, 9 (8%) died after discharge, with the majority having seizures during their fatal illness. The 110 survivors (median age 5 years) had significantly more neurological impairments on the screening compared to 282 controls (34/110 (30.9%) versus 11/282 (3.9%), OR = 11.0, 95% CI 5.3-22.8). Fifteen percent of the cases had active epilepsy. Conclusions. This study demonstrates the considerable burden of CSE in African children. Strategies to manage children with CSE that are acceptable to the community need to be explored to improve the longer-term outcome.


Testing a new taxonomic model for the assessment of medical devices: Is it plausible and applicable? Insights from HTA reports and interviews with HTA institutions in Europe.
Medical devices (MDs) encompass a broad and heterogeneous range of technologies. While practices vary considerably across countries, MDs often find application in patient care with little or no evaluation of their effectiveness and safety following market approval. A recently proposed taxonomy of MDs considered devices from the viewpoint of Health Technology Assessment (HTA). The aim of the work presented here was to test its plausibility and applicability by considering real-world HTA practices. HTA reports on MDs from European institutions were collected in a systematic manner and the evaluated devices and/or related procedures were matched to a position on the taxonomy. Following this, representatives from 16 European HTA institutions were asked about the usefulness of the taxonomy in semi-structured interviews. 1237 HTA reports (2004-2015) from 33 European institutions were included in the sample. The majority of reports was on technologies from the taxonomic positions initially estimated as having high relevance. Most of the experts interviewed stated that they found the taxonomy useful, particularly regarding its potential to aid in selecting technologies for assessment and to highlight potential methodological particularities per taxonomic position. Overall, the distribution of identified reports on the matrix confirmed that the initial estimation of the relevance and necessity of HTA provided in the taxonomic model is plausible. In addition, interviews with representatives of European HTA institutions showed that the taxonomy could be useful.


Quality of life after TIA and stroke: ten-year results of the Oxford Vascular Study.
To evaluate the 5-year impact of stroke and TIA on utility and quality-adjusted survival. TIA and stroke patients from a UK population-based study (Oxford Vascular Study) were recruited from 2002 to 2007, and followed up until 2012. Quality of life was assessed over 5 years using the EQ-5D (EuroQol-5 Dimensions), with responses converted into utilities ranging from -0.59 (worse than death) to 1 (perfect health), using UK population valuations. Utilities for stroke and TIA patients were compared with those in matched controls obtained from the 2006 Health Survey for England. Five-year quality-adjusted life years were estimated by combining utility and survival information. Four hundred forty TIA and 748 stroke patients were ascertained and included. Utility remained constant at approximately 0.78 over the 5 years after TIA. Utility improved from 0.64 one month after stroke to 0.70 at 6 months (p = 0.006), remaining at approximately 0.70 thereafter. Matched controls had considerably higher utility levels than stroke/TIA patients (0.85, p < 0.001). Event severity and recurrent stroke were significant predictors of decreased long-term utility. Five-year quality-adjusted life expectancy was 3.32 (95% confidence interval: 3.22-3.48) quality-adjusted life years after TIA and 2.21 (2.15-2.37) after stroke, varying considerably by severity (minor: 2.94; moderate: 1.65; and severe: 0.70). Quality-adjusted survival is low over the 5 years after stroke and TIA, with severity and recurrent stroke being major predictors. There remains considerable scope for improvements in acute treatment and secondary prevention to improve the quality of life after TIA and stroke.


Self-administered acupuncture as an alternative to deliberate self-harm: a feasibility study.
The aim of this mixed methods feasibility study was to demonstrate the acceptability, practicality, and safety of training patients who regularly use deliberate self harm (DSH) to self-administer acupuncture as an alternative coping skill for emotional distress. Ten adult patients with a diagnosis of emotionally unstable personality disorder who regularly self-harmed were recruited to the study following baseline assessment by a psychiatrist. An acupuncturist taught participants to self-acupuncture. During the 6-week intervention participants recorded their emotional distress, coping behaviors, thoughts, and feelings in a diary. Face-to-face interviews were used to explore participants' motives for DSH and their experience of acupuncture. Framework analysis was conducted on interview transcripts and diary entries to identify common themes. Mood at baseline and six weeks was measured using the BDI and changes in the use of coping behaviors and acupuncture were measured using diary entries. Subjects used acupuncture regularly through the six-week intervention and over this period there was a reduction in the frequency of DSH. Qualitative analysis identified two broad themes relating to the process and the effects of acupuncture. There was wide variation in the effects experienced by subjects which broadly mapped onto to the wide range of motives behind DSH. BDI scores showed a near significant reduction (p = 0.055) from 44.4. to 34.4 over the 6-week intervention. Patients presenting with deliberate self harm can be safely trained to self-administer acupuncture as an alternative coping skill. Acceptability and effectiveness may vary between patients depending on the complex motives underlying their self-harming behavior. While the pilot study was designed to explore the feasibility of the intervention, results from this limited sample suggest that use of self-administered acupuncture may reduce the frequency of self harming behavior and reduce emotional distress as measured using the BDI.


Severe thrombocytopenia and patterns of bleeding in neonates: results from a prospective observational study and implications for use of platelet transfusions.
To describe patterns of clinical bleeding in neonates with severe thrombocytopenia (ST and platelet count <60 × 10(9) L(-1)), and to investigate the factors related to bleeding. Seven tertiary-level neonatal units enrolled neonates (n = 169) with ST. Data were collected prospectively on all clinically apparent haemorrhages. Relationships between bleeding, platelet count and baseline characteristics were explored through regression analysis. Bleeding was recorded in most neonates with ST (138/169; 82%), including 123 neonates with minor bleeding and 15 neonates with major bleeding. The most common sites of minor bleeding were from the renal tract (haematuria 40%), endotracheal tube (21%), nasogastric tube (10%) and skin (15%). Gestational age <34 weeks, development of ST within 10 days of birth and necrotizing enterocolitis were the strongest predictors for an increased number of bleeding events. For neonates with ST, a lower platelet count was not a strong predictor of increased bleeding. The majority of neonates with ST bleed, although most episodes are minor. These findings establish the importance of clinical factors for bleeding risk, rather than minimum platelet count. Further studies should assess the clinical significance of different types of minor bleed for neonatal outcomes, the predictive value of minor bleeding for major bleeding and the role of platelet transfusions in preventing bleeding.


A close eye on the eagle-eyed visual acuity hypothesis of autism.
Autism spectrum disorders (ASD) have been associated with sensory hypersensitivity. A recent study reported visual acuity (VA) in ASD in the region reported for birds of prey. The validity of the results was subsequently doubted. This study examined VA in 34 individuals with ASD, 16 with schizophrenia (SCH), and 26 typically developing (TYP). Participants with ASD did not show higher VA than those with SCH and TYP. There were no substantial correlations of VA with clinical severity in ASD or SCH. This study could not confirm the eagle-eyed acuity hypothesis of ASD, or find evidence for a connection of VA and clinical phenotypes. Research needs to further address the origins and circumstances associated with altered sensory or perceptual processing in ASD.


No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure.
Single nucleotide polymorphisms (SNPs) within the MIR137, TCF4, and ZNF804A genes show genome-wide association to schizophrenia. However, the biological basis for the associations is unknown. Here, we tested the effects of these genes on brain structure in 1300 healthy adults. Using volumetry and voxel-based morphometry, neither gene-wide effects--including the combined effect of the genes--nor single SNP effects--including specific psychosis risk SNPs--were found on total brain volume, grey matter, white matter, or hippocampal volume. These results suggest that the associations between these risk genes and schizophrenia are unlikely to be mediated via effects on macroscopic brain structure.


Immunotherapy for transplantation-associated viral infections.
Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections following allogeneic hematopoietic stem cell transplantation (HSCT) are a major cause of morbidity and mortality. Early clinical trials demonstrate that adoptive transfer of donor-derived virus-specific T cells to restore virus-specific immunity is an effective strategy to control CMV and EBV infection after HSCT, conferring protection in 70%-90% of patients. The field has evolved rapidly to develop solutions to some of the manufacturing challenges identified in early clinical studies, such as prolonged in vitro culture, optimization of the purity of the virus-specific T cell product, the potential limitations of targeting a single viral antigen, and how to manage the patient with a virus-naive donor. This Review both discusses the seminal early studies and explores cutting-edge novel technologies that broaden the feasibility of and the scope for delivering virus-specific T cells to patients after HSCT.


Why do humans reason? Arguments for an argumentative theory.
Reasoning is generally seen as a means to improve knowledge and make better decisions. However, much evidence shows that reasoning often leads to epistemic distortions and poor decisions. This suggests that the function of reasoning should be rethought. Our hypothesis is that the function of reasoning is argumentative. It is to devise and evaluate arguments intended to persuade. Reasoning so conceived is adaptive given the exceptional dependence of humans on communication and their vulnerability to misinformation. A wide range of evidence in the psychology of reasoning and decision making can be reinterpreted and better explained in the light of this hypothesis. Poor performance in standard reasoning tasks is explained by the lack of argumentative context. When the same problems are placed in a proper argumentative setting, people turn out to be skilled arguers. Skilled arguers, however, are not after the truth but after arguments supporting their views. This explains the notorious confirmation bias. This bias is apparent not only when people are actually arguing, but also when they are reasoning proactively from the perspective of having to defend their opinions. Reasoning so motivated can distort evaluations and attitudes and allow erroneous beliefs to persist. Proactively used reasoning also favors decisions that are easy to justify but not necessarily better. In all these instances traditionally described as failures or flaws, reasoning does exactly what can be expected of an argumentative device: Look for arguments that support a given conclusion, and, ceteris paribus, favor conclusions for which arguments can be found.


Electronic word of mouth on twitter about physical activity in the United States: exploratory infodemiology study.
Twitter is a widely used social medium. However, its application in promoting health behaviors is understudied. In order to provide insights into designing health marketing interventions to promote physical activity on Twitter, this exploratory infodemiology study applied both social cognitive theory and the path model of online word of mouth to examine the distribution of different electronic word of mouth (eWOM) characteristics among personal tweets about physical activity in the United States. This study used 113 keywords to retrieve 1 million public tweets about physical activity in the United States posted between January 1 and March 31, 2011. A total of 30,000 tweets were randomly selected and sorted based on numbers generated by a random number generator. Two coders scanned the first 16,100 tweets and yielded 4672 (29.02%) tweets that they both agreed to be about physical activity and were from personal accounts. Finally, 1500 tweets were randomly selected from the 4672 tweets (32.11%) for further coding. After intercoder reliability scores reached satisfactory levels in the pilot coding (100 tweets separate from the final 1500 tweets), 2 coders coded 750 tweets each. Descriptive analyses, Mann-Whitney U tests, and Fisher exact tests were performed. Tweets about physical activity were dominated by neutral sentiments (1270/1500, 84.67%). Providing opinions or information regarding physical activity (1464/1500, 97.60%) and chatting about physical activity (1354/1500, 90.27%) were found to be popular on Twitter. Approximately 60% (905/1500, 60.33%) of the tweets demonstrated users' past or current participation in physical activity or intentions to participate in physical activity. However, social support about physical activity was provided in less than 10% of the tweets (135/1500, 9.00%). Users with fewer people following their tweets (followers) (P=.02) and with fewer accounts that they followed (followings) (P=.04) were more likely to talk positively about physical activity on Twitter. People with more followers were more likely to post neutral tweets about physical activity (P=.04). People with more followings were more likely to forward tweets (P=.04). People with larger differences between number of followers and followings were more likely to mention companionship support for physical activity on Twitter (P=.04). Future health marketing interventions promoting physical activity should segment Twitter users based on their number of followers, followings, and gaps between the number of followers and followings. The innovative application of both marketing and public health theory to examine tweets about physical activity could be extended to other infodemiology or infoveillance studies on other health behaviors (eg, vaccinations).


Perceived threat modulates inhibitory performance.
Highly arousing, affective stimuli have adverse effects on cognition and performance. Perception of affective stimuli is, however, highly subjective and may impact on the interaction of emotion and cognition. Here, we tested the impact of high- versus low-threatening stimuli on response inhibition as a function of perceived threat intensity. Response inhibition was probed using a stop-signal paradigm in 62 healthy adults. We used stop-signals that had previously been paired with an unpleasant electrodermal stimulation (i.e., high-threat stimuli) or that had never been paired with electrodermal stimulation (i.e., low-threat stimuli). High-threat stimuli did not affect stopping performance in general. Only participants who perceived the high-threat stimuli as highly painful showed impaired response inhibition on high-threat trials relative to low-threat trials. Participants who perceived the high-threat as mildly painful, however, showed improved response inhibition on high-threat trials. This effect was not moderated by the current anxious state. This suggests that the impact of negative affective stimuli on cognition critically depends on subjective threat perception. Ratings of affective stimuli should be included in studies probing the emotion-cognition interaction because subjective perception might strongly impact on that interaction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Does the Framingham Stroke Risk Profile predict white-matter changes in late-life depression?
Cardiovascular risk factors and diseases are important etiological factors in depression, particularly late-life depression. Brain changes associated with vascular disease and depression can be detected using magnetic resonance imaging. Using diffusion tensor imaging (DTI), we investigated whether the Framingham Stroke Risk Profile (FSRP), a well-validated risk prediction algorithm, is associated with changes in white-matter connectivity. We hypothesized that depressed participants would show reduced white-matter integrity with higher FSRP, and non-depressed controls (matched for mean vascular risk) would show minimal co-variance with white-matter changes. Thirty-six participants with major depression (age 71.8 ± 7.7 years, mean FSRP 10.3 ± 7.6) and 25 controls (age 71.8 ± 7.3 years, mean FSRP 10.1 ± 7.7) were clinically interviewed and examined, followed by 60-direction DTI on a 3.0 Tesla scanner. Image analysis was performed using FSL tools (www.fmrib.ox.ac.uk/fsl) to assess the correlation between FSRP and fractional anisotropy (FA). Voxelwise statistical analysis of the FA data was carried out using Tract Based Spatial Statistics. The significance threshold for correlations was set at p < 0.05 using threshold-free cluster-enhancement. Partial correlation analysis investigated significant correlations in each group. Participants in the depressed group showed highly significant correlations between FSRP and FA within the body of corpus callosum (r = -0.520, p = 0.002), genu of corpus callosum (r = -0.468, p = 0.005), splenium of corpus callosum (r = -0.536, p = 0.001), and cortico-spinal tract (r = -0.473, p = 0.005). In controls, there was only one significant correlation in the body of corpus callosum (r = -0.473, p = 0.023). FSRP is associated with impairment in white-matter integrity in participants with depression; these results suggest support for the vascular depression hypothesis.


Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.
Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons). The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. Cancer Research UK.


Risk of pneumonia and pneumococcal disease in people hospitalized with diabetes mellitus: English record-linkage studies.
The risk of invasive pneumococcal disease is higher in people with diabetes mellitus than those without. People with diabetes should be considered for routine pneumococcal immunization. This policy has been in place in England for more than a decade. We aimed to estimate, at the population level, the current scale of excess risk of pneumococcal disease in patients with diabetes, and whether the risks have decreased in recent years with the introduction of a pneumococcal vaccine. We used two data sets of linked hospital admission and death records-the Oxford Record Linkage Study (1963-1998) and all-England linked hospital episode statistics (1999-2011). As a measure of relative risk, we calculated the rate ratio of pneumococcal disease in cohorts of people hospitalized with diabetes compared with cohorts without a record of diabetes. The risk of pneumococcal disease in patients hospitalized with diabetes mellitus has declined a little, but it is still high. The all-ages rate ratio in England declined from 1.92 (95% CI 1.89-1.94) in 1999-2002 to 1.68 (95% CI 1.65-1.71) in 2007-2011. In people aged under 60 years, rate ratios were higher and their decline was more substantial: rate ratios declined from 3.37 (95% CI 3.28-3.46) in 1999-2002 to 2.33 (95% CI 2.21-2.45) in 2007-2011. Patients admitted to hospital with diabetes mellitus remain at increased risk of pneumococcal infection despite a national immunization policy. Possible explanations for the elevated risk include low vaccine uptake or low effectiveness of available vaccine. Clinicians should be aware of the risk of pneumococcal infection in people with diabetes.


Triggering and amplifying pathways of regulation of insulin secretion by glucose.
Glucose stimulates insulin secretion by generating triggering and amplifying signals in beta-cells. The triggering pathway is well characterized. It involves the following sequence of events: entry of glucose by facilitated diffusion, metabolism of glucose by oxidative glycolysis, rise in the ATP-to-ADP ratio, closure of ATP-sensitive K+ (KATP) channels, membrane depolarization, opening of voltage-operated Ca2+ channels, Ca2+ influx, rise in cytoplasmic free Ca2+ concentration ([Ca2+]i), and activation of the exocytotic machinery. The amplifying pathway can be studied when beta-cell [Ca2+]i is elevated and clamped by a depolarization with either a high concentration of sulfonylurea or a high concentration of K+ in the presence of diazoxide (K(ATP) channels are then respectively blocked or held open). Under these conditions, glucose still increases insulin secretion in a concentration-dependent manner. This increase in secretion is highly sensitive to glucose (produced by as little as 1-6 mmol/l glucose), requires glucose metabolism, is independent of activation of protein kinases A and C, and does not seem to implicate long-chain acyl-CoAs. Changes in adenine nucleotides may be involved. The amplification consists of an increase in efficacy of Ca2+ on exocytosis of insulin granules. There exists a clear hierarchy between both pathways. The triggering pathway predominates over the amplifying pathway, which remains functionally silent as long as [Ca2+]i has not been raised by the first pathway; i.e., as long as glucose has not reached its threshold concentration. The alteration of this hierarchy by long-acting sulfonylureas or genetic inactivation of K(ATP) channels may lead to inappropriate insulin secretion at low glucose. The amplifying pathway serves to optimize the secretory response not only to glucose but also to nonglucose stimuli. It is impaired in beta-cells of animal models of type 2 diabetes, and indirect evidence suggests that it is altered in beta-cells of type 2 diabetic patients. Besides the available drugs that act on K(ATP) channels and increase the triggering signal, novel drugs that correct a deficient amplifying pathway would be useful to restore adequate insulin secretion in type 2 diabetic patients.


Recent advances in understanding dengue.
Dengue is an emerging threat to billions of people worldwide. In the last 20 years, the incidence has increased four-fold and this trend appears to be continuing. Caused by one of four viral serotypes, dengue can present as a wide range of clinical phenotypes with the severe end of the spectrum being defined by a syndrome of capillary leak, coagulopathy, and organ impairment. The pathogenesis of severe disease is thought to be in part immune mediated, but the exact mechanisms remain to be defined. The current treatment of dengue relies on supportive measures with no licensed therapeutics available to date. There have been recent advances in our understanding of a number of areas of dengue research, of which the following will be discussed in this review: the drivers behind the global dengue pandemic, viral structure and epitope binding, risk factors for severe disease and its pathogenesis, as well as the findings of recent clinical trials including therapeutics and vaccines. We conclude with current and future dengue control measures and key areas for future research.


Minimally invasive surgery for spinal cerebrospinal fluid leaks in spontaneous intracranial hypotension.
Spinal CSF leaks cause spontaneous intracranial hypotension (SIH). Surgical closure of spinal CSF leaks is the treatment of choice for persisting leaks. Surgical approaches vary, and there are no studies in which minimally invasive techniques were used. In this study, the authors aimed to detail the safety and feasibility of minimally invasive microsurgical sealing of spinal CSF leaks using nonexpandable tubular retractors. Consecutive patients with SIH and a confirmed spinal CSF leak treated at a single institution between April 2019 and December 2020 were included in the study. Surgery was performed via a dorsal 2.5-cm skin incision using nonexpandable tubular retractors and a tailored interlaminar fenestration and, if needed, a transdural approach. The primary outcome was successful sealing of the dura, and the secondary outcome was the occurrence of complications. Fifty-eight patients, 65.5% of whom were female (median age 46 years [IQR 36-55 years]), with 38 ventral leaks, 17 lateral leaks, and 2 CSF venous fistulas were included. In 56 (96.6%) patients, the leak could be closed, and in 2 (3.4%) patients the leak was missed because of misinterpretation of the imaging studies. One of these patients underwent successful reoperation, and the other patient decided to undergo surgery at another institution. Two other patients had to undergo reoperation because of insufficient closure and a persisting leak. The rate of permanent neurological deficit was 1.7%, the revision rate for a persisting or recurring leak was 3.4%, and the overall revision rate was 10.3%. The rate of successful sealing during the primary closure attempt was 96.6% and 3.4% patients needed a secondary attempt. Clinical short-term outcome at discharge was unchanged in 14 patients and improved in 25 patients, and 19 patients had signs of rebound intracranial hypertension. Minimally invasive surgery with tubular retractors and a tailored interlaminar fenestration and, if needed, a transdural approach is safe and effective for the treatment of spinal CSF leaks. The authors suggest performing a minimally invasive closure of spinal CSF leaks in specialized centers.


A Study of Knowledge, Experience, and Beliefs About Hepatitis B Virus (HBV) Infection in South Western Uganda.
Introduction: United Nations sustainable development goals aim for the elimination of viral hepatitis as a public health threat by 2030, leading to efforts to upscale the availability and accessibility of hepatitis B virus (HBV) vaccination, diagnosis, and treatment globally. However, a variety of societal factors, including beliefs, traditions, and stigma, can be a major obstacle to all of these interventions. We therefore set out to investigate how HBV is understood and described in communities in Uganda, and whether there is evidence of potential stigma. Method: We carried out a qualitative formative study in two sites in South Western Uganda: a village in Kalungu district (site A) and an area on the outskirts of Masaka town (site B). We undertook a rapid assessment to investigate how adults describe HBV infection and their perceptions about the infection. We collected data by conducting a transect walk, observations, community group discussions, and in-depth interviews, sampling a total of 131 individuals. We used inductive content analysis to extract key themes associated with HBV. Results: There is no specific word for HBV infection in local languages, and knowledge about this infection is varied. While some individuals were completely unfamiliar with HBV infection, some had heard of HBV. Radio was a common source of information. There was awareness of HBV as a cause of liver disease, but limited knowledge regarding the cause, mode of transmission, and treatment. Stigma in HBV may be rare in this community due to limited understanding and experience of HBV. Conclusion: There is an ongoing need to improve awareness and understanding of HBV in this community. Careful dissemination of accurate information is required to promote acceptance of interventions for prevention, diagnosis, and treatment.