Evaporation and Electrowetting of Sessile Droplets on Slippery Liquid-Like Surfaces and Slippery Liquid-Infused Porous Surfaces (SLIPS).
Sessile droplet evaporation underpins a wide range of applications from inkjet printing to coating. However, drying times can be variable and contact-line pinning often leads to undesirable effects, such as ring stain formation. Here, we show voltage programmable control of contact angles during evaporation on two pinning-free surfaces. We use an electrowetting-on-dielectric approach and Slippery Liquid-Infused Porous (SLIP) and Slippery Omniphobic Covalently Attached Liquid-Like (SOCAL) surfaces to achieve a constant contact angle mode of evaporation. We report evaporation sequences and droplet lifetimes across a broad range of contact angles from 105°-67°. The values of the contact angles during evaporation are consistent with expectations from electrowetting and the Young-Lippman equation. The droplet contact areas reduce linearly in time, and this provides estimates of diffusion coefficients close to the expected literature value. We further find that the total time of evaporation over the broad contact angle range studied is only weakly dependent on the value of the contact angle. We conclude that on these types of slippery surfaces, droplet lifetimes can be predicted and controlled by the droplet's volume and physical properties (density, diffusion coefficient, and vapor concentration difference to the vapor phase) largely independent of the precise value of contact angle. These results are relevant to applications, such as printing, spraying, coating, and other processes, where controlling droplet evaporation and drying is important.


Human pulmonary vascular responses to hypoxia and hypercapnia.
The ability of alveolar gas composition to influence pulmonary vascular tone has been appreciated for over 50 years. In particular, it has been proposed that both O2 and CO2 could play a role in the matching of perfusion to ventilation within the lung, improving the overall efficiency of gas exchange. A wide variety of experimental approaches has been used to investigate pulmonary vascular effects of the respiratory gases in a range of mammalian species. In this article, we review experiments performed in healthy humans, identify particular difficulties in the interpretation of such experiments, and discuss possible approaches to future study.


C-terminus of heat shock cognate 70 interacting protein increases following stroke and impairs survival against acute oxidative stress.
The decision to remove or refold oxidized, denatured, or misfolded proteins by heat shock protein 70 and its binding partners is critical to determine cell fate under pathophysiological conditions. Overexpression of the ubiquitin ligase C-terminus of HSC70 interacting protein (CHIP) can compensate for failure of other ubiquitin ligases and enhance protein turnover and survival under chronic neurological stress. The ability of CHIP to alter cell fate after acute neurological injury has not been assessed. Using postmortem human tissue samples, we provide the first evidence that cortical CHIP expression is increased after ischemic stroke. Oxygen glucose deprivation in vitro led to rapid protein oxidation, antioxidant depletion, proteasome dysfunction, and a significant increase in CHIP expression. To determine if CHIP upregulation enhances neural survival, we overexpressed CHIP in vitro and evaluated cell fate 24 h after acute oxidative stress. Surprisingly, CHIP overexpressing cells fared worse against oxidative injury, accumulated more ubiquitinated and oxidized proteins, and experienced decreased proteasome activity. Conversely, using small interfering RNA to decrease CHIP expression in primary neuronal cultures improved survival after oxidative stress, suggesting that increases in CHIP observed after stroke like injuries are likely correlated with diminished survival and may negatively impact the neuroprotective potential of heat shock protein 70.


The human olfactory receptor repertoire.
The mammalian olfactory apparatus is able to recognize and distinguish thousands of structurally diverse volatile chemicals. This chemosensory function is mediated by a very large family of seven-transmembrane olfactory (odorant) receptors encoded by approximately 1,000 genes, the majority of which are believed to be pseudogenes in humans. The strategy of our sequence database mining for full-length, functional candidate odorant receptor genes was based on the high overall sequence similarity and presence of a number of conserved sequence motifs in all known mammalian odorant receptors as well as the absence of introns in their coding sequences. We report here the identification and physical cloning of 347 putative human full-length odorant receptor genes. Comparative sequence analysis of the predicted gene products allowed us to identify and define a number of consensus sequence motifs and structural features of this vast family of receptors. A new nomenclature for human odorant receptors based on their chromosomal localization and phylogenetic analysis is proposed. We believe that these sequences represent the essentially complete repertoire of functional human odorant receptors. The identification and cloning of all functional human odorant receptor genes is an important initial step in understanding receptor-ligand specificity and combinatorial encoding of odorant stimuli in human olfaction.


Human consciousness and its relationship to social neuroscience: A novel hypothesis.
A common modern view of consciousness is that it is an emergent property of the brain, perhaps caused by neuronal complexity, and perhaps with no adaptive value. Exactly what emerges, how it emerges, and from what specific neuronal process, is in debate. One possible explanation of consciousness, proposed here, is that it is a construct of the social perceptual machinery. Humans have specialized neuronal machinery that allows us to be socially intelligent. The primary role for this machinery is to construct models of other people's minds thereby gaining some ability to predict the behavior of other individuals. In the present hypothesis, awareness is a perceptual reconstruction of attentional state; and the machinery that computes information about other people's awareness is the same machinery that computes information about our own awareness. The present article brings together a variety of lines of evidence including experiments on the neural basis of social perception, on hemispatial neglect, on the out-of-body experience, on mirror neurons, and on the mechanisms of decision-making, to explore the possibility that awareness is a construct of the social machinery in the brain.


Alternate row placement is ineffective for cultural control of Meloidogyne incognita in cotton.
The objective of this study was to determine if planting cotton into the space between the previous year's rows reduces crop loss due to Meloidogyne incognita compared to planting in the same row every year. Row placement had a significant (P </= 0.05) effect on nematode population levels only on 8 July 2005. Plots receiving 1,3-dichloropropene plus aldicarb had lower nematode population levels than non-fumigated plots on 24 May and 8 July in 2005, but not in 2004. The effect of nematicide treatment on nematode populations was not affected by row placement. Row placement did not have a significant effect on root galling or yield in 2004 or 2005. Nematicide treatment decreased root galling in all years, and the decrease was not influenced by row placement. Yield was increased by nematicide application in 2004 and 2005, and the increase was not affected by row placement. Percentage yield loss was not affected by row placement. Changing the placement of rows reduced nematode population levels only on one sampling date in one year, but end-of-season root galling and lint yield were not affected by changing the placement of rows, nor was the effect of fumigation on yield influenced by row placement. Therefore, row placement is unlikely to contribute to M. incognita management in cotton.


Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress.
We hypothesized that curcumin would improve resistance and conduit artery endothelial function and large elastic artery stiffness in healthy middle-aged and older adults. Thirty-nine healthy men and postmenopausal women (45-74 yrs) were randomized to 12 weeks of curcumin (2000 mg/day Longvida®; n=20) or placebo (n=19) supplementation. Forearm blood flow response to acetylcholine infusions (FBFACh; resistance artery endothelial function) increased 37% following curcumin supplementation (107±13 vs. 84±11 AUC at baseline, P=0.03), but not placebo (P=0.2). Curcumin treatment augmented the acute reduction in FBFACh induced by the nitric oxide synthase inhibitor NG monomethyl-L-arginine (L-NMMA; P=0.03), and reduced the acute increase in FBFACh to the antioxidant vitamin C (P=0.02), whereas placebo had no effect (both P>0.6). Similarly, brachial artery flow-mediated dilation (conduit artery endothelial function) increased 36% in the curcumin group (5.7±0.4 vs. 4.4±0.4% at baseline, P=0.001), with no change in placebo (P=0.1). Neither curcumin nor placebo influenced large elastic artery stiffness (aortic pulse wave velocity or carotid artery compliance) or circulating biomarkers of oxidative stress and inflammation (all P>0.1). In healthy middle-aged and older adults, 12 weeks of curcumin supplementation improves resistance artery endothelial function by increasing vascular nitric oxide bioavailability and reducing oxidative stress, while also improving conduit artery endothelial function.


The influence of extracellular and phagolysosomal pH changes on the bactericidal activity of bovine neutrophils against Staphylococcus aureus.
The influence of the pH of suspending medium on bovine neutrophil (PMN) function was assessed in tests of phagocytosis and killing of Staphylococcus aureus. Intracellular killing was markedly inhibited by moderate extracellular acidification whereas phagocytosis was little affected, except at the lowest pH level (pH 5.0). The killing of S. aureus by extracts of isolated PMN lysosomal granules showed a similar pH dependence and was optimal at pH levels above neutrality. Survival of S. aureus within PMN from different cows varied significantly and the relative differences in PMN bactericidal efficiency were maintained at all pH levels. The acidification of extracellular medium during incubation which resulted from metabolic activity of the PMN themselves, increased with increasing ratios of bacteria:PMN and varied significantly among cows. Addition of methylamine (10 mM) to elevate phagolysosomal pH inhibited phagocytosis and had no effect on intracellular survival of S. aureus. However, a lower concentration (1.5 mM) did not affect phagocytosis, but reduced bacterial survival without altering the relative differences in efficiency of PMN from different cows. It is suggested that the acidity of the extracellular medium may both reflect and influence the pH changes occurring within PMN phagosomes and, thereby, modulate the efficiency of intracellular destruction of S. aureus.


Molecular phylogenetics of ponerine ants (Hymenoptera: Formicidae: Ponerinae).
Recent molecular phylogenetic studies of ants (Hymenoptera: Formicidae) have revolutionized our understanding of how these ecologically dominant organisms diversified, but detailed phylogenies are lacking for most major ant subfamilies. I report the results of the first detailed phylogenetic study of the ant subfamily Ponerinae, a diverse cosmopolitan lineage whose properties make it an attractive model system for investigating social and ecological evolution in ants. Molecular sequence data were obtained from four nuclear genes (wingless, long-wavelength rhodopsin, rudimentary [CAD], 28S rDNA; total of ~3.3 kb) for 86 ponerine taxa, representing all three ponerine tribes, 22 of the 28 currently recognized genera, and 14 of the 18 informal subgenera of Pachycondyla, a heterogeneous grouping whose monophyly is doubtful on morphological grounds. Phylogenetic reconstructions using maximum likelihood and Bayesian inference support the monophyly of Ponerinae and tribe Platythyreini, but fail to support the monophyly of the large tribe Ponerini due to its inclusion of the unusual genus Thaumatomyrmex. Pachycondyla is inferred to be broadly non-monophyletic. Numerous novel generic and suprageneric relationships are inferred within Ponerini, which was found to consist of four major multi-generic clades (the Ponera, Pachycondyla, Plectroctena and Odontomachus genus groups) plus the single genera Hypoponera and Harpegnathos. Uncertainty remains in some regions of the phylogeny, including at the base of Ponerini, possibly reflecting rapid radiation. Divergence dating using a Bayesian relaxed clock method estimates an origin for stem Ponerinae in the upper Cretaceous, a major burst of diversification near the K/T boundary, and a rich and continual history of diversification during the Cenozoic. These results fail to support the predictions of the "dynastic-succession hypothesis" previously developed to explain the high species diversity of Ponerinae. Though model-based reconstructions of historical biogeography and trait evolution were not attempted in this study, the phylogeny suggests that ponerine evolution was marked by regionalized radiations and frequent faunal exchange between major biogeographic provinces. The reported results also imply multiple origins of cryptobiotic foraging, mass raiding behavior, and gamergate reproduction within Ponerinae, highlighting the value of the subfamily as a model for studying the incipient evolution of these and other ecological and behavioral traits.


DNA polymerase beta: contributions of template-positioning and dNTP triphosphate-binding residues to catalysis and fidelity.
The specific catalytic roles of two groups of DNA polymerase beta active site residues identified from crystal structures were investigated: residues possibly involved in DNA template positioning (Lys280, Asn294, and Glu295) and residues possibly involved in binding the triphosphate moiety of the incoming dNTP (Arg149, Ser180, Arg183, and Ser188). Eight site-specific mutants were constructed: K280A, N294A, N294Q, E295A, R149A, S180A, R183A, and S188A. Two-dimensional NMR analysis was employed to show that the global conformation of the mutants has not been perturbed significantly. Pre-steady-state kinetic analyses with single-nucleotide gapped DNA substrates were then performed to obtain the rate of catalysis at saturating dNTP (k(pol)), the apparent dissociation constant for dNTP (K(d)), catalytic efficiency k(pol)/K(d), and fidelity. Of the three template-positioning residues, Asn294 and Glu295 (but not Lys280) contribute significantly to k(pol). Taken together with other data, the results suggest that these two residues help to stabilize the transition state during catalysis even though they interact with the DNA template backbone rather than directly with the incoming dNTP or the opposite base on the template. Furthermore, the fidelity increases by up to 19-fold for N294Q due to differential k(pol) effects between correct and incorrect nucleotides. Of the four potential triphosphate-binding residues, Ser180 and Arg183 contribute significantly to k(pol) while the effects of R149A are relatively small and are primarily on K(d), and Ser188 appears to play a minimal role in the catalysis by Pol beta. These results identify several residues important for catalysis and quantitate the contributions of each of those residues. The functional data are discussed in relation to the prediction on the basis of available crystal structures.


The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats.
Liver cirrhosis and portal hypertension are accompanied by portal-systemic collaterals formation and lethal complications. Angiogenesis participates in the development of collaterals. Spironolactone is an aldosterone receptor antagonist used to control fluid overload in cirrhotic patients although recent studies suggest that it also inhibits angiogenesis. This study investigated the effect of spironolactone on abnormal angiogenesis and portal-systemic collaterals in cirrhosis. Liver cirrhosis was induced in Sprague-Dawley rats by common bile duct ligation (BDL), and sham-operated rats were the controls. The BDL and sham rats received spironolactone (20 mg/kg/d, oral gavage) or vehicle from day 15 to 28 after the operations. Spironolactone did not influence the portal and systemic hemodynamic, and the renal and hepatic biochemistry data, but it significantly ameliorated hepatic fibrosis, portal-systemic shunting, and mesenteric angiogenesis. Plasma vascular endothelial growth factor (VEGF) levels and the mesenteric protein expression of VEGF and phosphor-vascular endothelial growth factor receptor 2 (VEGFR-2) decreased in the spironolactone group. Spironolactone did not affect motor activity or plasma ammonia levels. The down-regulation of VEGF pathway participates, albeit partly, in the antiangiogenic effect of spironolactone. Thus, spironolactone treatment in patients with liver cirrhosis may provide additional benefits aside from ascites control.


Nurse preparation and organizational support for supervision of unlicensed assistive personnel in nursing homes: a qualitative exploration.
Nursing supervision of the routine daily care (e.g., grooming, feeding, and toileting) that is delegated to unlicensed assistive personnel (UAP) is critical to nursing home service delivery. The conditions under which the supervisory role is organized and operationalized at the work-unit level, taking into account workloads, registered nurse/licensed practical nurse staffing, and role expectations, are not well understood. The purpose of this paper is to describe the organizational, managerial, and nurse-level factors associated with the nurse's role as supervisor of UAP in nursing homes. An ethnographic approach to data collection included 31 interviews, 170 hr of observation, and organizational document review at three nursing homes. Analysis included micro-coding and content analysis. Findings revealed (a) considerable variation in organizational resources, systems, and processes to support organization and operationalization of the supervisory role; and (b) limited evidence of nurses' estimation of the potential benefits of training and organizational systems to support supervisory practice and the complexity of the supervisory role. Delivery of high-quality nursing home care is a matter of national importance, and these findings offer a call to action for nursing home leaders in policy, academia, and ownership and management positions. Nurses must be equipped with competencies and skills that reflect the complex organizational environments in which they work. Additionally, nursing home administrators and managers must be equipped with the competencies and skills needed to effectively and efficiently organize and operationalize care delivery practices to support nurses' role enactment.


Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort.
We investigated the association between refractive error in a Japanese population and myopia-related genes identified in two recent large-scale genome-wide association studies. Single-nucleotide polymorphisms (SNPs) in 51 genes that were reported by the Consortium for Refractive Error and Myopia and/or the 23andMe database were genotyped in 3712 healthy Japanese volunteers from the Nagahama Study using HumanHap610K Quad, HumanOmni2.5M, and/or HumanExome Arrays. To evaluate the association between refractive error and recently identified myopia-related genes, we used three approaches to perform quantitative trait locus analyses of mean refractive error in both eyes of the participants: per-SNP, gene-based top-SNP, and gene-based all-SNP analyses. Association plots of successfully replicated genes also were investigated. In our per-SNP analysis, eight myopia gene associations were replicated successfully: GJD2, RASGRF1, BICC1, KCNQ5, CD55, CYP26A1, LRRC4C, and B4GALNT2.Seven additional gene associations were replicated in our gene-based analyses: GRIA4, BMP2, QKI, BMP4, SFRP1, SH3GL2, and EHBP1L1. The signal strength of the reported SNPs and their tagging SNPs increased after considering different linkage disequilibrium patterns across ethnicities. Although two previous studies suggested strong associations between PRSS56, LAMA2, TOX, and RDH5 and myopia, we could not replicate these results. Our results confirmed the significance of the myopia-related genes reported previously and suggested that gene-based replication analyses are more effective than per-SNP analyses. Our comparison with two previous studies suggested that BMP3 SNPs cause myopia primarily in Caucasian populations, while they may exhibit protective effects in Asian populations.


EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma.
The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.


What Have We Learned from Expedition III and EPOCH Trials? Perspective of the CTAD Task Force.
Although the results were disappointing from two recent clinical trials of amyloid-targeting drugs in mild-to-moderate AD, the trials provided information that will be important for future studies, according to the EU-US CTAD Task Force, which met in November 2017 to discuss the EXPEDITION3 and EPOCH trials. These trials tested two of the predominant drug development strategies for AD: amyloid immunotherapy and BACE inhibition in populations largely composed of mild AD dementia patients. The results of these trials support the emerging consensus that effective amyloid-targeted treatment will require intervention in early, even pre-symptomatic stages of the disease. Further, the Task Force suggested that a refinement of the amyloid hypothesis may be needed and that other hypotheses should be more fully explored. In addition, they called for improved biomarkers and other outcome assessments to detect the earliest changes in the development of AD.


Characterizing the distribution of methane sources and cycling in the deep sea via in situ stable isotope analysis.
The capacity to make in situ geo-referenced measurements of methane concentration and stable isotopic composition (δ(13)C(CH4)) would greatly improve our understanding of the distribution and type of methane sources in the environment, allow refined determination of the extent to which microbial production and consumption contributes to methane cycling, and enable the testing of hypotheses about the sensitivity of methane cycling to changes in environmental conditions. In particular, characterizing biogeochemical methane cycling dynamics in the deep ocean is hampered by a number of challenges, especially in environments where high methane concentrations preclude intact recovery of undisturbed samples. To that end, we have developed an in situ analyzer capable of δ(13)C(CH4) measurements in the deep ocean. Here we present data from laboratory and field studies in which we characterize the instrument's analytical capabilities and performance and provide the first in situ stable isotope based characterization of the influence of anaerobic methane oxidation on methane flux from seep sediments. These data illustrate how in situ measurements can permit finer-scale analyses of variations in AOM activity, and facilitate advances in using δ(13)C(CH4) and other isotopic systems to interrogate biogeochemical cycles in the deep sea and other remote or challenging environments.


Stress cardiac magnetic resonance imaging with observation unit care reduces cost for patients with emergent chest pain: a randomized trial.
We determine whether imaging with cardiac magnetic resonance imaging (MRI) in an observation unit would reduce medical costs among patients with emergent non-low-risk chest pain who otherwise would be managed with an inpatient care strategy. Emergency department patients (n=110) at intermediate or high probability for acute coronary syndrome without electrocardiographic or biomarker evidence of a myocardial infarction provided consent and were randomized to stress cardiac MRI in an observation unit versus standard inpatient care. The primary outcome was direct hospital cost calculated as the sum of hospital and provider costs. Estimated median cost differences (Hodges-Lehmann) and distribution-free 95% confidence intervals (Moses) were used to compare groups. There were 110 participants with 53 randomized to cardiac MRI and 57 to inpatient care; 8 of 110 (7%) experienced acute coronary syndrome. In the MRI pathway, 49 of 53 underwent stress cardiac MRI, 11 of 53 were admitted, 1 left against medical advice, 41 were discharged, and 2 had acute coronary syndrome. In the inpatient care pathway, 39 of 57 patients initially received stress testing, 54 of 57 were admitted, 3 left against medical advice, and 6 had acute coronary syndrome. At 30 days, no subjects in either group experienced acute coronary syndrome after discharge. The cardiac MRI group had a reduced median hospitalization cost (Hodges-Lehmann estimate $588; 95% confidence interval $336 to $811); 79% were managed without hospital admission. Compared with inpatient care, an observation unit strategy involving stress cardiac MRI reduced incident cost without any cases of missed acute coronary syndrome in patients with emergent chest pain.


A review and critique of modelling in prioritising and designing screening programmes.
To undertake a structured review and critical appraisal of methods for the model-based cost-utility analysis of screening programmes. Also to develop guidelines and an assessment checklist of good practice in the development of screening models. Major electronic databases of healthcare and operational research literatures were searched up to June 2003. Searches of the literature were undertaken to identify applied and methodological studies of economic evaluations of healthcare screening programmes. All applied screening models were also reviewed in three broad disease areas (cancer, cardiovascular disease and diabetes), as well as antenatal screening. A second-level review focused on particular aspects of the modelling process through case study assessments of screening models for three specific disease areas (colorectal cancer, abdominal aortic aneurysms and antenatal screening for haemoglobinopathies). A separate literature review of studies reporting the utility effects of screening was also undertaken. Guidelines and an assessment checklist for good practice for screening modelling were developed. Few relevant methodological studies were identified, and no studies reporting direct empirical comparisons of alternative methodologies were retrieved. From the review of disease-based screening models, it was apparent that many alternative modelling methods had been applied, including some relatively new approaches that had not been widely disseminated. Natural history modelling is the preferred approach. Alternative modelling approaches were generally only used to extrapolate the observed effects of screening and were unsuitable for evaluating unobserved screening options. More complex model structures may incorporate important additional aspects of the disease natural history, although any benefits should outweigh the consequences of additional unobservable input parameters and increased complexity in implementing the model. No direct comparisons of more detailed and less detailed screening model structures informed areas in which more realistic representations of the disease process may be most beneficial, so only general aspects of good practice could be defined. Two structural aspects that were not well handled by existing screening models included post-diagnosis disease progression and screening uptake. Most models described the former using historical mortality rates, rather than treatment models that are representative of current treatment patterns for different stages of the disease. Constant screening uptake rates were applied to all screening programmes and attendance was not linked to disease incidence or progression. Evidence exists to inform a more detailed representation of screening uptake. The most commonly applied modelling techniques were cohort Markov models and individual sampling simulation models. Individual sampling simulation models may provide more flexibility in their representation of a screening decision problem, but any benefits should outweigh the consequences of the need to assess both variability and uncertainty. Complex mathematical models describing input parameters as continuous variables have analysed the cost-effectiveness of screening; these require further development to estimate the cost-utility of screening directly, or to inform a more detailed representation of the preclinical section of a natural history model (with a traditional state-based model describing pathways' post-clinical presentation). Calibration is a common aspect of screening models, whereby models are fitted to observed data describing outputs of the model in order to populate unobserved input parameters. The review concluded that the estimation of a reference case input parameter set is not recommended. The review of methods for the model-based cost-utility analysis of screening programmes identified the natural history modelling approach as the preferred general method of evaluation for screening programmes. State transition models have generally been used to represent disease natural histories, with individual sampling models more prevalent than in treatment intervention evaluations. No comparative methodological studies were identified, so no empirical data were available to inform the relative merits of alternative methodologies. The defined guidelines and assessment checklist are informed, therefore, by theoretical interpretations of the impact of alternative approaches to different components of the modelling process when applied to the cost-utility analysis of screening programmes. Further research is needed into methods with the potential to improve the accuracy of screening models, and to respond to the needs of model users.


Recent structural insights into the function of copper nitrite reductases.
Copper nitrite reductases (CuNiR) carry out the first committed step of the denitrification pathway of the global nitrogen cycle, the reduction of nitrite (NO2-) to nitric oxide (NO). As such, they are of major agronomic and environmental importance. CuNiRs occur primarily in denitrifying soil bacteria which carry out the overall reduction of nitrate to dinitrogen. In this article, we review the insights gained into copper nitrite reductase (CuNiR) function from three dimensional structures. We particularly focus on developments over the last decade, including insights from serial femtosecond crystallography using X-ray free electron lasers (XFELs) and from the recently discovered 3-domain CuNiRs.


Laparoscopic adjustable gastric banding: a prospective 4-year follow-up study.
A body mass index of > or =40 kg/m2 represents clinically severe obesity and warrants operative treatment if requested. The adjustable silicone gastric band and the Swedish adjustable gastric band are recently produced laparoscopic gastric restrictive devices. The aim of this study was to assess all complications linked to both the available gastric bands in a long-term follow-up. In a prospective study, the effects, complications, and outcomes of this procedure were analyzed. The complications found were divided into early and general complications, and complications correlated to the bands. The technique of laparoscopic adjustable gastric banding is described. Follow-up was performed by the operating team. Between July 1994 and August 1998, the authors operated on 158 patients and performed 102 adjustable silicone gastric bandings and 54 Swedish adjustable gastric bandings. The mean age at surgery was 36 years (range 17-72). The mean preoperative weight was 136 kg (89-230). Of 158 patients who underwent laparoscopic procedures, 156 (98%) could be followed up (mean 28 months; duration of follow-up, 6 weeks to 46 months). In early postoperative complications that required operation, one trocar wound hematoma (0.6%) and one wound infection of the port site (0.6%) were observed. The late complications that required reoperation were two pouch dilatations (1.3%), three band leakages (2%), one band migration (0.6%), and one late infection of the port (0.6%). A debanding operation was necessary in one patient because of esophageal dysmotility disorder. No early or late postoperative mortality was registered. The overall reoperation rate is currently about 7%. The operation is safe and effective. Moreover, adjustable gastric banding is fully reversible and is adjustable to the patient's needs. This study verifies the importance of correct operating technique. The authors' study and experience clearly indicate that laparoscopic adjustable gastric banding is an attractive alternative in the surgical treatment of morbid obesity.


Chronotype and sleep duration: the influence of season of assessment.
Little is known about human entrainment under natural conditions, partly due to the complexity of human behavior, torn between biological and social time and influenced by zeitgebers (light-dark cycles) that are progressively "polluted" (and thereby weakened) by artificial light. In addition, data about seasonal variations in sleep parameters are scarce. We, therefore, investigated seasonal variation in cross-sectional assessments of sleep/wake times of 9765 subjects from four European populations (EGCUT = Estonian Genome Centre, University of Tartu in Estonia; KORA = Cooperative Health Research in the Region of Augsburg in Germany; KORCULA = The Korcula study in Croatia; and ORCADES = The Orkney Complex Disease Study in Scotland). We identified time-of-year dependencies for the distribution of chronotype (phase of entrainment assessed as the mid-sleep time point on free days adjusted for sleep deficit of workdays) in cohorts from Estonia (EGCUT) and Germany (KORA). Our results indicate that season (defined as daylight saving time - DST and standard zonetime periods - SZT) specifications of photoperiod influence the distribution of chronotype (adjusted for age and sex). Second, in the largest investigated sample, from Estonia (EGCUT; N = 5878), we could detect that seasonal variation in weekly average sleep duration was dependent on individual chronotype. Later chronotypes in this cohort showed significant variation in their average sleep duration across the year, especially during DST (1 h advance in social time from the end of March to end of October), while earlier chronotypes did not. Later chronotypes not only slept less during the DST period but the average chronotype of the population assessed during this period was earlier than during the SZT (local time for a respective time zone) period. More in detail, hierarchical multiple regression analyses showed that, beyond season of assessment (DST or SZT), social jetlag (SJl; the discrepancy between the mid sleep on free and work days - which varied with age and sex) contributed to a greater extent to the variation in sleep duration than chronotype (after taking into account factors that are known to influence sleep duration, i.e. age, sex and body mass index). Variation in chronotype was also dependent on age, sex, season of assessment and SJl (which is highly correlated with chronotype - SJl was larger among later chronotypes). In summary, subjective assessments of sleep/wake times are very reliable to assess internal time and sleep duration (e.g. reproducing sleep duration and timing tendencies related to age and sex across the investigated populations), but season of assessment should be regarded as a potential confounder. We identified in this study photoperiod (seasonal adaptation) and SJl as two main factors influencing seasonal variation in chronotype and sleep duration. In conclusion, season of assessment, sex and age have an effect on epidemiological variation in sleep duration, chronotype and SJl, and should be included in studies investigating associations between these phenotypes and health parameters, and on the development of optimal prevention strategies.


The Impact of Gradual and Immediate Nicotine Reduction on Subjective Cigarette Ratings.
A recent clinical trial showed that an immediate transition to very low nicotine content (VLNC) cigarettes, compared with a gradual transition, produced greater reductions in smoking behavior, smoke exposure, and dependence. However, there was less compliance with the instruction to smoke only VLNC cigarettes in the immediate versus gradual reduction condition. The goal of this study was to test whether nicotine reduction method alters subjective ratings of VLNC cigarettes, and whether subjective ratings mediate effects of nicotine reduction method on smoking behavior, smoke exposure, dependence, and compliance. This is a secondary analysis of a randomized trial conducted across 10 sites in the United States. Smokers (n = 1250) were randomized to either a control condition, or to have the nicotine content of their cigarettes reduced immediately or gradually to 0.04 mg nicotine/g of tobacco during a 20-week study period. Participants completed the modified Cigarette Evaluation Questionnaire (mCEQ). After Week 20, the immediate reduction group scored significantly lower than the gradual reduction group on multiple subscales of the mCEQ (ps < .001). The Satisfaction subscale of the mCEQ mediated the impact of nicotine reduction method on smoke exposure, smoking behavior, dependence, compliance, and abstinence. Other subscales also mediated a subset of these outcomes. An immediate reduction in nicotine content resulted in lower product satisfaction than a gradual reduction, suggesting that immediate reduction further reduces cigarette reward value. This study will provide the Food and Drug Administration with information about the impact of nicotine reduction method on cigarette reward value. These data suggest that an immediate reduction in nicotine content will result in greater reductions in cigarette satisfaction than a gradual reduction, and this reduction in satisfaction is related to changes in smoking behavior and dependence.


Unusual infections in humans.
Nine cases of unusual infections in humans are presented. In each case, we present the clinical history, histopathologic changes (if indicated), morphologic features of the causative organism, diagnosis, discussion, differential diagnosis, therapy, and current literature. All of the cases are illustrated with pertinent photographs. The nine cases are as follows: (i) acanthocephaliasis, the first acquired human infection by Moniliformis moniliformis in the United States; (ii) dipylidiasis, an uncommon infection caused by the dog tapeworm, Dipylidium caninum; (iii) granulomatous amebic encephalitis, caused by the recently identified leptomyxid group of amebae; (iv) schistosomiasis, a dual infection of the urinary bladder with the rare presentation of both adult worms and eggs of Schistosoma haematobium and Schistosoma mansoni in tissue sections; (v) syphilitic gastritis, an uncommon presentation of Treponema pallidum infection, in a patient with an additional incidental infection by Helicobacter pylori; (vi) microsporidiosis, the only infection caused by a Pleistophora sp. in humans; (vii) sporotrichosis, a rare disseminated infection caused by Sporothrix schenckii with numerous yeast cells in the scrotum; (viii) angiostrongyliasis, the first and only infection caused by Angiostrongylus costaricensis acquired in either Puerto Rico or the United States; and (ix) botryomycosis of the skin and subcutaneous tissue, caused by gram-positive cocci with an unusually large number of granules.


Training Novices in Generation and Analysis of High-Dimensional Human Cell Phospho-Flow Cytometry Data.
This article presents a single experiment designed to introduce a trainee to multiple advanced bench and analysis techniques, including high-dimensional cytometry, profiling cell signaling networks, functional assays with primary human tissue, and single-cell analysis with machine learning tools. The trainee is expected to have only minimal laboratory experience and is not required to have any prior training in flow cytometry, immunology, or data science. This article aims to introduce the advanced research areas with a design that is robust enough that novice trainees will succeed, flexible enough to allow some project customization, and fundamental enough that the skills and knowledge gained will provide a template for future experiments. For advanced users, the updated phospho-flow protocol and the established controls, best practices, and expected outcomes presented here also provide a framework for adapting these tools in new areas with unexplored biology. © 2020 by John Wiley & Sons, Inc. Basic Protocol: Phospho-protein stimulation and mass cytometry data collection Support Protocol: Analysis of signaling mass cytometry data.


Evaluation of a biodegradable PLA-PEG-PLA internal biliary stent for liver transplantation: in vitro degradation and mechanical properties.
Internal biliary stenting during biliary reconstruction in liver transplantation decrease anastomotic biliary complications. Implantation of a resorbable internal biliary stent (RIBS) is interesting since it would avoid an ablation gesture. The objective of present work was to evaluate adequacy of selected PLA-b-PEG-b-PLA copolymers for RIBS aimed to secure biliary anastomose during healing and prevent complications, such as bile leak and stricture. The kinetics of degradation and mechanical properties of a RIBS prototype were evaluated with respect to the main bile duct stenting requirements in liver transplantation. For this purpose, RIBS degradation under biliary mimicking solution versus standard phosphate buffer control solution was discussed. Morphological changes, mass loss, water uptake, molecular weight, permeability, pH variations, and mechanical properties were examined over time. The permeability and mechanical properties were evaluated under simulated biliary conditions to explore the usefulness of a PLA-b-PEG-b-PLA RIBS to secure biliary anastomosis. Results showed no pH influence on the kinetics of degradation, with degradable RIBS remaining impermeable for at least 8 weeks, and keeping its mechanical properties for 10 weeks. Complete degradation is reached at 6 months. PLA-b-PEG-b-PLA RIBS have the required in vitro degradation characteristics to secure biliary anastomosis in liver transplantation and envision in vivo applications.


Spinal anesthesia for surgery longer than 60 min in infants: experience from the first 2 years of a spinal anesthesia program.
Spinal anesthesia (SA) is being increasingly used in infants to avoid the potential negative neurocognitive effects of general anesthesia (GA). However, SA has been reported to provide a relatively short duration of surgical anesthesia. We retrospectively reviewed SA cases for surgical procedures lasting more than 60 min in children up to 3 years old. All patients received bupivacaine 0.5% (1 mg/kg up to 7 mg) with clonidine 1 µg/kg ± epinephrine. The primary outcome was success of SA without subsequent conversion to GA. Thirty-five patients met inclusion criteria (all males, age 7 ± 5 months, weight 8 ± 2 kg). Procedures included male genital, groin and multiple site surgeries. Average surgical duration was 71 ± 12 min (range 60-111 min). SA was successful in 31 of 35 patients (89%; 95% confidence interval 78, 99%). The cause of failure was rarely due to the duration of surgery (1 of 4 patients). Six patients with successful SA required sedation with dexmedetomidine ± fentanyl. Differences in procedure duration and patient characteristics were not statistically significant between successful and failed SA. SA is a highly successful technique and may offer an alternative to GA in children undergoing appropriate surgery expected to last as long as 60-100 min.


Respiratory hospitalizations of children and residential exposure to traffic air pollution in Jerusalem.
Although exposure to traffic-related air pollution has been reported to be associated with respiratory morbidity in children, this association has not been examined in Israel. Jerusalem is ranked among the leading Israeli cities in transport-related air pollution. This case-control study examined whether pediatric hospitalization for respiratory diseases in Jerusalem is related to residential exposure to traffic-related air pollution. Cases (n=4844) were Jerusalem residents aged 0-14 years hospitalized for respiratory illnesses between 2000 and 2006. These were compared to children admitted electively (n=2161) or urgently (n=3085) for non-respiratory conditions. Individual measures of exposure included distance from residence to nearest main road, the total length of main roads, traffic volume, and bus load within buffers of 50, 150, and 300m around each address. Cases were more likely to have any diesel buses passing within 50m of their home (adjusted odds ratios=1.16 and 1.10, 95% confidence intervals 1.04-1.30 and 1.01-1.20 for elective and emergency controls, respectively). Our findings indicated that older girls (5-14) and younger boys (0-4) had increased risks of respiratory hospitalization, albeit with generally widened confidence intervals due to small sample sizes. Our results add to the limited body of evidence regarding associations between diesel exhaust particles and respiratory morbidity. The findings also point to possible differential associations between traffic-related air pollution and pediatric hospitalization among boys and girls in different age groups.


Site-directed mutagenesis reveals a unique requirement for tyrosine residues in IL-7Ralpha and TSLPR cytoplasmic domains in TSLP-dependent cell proliferation.
Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine, which plays an important role in the regulation of immune responses to allergens. TSLP binds to a heterodimeric receptor complex composed of the IL-7 receptor alpha chain (IL-7Ralpha) and the TSLP receptor (TSLPR, also known as CRLF2). It has previously been suggested that the lone tyrosine residue in the mouse TSLPR cytoplasmic domain is required for cell proliferation using chimeric receptor systems. Also the role of tyrosine residues in the IL-7Ralpha cytoplasmic domain in TSLP signaling has not yet been investigated. We undertook a systematic analysis to test the role of tyrosine residues of both the IL-7Ralpha and the TSLPR in inducing cell proliferation in a growth factor dependent cell line, Ba/F3. A multiple sequence alignment of the IL-7Ralpha and TSLPR cytoplasmic domains revealed conservation of most, but not all, cytoplasmic tyrosine residues across several species. Our site-directed mutagenesis experiments revealed that the single tyrosine residue in human TSLPR was not required for TSLP-dependent cell proliferation. It has previously been reported that Y449 of human IL-7Ralpha is required for IL-7 dependent proliferation. Interestingly, in contrast to IL-7 signaling, none of tyrosine residues in the human IL-7Ralpha cytoplasmic domain were required for TSLP-dependent cell proliferation in the presence of a wild type TSLPR. However, the mutation of all cytoplasmic four tyrosine residues of human IL-7Ralpha and human TSLPR to phenylalanine residues abolished the proliferative ability of the TSLP receptor complex in response to TSLP. These results suggest that TSLP requires at least one cytoplasmic tyrosine residue to transmit proliferative signals. Unlike other members of IL-2 cytokine family, tyrosine residues in IL-7Ralpha and TSLPR cytoplasmic domains play a redundant role in TSLP-mediated cell growth.


Chromosome 13q13-q14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype.
The nosology of major psychoses is challenged by the findings that schizophrenia (SZ) and bipolar disorder (BP) share several neurobiological, neuropsychological and clinical phenotypic characteristics. Moreover, several vulnerability loci or genes may be common to the two DSM disorders. We previously reported, in a sample of 21 kindreds (sample 1), a genome-wide suggestive linkage in 13q13-q14 with a common locus (CL) phenotype that crossed the diagnostic boundaries by combining SZ, BP and schizoaffective disorders. Our objectives were to test phenotype specificity in a separate sample (sample 2) of 27 kindreds from Eastern Quebec and to also analyze the combined sample of 48 kindreds (1274 family members). We performed nonparametric and parametric analyses and tested as phenotypes: SZ alone, BP alone, and a CL phenotype. We replicated in sample 2 our initial finding with CL with a maximum NPL(pair) score of 3.36 at D13S1272 (44 Mb), only 2.1 Mb telomeric to our previous maximum result. In the combined sample, the peak with CL was at marker D13S1297 (42.1 Mb) with a NPL(pair) score reaching 5.21, exceeding that obtained in each sample and indicating consistency across the two samples. Our data suggest a susceptibility locus in 13q13-q14 that is shared by schizophrenia and mood disorder. That locus would be additional to another well documented and more distal 13q locus where the G72/G30 gene is mapped.


Cloning of a third mammalian Na+-Ca2+ exchanger, NCX3.
NCX3 is the third isoform of a mammalian Na+-Ca2+ exchanger to be cloned. NCX3 was identified from rat brain cDNA by polymerase chain reaction (PCR) using degenerate primers derived from the sequences of two conserved regions of NCX1 and NCX2. The NCX3 PCR product was used to isolate two overlapping clones totalling 4.8 kilobases (kb) from a rat brain cDNA library. The overlapping clones were sequenced and joined at a unique Bsp106I restriction enzyme site to form a full-length cDNA clone. The NCX3 cDNA clone has an open reading frame of 2.8 kb encoding a protein of 927 amino acids. At the amino acid level, NCX3 shares 73% identity with NCX1 and 75% identity with NCX2 and is predicted to share the same membrane topology as NCX1 and NCX2. Following addition of a poly(A)+ tail to the NCX3 clone, exchanger activity could be expressed in Xenopus oocytes. NCX3 was also expressed in the mammalian BHK cell line. NCX3 transcripts are 6 kb in size and are highly restricted to brain and skeletal muscle. Linkage analysis in the mouse indicated that the NCX family of genes is dispersed, since the NCX1, NCX2, and NCX3 genes mapped to mouse chromosomes 17, 7, and 12, respectively.


Surgery-induced reactive oxygen species enhance colon carcinoma cell binding by disrupting the liver endothelial cell lining.
Resection of primary colorectal cancer is associated with enhanced risk of development of liver metastases. It was previously demonstrated that surgery initiated an early inflammatory response resulting in elevated tumour cell adhesion in the liver. Because reactive oxygen species (ROS) are shown to be produced and released during surgery, the effects of ROS on the liver vascular lining and tumour cell adhesion were investigated. Human endothelial cell monolayers (human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells of the lung (HMEC-1s)) were exposed to ROS production, after which electrical impedance, cellular integrity and tumour cell adhesion were investigated. Furthermore, surgery-induced tumour cell adhesion as well as the role of ROS and liver macrophages (Kupffer cells) in this process were studied in vivo. Production of ROS decreased cellular impedance of endothelial monolayers dramatically. Moreover, formation of intercellular gaps in endothelial monolayers was observed, exposing subendothelial extracellular matrix (ECM) on which colon carcinoma cells adhered via integrin molecules. Endothelial damage was, however, prevented in the presence of ROS-scavenging enzymes. Additionally, surgery induced downregulation of both rat and human liver tight junction molecules. Treatment of rats with the ROS scavenger edaravone prevented surgery-induced tumour cell adhesion and downregulation of tight junction proteins in the liver. Interestingly, depletion of Kupffer cells prior to surgery significantly reduced the numbers of adhered tumour cells and prevented disruption of expression of tight junction proteins. In this study it is shown that surgery-induced ROS production by macrophages damages the vascular lining by downregulating tight junction proteins. This leads to exposure of ECM, to which circulating tumour cells bind. In light of this, perioperative therapeutic intervention, preventing surgery-induced inflammatory reactions, may reduce the risk of developing liver metastases, thereby improving the clinical outcome of patients with colorectal cancer.


Proposed changes to the reimbursement of pharmaceuticals and medical devices in Poland and their impact on market access and the pharmaceutical industry.
In Poland, two proposed amendments to the reimbursement act are currently in preparation; these are likely to substantially change the pricing and reimbursement landscape for both drugs and medical devices. Proposed changes include: alignment of medical device reimbursement with that of pharmaceuticals; relaxing the strict reimbursement criteria for ultra-orphan drugs; establishment of an additional funding category for vaccines; introduction of compassionate use, and a simplified reimbursement pathway for well-established off-label indications; appreciation of manufacturers' innovation and research and development efforts by creating a dedicated innovation budget; introduction of a mechanism preventing excessive parallel import; prolonged duration of reimbursement decisions and reimbursement lists; and increased flexibility in defining drug programmes. Both amendments are still at a draft stage and many aspects of the new regulations remain unclear. Nonetheless, the overall direction of some of the changes is already evident and warrants discussion due to their high expected impact on pharmaceutical and device manufacturers. Here we evaluate the main changes proposed to the reimbursement of drugs, vaccines, and medical devices, and examine the impact they are likely to have on market access and pharmaceutical industry in Poland.


The protective action decision model: theoretical modifications and additional evidence.
The Protective Action Decision Model (PADM) is a multistage model that is based on findings from research on people's responses to environmental hazards and disasters. The PADM integrates the processing of information derived from social and environmental cues with messages that social sources transmit through communication channels to those at risk. The PADM identifies three critical predecision processes (reception, attention, and comprehension of warnings or exposure, attention, and interpretation of environmental/social cues)--that precede all further processing. The revised model identifies three core perceptions--threat perceptions, protective action perceptions, and stakeholder perceptions--that form the basis for decisions about how to respond to an imminent or long-term threat. The outcome of the protective action decision-making process, together with situational facilitators and impediments, produces a behavioral response. In addition to describing the revised model and the research on which it is based, this article describes three applications (development of risk communication programs, evacuation modeling, and adoption of long-term hazard adjustments) and identifies some of the research needed to address unresolved issues.


Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy.
Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. The US Food and Drug Administration-approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.


Expanding the Active Inference Landscape: More Intrinsic Motivations in the Perception-Action Loop.
Active inference is an ambitious theory that treats perception, inference, and action selection of autonomous agents under the heading of a single principle. It suggests biologically plausible explanations for many cognitive phenomena, including consciousness. In active inference, action selection is driven by an objective function that evaluates possible future actions with respect to current, inferred beliefs about the world. Active inference at its core is independent from extrinsic rewards, resulting in a high level of robustness across e.g., different environments or agent morphologies. In the literature, paradigms that share this independence have been summarized under the notion of intrinsic motivations. In general and in contrast to active inference, these models of motivation come without a commitment to particular inference and action selection mechanisms. In this article, we study if the inference and action selection machinery of active inference can also be used by alternatives to the originally included intrinsic motivation. The perception-action loop explicitly relates inference and action selection to the environment and agent memory, and is consequently used as foundation for our analysis. We reconstruct the active inference approach, locate the original formulation within, and show how alternative intrinsic motivations can be used while keeping many of the original features intact. Furthermore, we illustrate the connection to universal reinforcement learning by means of our formalism. Active inference research may profit from comparisons of the dynamics induced by alternative intrinsic motivations. Research on intrinsic motivations may profit from an additional way to implement intrinsically motivated agents that also share the biological plausibility of active inference.


Whole-grain ready-to-eat oat cereal, as part of a dietary program for weight loss, reduces low-density lipoprotein cholesterol in adults with overweight and obesity more than a dietary program including low-fiber control foods.
Weight loss and consumption of viscous fibers both lower low-density lipoprotein (LDL) cholesterol levels. We evaluated whether or not a whole-grain, ready-to-eat (RTE) oat cereal containing viscous fiber, as part of a dietary program for weight loss, lowers LDL cholesterol levels and improves other cardiovascular disease risk markers more than a dietary program alone. Randomized, parallel-arm, controlled trial. Free-living, overweight and obese adults (N=204, body mass index 25 to 45) with baseline LDL cholesterol levels 130 to 200 mg/dL (3.4 to 5.2 mmol/L) were randomized; 144 were included in the main analysis of participants who completed the trial without significant protocol violations. Two portions per day of whole-grain RTE oat cereal (3 g/day oat b-glucan) or energy-matched low-fiber foods (control), as part of a reduced energy ( approximately 500 kcal/day deficit) dietary program that encouraged limiting consumption of foods high in energy and fat, portion control, and regular physical activity. Fasting lipoprotein levels, waist circumference, triceps skinfold thickness, and body weight were measured at baseline and weeks 4, 8, 10, and 12. LDL cholesterol level was reduced significantly more with whole-grain RTE oat cereal vs control (-8.7+/-1.0 vs -4.3+/-1.1%, P=0.005). Total cholesterol (-5.4+/-0.8 vs -2.9+/-0.9%, P=0.038) and non-high-density lipoprotein-cholesterol (-6.3+/-1.0 vs -3.3+/-1.1%, P=0.046) were also lowered significantly more with whole-grain RTE oat cereal, whereas high-density lipoprotein and triglyceride responses did not differ between groups. Weight loss was not different between groups (-2.2+/-0.3 vs -1.7+/-0.3 kg, P=0.325), but waist circumference decreased more (-3.3+/-0.4 vs -1.9+/-0.4 cm, P=0.012) with whole-grain RTE oat cereal. Larger reductions in LDL, total, and non-high-density lipoprotein cholesterol levels and waist circumference were evident as early as week 4 in the whole-grain RTE oat cereal group. Consumption of a whole-grain RTE oat cereal as part of a dietary program for weight loss had favorable effects on fasting lipid levels and waist circumference.


Diversifying selection and host adaptation in two endosymbiont genomes.
The endosymbiont Wolbachia pipientis infects a broad range of arthropod and filarial nematode hosts. These diverse associations form an attractive model for understanding host:symbiont coevolution. Wolbachia's ubiquity and ability to dramatically alter host reproductive biology also form the foundation of research strategies aimed at controlling insect pests and vector-borne disease. The Wolbachia strains that infect nematodes are phylogenetically distinct, strictly vertically transmitted, and required by their hosts for growth and reproduction. Insects in contrast form more fluid associations with Wolbachia. In these taxa, host populations are most often polymorphic for infection, horizontal transmission occurs between distantly related hosts, and direct fitness effects on hosts are mild. Despite extensive interest in the Wolbachia system for many years, relatively little is known about the molecular mechanisms that mediate its varied interactions with different hosts. We have compared the genomes of the Wolbachia that infect Drosophila melanogaster, wMel and the nematode Brugia malayi, wBm to that of an outgroup Anaplasma marginale to identify genes that have experienced diversifying selection in the Wolbachia lineages. The goal of the study was to identify likely molecular mechanisms of the symbiosis and to understand the nature of the diverse association across different hosts. The prevalence of selection was far greater in wMel than wBm. Genes contributing to DNA metabolism, cofactor biosynthesis, and secretion were positively selected in both lineages. In wMel there was a greater emphasis on DNA repair, cell division, protein stability, and cell envelope synthesis. Secretion pathways and outer surface protein encoding genes are highly affected by selection in keeping with host:parasite theory. If evidence of selection on various cofactor molecules reflects possible provisioning, then both insect as well as nematode Wolbachia may be providing substances to hosts. Selection on cell envelope synthesis, DNA replication and repair machinery, heat shock, and two component switching suggest strategies insect Wolbachia may employ to cope with diverse host and intra-host environments.


Directed Therapy: An Approach to the Improved Treatment of Exfoliation syndrome.
Exfoliation syndrome (XFS) is an age-related, generalized disorder of the extracellular matrix characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues and is the most common identifiable cause of open-angle glaucoma worldwide. Exfoliation syndrome plays an etiologic role in open-angle glaucoma, angle-closure glaucoma, cataract, and retinal vein occlusion. It is accompanied by an increase in serious complications at the time of cataract extraction, such as zonular dialysis, capsular rupture, and vitreous loss. It is associated systemically with an increasing number of vascular disorders, hearing loss, and Alzheimer's disease. Exfoliation syndrome appears to be a disease of elastic tissue microfibrils. Directed therapy simply means devising specific treatments for specific diseases. There was little incentive to attempt to distinguish between various open-angle glaucomas if the treatments were essentially the same. However, this view also prevented the application of directed therapy in those instances in which such was available and applicable. Pilocarpine has multiple beneficial actions in eyes with XFS. Not only does it lower IOP, but by increasing aqueous outflow, it should enable the trabecular meshwork to clear more rapidly, and by limiting pupillary movement, should slow the progression of the disease. Theoretically, miotics should be the first line of treatment. Pilocarpine 2% q.h.s. can provide sufficient limitation of pupillary mobility without causing these side effects. In 2007, two common single nucleotide polymorphisms in the coding region of the lysyl oxidase-like 1 (LOXL1) gene located on chromosome 15 were specifically associated with XFS and XFG. LOXL1 is a member of the lysyl oxidase family of enzymes, which are essential for the formation, stabilization, maintenance, and remodelling of elastic fibers and prevent age-related loss of elasticity of tissues. LOXL1 protein is a major component of exfoliation deposits and appears to play a role in its accumulation and in concomitant elastotic processes in intra- and extraocular tissues of XFS patients. This discovery should open the way to new approaches and directions of therapy for this protean disorder.


High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.
Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28-30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer. Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30-20.10, P=0.02). Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.


Down-regulation of aryl hydrocarbon receptor intensifies carcinogen-induced retinal lesion via SOCS3-STAT3 signaling.
The aryl hydrocarbon receptor (AHR) is a ligand-activated receptor that regulates the metabolism of several xenobiotics and participates in ocular inflammation. Although severe inflammation is a major risk of retinal damage, the underlying mechanism is not well established. In this study, to elucidate how AHR mediates inflammation homeostasis, we hypothesized that AHR expression may diminish during long-term exposure to benzo [a] pyrene (B [a]P), a carcinogen in cigarette smoke. The blockage of AHR function considerably impaired suppressor of cytokine signaling 3 (SOCS3) negative feedback regulation and upregulated B [a]P-induced pro-inflammation. Signal transducer and activator of transcription 3 (STAT3) was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells (ARPE-19). The STAT3-inducible element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type ARPE-19 cells. Moreover, AHR dysfunction led to STAT3 hypo-ubiquitination and changed the STAT3-SOCS3 interaction. Increased STAT3-SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in ARPE-19 cells. Furthermore, the in vivo results showed that STAT3 inhibition during AHR impairment by long-term B [a] P exposure preserved the retina thickness and reversed the visual function in male C57Bl/6 mice. Overall, long-term B [a] P exposure may attenuate AHR function, dysregulating the homeostasis of the SOCS3-STAT3 axis with intensive STAT3 activation. This finding is significant given that the disintegration of the AHR-SOCS3 axis is a sensitive factor involved in AMD-like lesion development in the retina, revealing that the low AHR level may be associated with cigarette smoking or xenobiotics exposure, causing retina inflammation and damage.


Coherent Electron Trajectory Control in Graphene.
We investigate coherent electron dynamics in graphene, interacting with the electric field waveform of two orthogonally polarized, few-cycle laser pulses. Recently, we demonstrated that linearly polarized driving pulses lead to sub-optical-cycle Landau-Zener quantum path interference by virtue of the combination of intraband motion and interband transition [Higuchi et al., Nature 550, 224 (2017)NATUAS0028-083610.1038/nature23900]. Here we introduce a pulsed control laser beam, orthogonally polarized to the driving pulses, and observe the ensuing electron dynamics. The relative delay between the two pulses is a tuning parameter to control the electron trajectory, now in a complex fashion exploring the full two-dimensional reciprocal space in graphene. Depending on the relative phase, the electron trajectory in the reciprocal space can, e.g., be deformed to suppress the quantum path interference resulting from the driving laser pulse. Intriguingly, this strong-field-based complex matter wave manipulation in a two-dimensional conductor is driven by a high repetition rate laser oscillator, rendering unnecessary complex and expensive amplified laser systems.


Prosthesis-Specific Predictors of Paravalvular Regurgitation after Transcatheter Aortic Valve Replacement: Impact of Calcification and Sizing on Balloon-Expandable versus Self-Expandable Transcatheter Heart Valves.
The study aim was to investigate prosthesis-specific predictors for paravalvular aortic regurgitation (PAR) in self-expandable versus balloon-expandable transcatheter heart valves (THVs). PAR is frequently observed after transcatheter aortic valve replacement (TAVR). As self-expandable and balloon-expandable THVs engage differently with the native aortic valve structures, factors that impact PAR may differ between the prosthesis types. A total of 137 TAVR patients who underwent pre-procedural multidetector computed tomography and post-procedural transthoracic echocardiography were studied. Predictors for PAR, including annulus area oversizing and aortic valve calcification mass and volume, were analyzed in a multivariate model. The Medtronic CoreValve (MCV) prosthesis was utilized in 68 patients (50%), and the Edwards SAPIEN (ES) prosthesis in 69 (50%). More than mild PAR was observed in 43 patients (32%). Among MCV patients, aortic valve calcification volume and mass were higher in those with more than mild PAR than in those with none or mild PAR (p = 0.04, p = 0.03, respectively). Among ES patients, the annulus area and perimeter oversizing were lower in those with more than mild PAR compared to those with no or mild PAR (p = 0.001). By univariate and multivariate logistic regression analysis, aortic valve calcification mass was the only independent predictor for PAR in MCV patients (p = 0.02), whereas in ES patients it was THV undersizing (p = 0.002), irrespective of the calcific burden. For self-expandable THVs, aortic valve calcification mass was the strongest predictor of PAR, whereas for balloon-expandable THVs it was prosthesis undersizing. Hence, in patients evaluated for TAVR these parameters should guide the selection of prosthesis type.


A deficit in contralesional object representation associated with attentional limitations after parietal damage.
Stankiewicz, Hummel, and Cooper (1998) proposed that detailed coding of part-whole relations for objects is contingent on objects being attended. We report a neuropsychological test of this assertion. We examined the effects of left-right reflection on object matching in a group of patients with parietal damage and impaired attention to the contralesional side of space (Experiment 1). The patients were poor at matching objects subject to left-right reflection, relative to identical stimuli (Experiment 2). This was not due to a lack of sensitivity to information on the contralesional side. In a subsequent study, the patients were better at matching identical whole objects at fixation than when they just received half the object in their ipsilesional field (Experiment 3). However, unlike both nonlesioned controls and control patients with frontal lesions, the parietal patients were unaffected by altering the relative spatial locations of object features in their contralesional field (Experiment 4). The basic result, of poor performance with left-right-reflected items, was also replicated using a priming rather than an explicit matching procedure (Experiment 5). These results provide confirmation that visual attention, mediated by the posterior parietal cortex, is important for generating part-whole codes that facilitate the matching of mirror-reflected objects.


Magnetic microrheometry of tumor-relevant stiffness levels and probabilistic quantification of viscoelasticity differences inside 3D cell culture matrices.
The progression of breast cancer involves cancer-cell invasions of extracellular matrices. To investigate the progression, 3D cell cultures are widely used along with different types of matrices. Currently, the matrices are often characterized using parallel-plate rheometry for matrix viscoelasticity, or liquid-like viscous and stiffness-related elastic characteristics. The characterization reveals averaged information and sample-to-sample variation, yet, it neglects internal heterogeneity within matrices, experienced by cancer cells in 3D culture. Techniques using optical tweezers and magnetic microrheometry have measured heterogeneity in viscoelasticity in 3D culture. However, there is a lack of probabilistic heterogeneity quantification and cell-size-relevant, microscale-viscoelasticity measurements at breast-tumor tissue stiffness up to ≃10 kPa in Young's modulus. Here, we have advanced methods, for the purpose, which use a magnetic microrheometer that applies forces on magnetic spheres within matrices, and detects the spheres displacements. We present probabilistic heterogeneity quantification using microscale-viscoelasticity measurements in 3D culture matrices at breast-tumor-relevant stiffness levels. Bayesian multilevel modeling was employed to distinguish heterogeneity in viscoelasticity from the effects of experimental design and measurement errors. We report about the heterogeneity of breast-tumor-relevant agarose, GrowDex, GrowDex-collagen and fibrin matrices. The degree of heterogeneity differs for stiffness, and phase angle (i.e. ratio between viscous and elastic characteristics). Concerning stiffness, agarose and GrowDex show the lowest and highest heterogeneity, respectively. Concerning phase angle, fibrin and GrowDex-collagen present the lowest and the highest heterogeneity, respectively. While this heterogeneity information involves softer matrices, probed by ≃30 μm magnetic spheres, we employ larger ≃100 μm spheres to increase magnetic forces and acquire a sufficient displacement signal-to-noise ratio in stiffer matrices. Thus, we show pointwise microscale viscoelasticity measurements within agarose matrices up to Young's moduli of 10 kPa. These results establish methods that combine magnetic microrheometry and Bayesian multilevel modeling for enhanced heterogeneity analysis within 3D culture matrices.


Self-rated global measure of the frequency, intensity, and burden of side effects.
No standard side-effect measure currently available can be easily used in clinical practice for patients receiving treatment for depression. The Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) Scale was developed to document these three domains of side effects in patients treated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project. This article presents data on the reliability and validity of the FIBSER. The STAR*D prospectively enrolled 4,041 outpatients with nonpsychotic major depressive disorder (MDD) who were seeking medical care (as opposed to symptomatic volunteers recruited via advertisements). The patients were treated with citalopram. Clinical assessments, including the FIBSER, were completed at 2, 4, 6, 9, 12, and, if necessary, 14 weeks after enrollment. The FIBSER was shown to be reliable, with high correlations between observations taken a short time apart, and correlations decreasing as time between observations increased. There were also consistent relationships between items over time. The FIBSER has both face and construct validity. Thus, the FIBSER is a reliable and valid self-report measure of side effects in a population receiving treatment for depression. Although it does not measure the impact of specific side effects, it does measure three domains of impact: frequency, intensity, and burden of the side effects. Its brevity makes it a useful tool for routine clinical practice. These advantages are not available in other side-effect measures.


The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection.
Urinary catheter use is prevalent in health care settings, and polymicrobial colonization by urease-positive organisms, such as Proteus mirabilis and Providencia stuartii, commonly occurs with long-term catheterization. We previously demonstrated that coinfection with P. mirabilis and P. stuartii increased overall urease activity in vitro and disease severity in a model of urinary tract infection (UTI). In this study, we expanded these findings to a murine model of catheter-associated UTI (CAUTI), delineated the contribution of enhanced urease activity to coinfection pathogenesis, and screened for enhanced urease activity with other common CAUTI pathogens. In the UTI model, mice coinfected with the two species exhibited higher urine pH values, urolithiasis, bacteremia, and more pronounced tissue damage and inflammation compared to the findings for mice infected with a single species, despite having a similar bacterial burden within the urinary tract. The presence of P. stuartii, regardless of urease production by this organism, was sufficient to enhance P. mirabilis urease activity and increase disease severity, and enhanced urease activity was the predominant factor driving tissue damage and the dissemination of both organisms to the bloodstream during coinfection. These findings were largely recapitulated in the CAUTI model. Other uropathogens also enhanced P. mirabilis urease activity in vitro, including recent clinical isolates of Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa We therefore conclude that the underlying mechanism of enhanced urease activity may represent a widespread target for limiting the detrimental consequences of polymicrobial catheter colonization, particularly by P. mirabilis and other urease-positive bacteria.


Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate.
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2 (-/-)) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2 (-/-) mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.


Variations in reporting of outcomes in randomized trials on diet and physical activity in pregnancy: A systematic review.
Trials on diet and physical activity in pregnancy report on various outcomes. We aimed to assess the variations in outcomes reported and their quality in trials on lifestyle interventions in pregnancy. We searched major databases without language restrictions for randomized controlled trials on diet and physical activity-based interventions in pregnancy up to March 2015. Two independent reviewers undertook study selection and data extraction. We estimated the percentage of papers reporting 'critically important' and 'important' outcomes. We defined the quality of reporting as a proportion using a six-item questionnaire. Regression analysis was used to identify factors affecting this quality. Sixty-six randomized controlled trials were published in 78 papers (66 main, 12 secondary). Gestational diabetes (57.6%, 38/66), preterm birth (48.5%, 32/66) and cesarian section (60.6%, 40/66), were the commonly reported 'critically important' outcomes. Gestational weight gain (84.5%, 56/66) and birth weight (87.9%, 58/66) were reported in most papers, although not considered critically important. The median quality of reporting was 0.60 (interquartile range 0.25, 0.83) for a maximum score of one. Study and journal characteristics did not affect quality. Many studies on lifestyle interventions in pregnancy do not report critically important outcomes, highlighting the need for core outcome set development.


A matter of hand: Causal links between hand dominance, structural organization of fronto-parietal attention networks, and variability in behavioural responses to transcranial magnetic stimulation.
Considerable evidence suggests that, on a group level, human visuospatial attention is asymmetrically organized, with a right-hemispheric dominance. The asymmetrical organization of the superior longitudinal fasciculus (SLF) has been shown to account for the right-hemispheric dominance in visual attention. However, such account is by no means universal, and large individual differences in asymmetrical performance on visuospatial tasks have been reported. Furthermore, the variability in the SLF lateralization has been shown to correlate with behavioural asymmetries. Continuous theta burst stimulation (cTBS) enables to temporarily interfere with cortical activity. cTBS applied over the posterior parietal cortex (PPC) has been previously used to systematically study attentional asymmetries. Interestingly, large individual differences in the effectiveness of stimulation have been reported. In accordance with earlier both animal and human studies, one possible cause underlying these striking individual differences might lie in the structural organization of frontoparietal pathways subserving visuospatial attention. Thus, the current study employed diffusion tractography to examine the relationship between the variability in the structural organization of the SLF and the individual differences in attentional shifts induced by a modified cTBS (cTBSmod; triplets of pulses at 30 Hz, repeated at 6 Hz) applied over the IPS, as measured by a line bisection task. Consistent with previous studies, on a group level, cTBSmod applied over the right intraparietal sulcus (IPS) triggered a rightward bisection bias shift, and there were no significant effects of cTBSmod applied over the left IPS. However, further analyses demonstrated that both handedness and structural variability (as assessed based on hindrance modulated orientational anisotropy) within the middle and the ventral branches of the SLF predicted individual differences in the cTBSmod-induced attentional shifts. Our study thus suggests that the effects of cTBSmod over the IPS may depend on intra-hemispheric interactions between cortical loci controlling visual attention. To conclude, our findings provide converging evidence for the notion put forward previously that inter-individual variability in the structural organization of intra-hemispheric frontoparietal connections has important implications for the functional models of human visual attention. Moreover, we hypothesize that this may also be relevant for the understanding of attentional disorders and their rehabilitation.


Revision lateral skull base surgery.
To describe functional and reconstructive results after revision lateral skull base surgery with comparison of benign and malignant lesions. Retrospective case review. Tertiary referral center. All patients undergoing revision surgery for benign and malignant lateral skull base tumors. Surgical resection of recurrent lateral skull base tumors and reconstruction of resulting defects. Cranial nerve function postoperative complications. Forty operations for recurrent lateral skull base tumors occurred between January 1, 1987, and December 31, 2003, with follow-up of at least 1 year. Thirty-three operations were for benign lesions, 27 of which were glomus tumors. Seven operations were for malignant tumors. Fifty-eight percent of patients had preoperative cranial nerve deficits (66% of benign tumors and 14% of malignancies). The most common preoperative deficit occurred in the Xth cranial nerve. Postoperative cranial nerve deficits were seen in 95% of patients and multiple nerve deficits were seen in 75%. The most common postoperative deficits were observed in the IXth and Xth cranial nerves. Thirty-one patients had one previous procedure, six had two previous procedures, and three had three previous procedures. Abdominal fat and temporoparietal fascia were the most common reconstruction materials. There was one case of meningitis, two cerebrospinal fluid leaks, and one pseudomeningocele. There was one recurrent adenoid cystic tumor resulting in death and two partially resected glomus tumors. Subsequent procedures are discussed. Postoperative cranial deficits are more common after revision skull base surgery than after primary surgery. Complete resection without recurrence can be expected for revision skull base surgery. Modern reconstruction techniques reduce major postoperative complications and morbidity from cranial nerve deficits.


Benzodiazepine use and abuse in Canada.
Benzodiazepines are frequently prescribed, yet the extent of their use in Canada has not been described. Such data would be valuable in assessing patient exposure to benzodiazepines and would provide a context to estimate the risk-benefit ratio of these drugs. Analysis of benzodiazepine sales in 1978-87 in Canada, expressed as the defined daily dose (DDD) per 1000 inhabitants per day, showed that the use of these drugs was stable during the first half of the decade, at 33 DDD/1000 inhabitants per day, then steadily increased from 1983 to 1987, reaching 48 DDD/1000 inhabitants per day in 1987. The total use of slowly eliminated benzodiazepines declined, whereas the overall use of rapidly eliminated benzodiazepines increased linearly. In 1978-83 Canada had the second-lowest total benzodiazepine use among several Western countries. The patterns of use and abuse of rapidly eliminated benzodiazepines in 1978-84 showed a close correlation. Our findings indicate that data on drug use can be monitored and linked to clinical data, providing a mechanism for monitoring the relation between use and related illness.


Approximate analyses of the refractive attenuation of laser beam intensities by turbulent absorbing media.
Consideration is given to certain physical phenomena that can attenuate the intensity of a laser beam by refractively spreading or scattering the beam as it propagates. The total attenuation caused by these effects can be well above the usual geometric spreading and absorption losses. Two specific phenomena are analyzed: the nonlinear thermal blooming of the beam (thermal lens effect) and the spreading caused by random variations of the index of refraction of the medium in which the beam is propagating (turbulence effects). The intent of the investigation is to obtain reasonably simple analytic expressions that can be used to estimate or set bounds on the extent of the attenuation. Such expressions are obtained for both the transient and the steady-state effects of thermal blooming when the medium is moving relative to the laser beam, and various estimates are also obtained for the turbulence-induced attenuation of the peak intensity of a beam. For comparison, estimates are also given of the effective attenution of the beam when it is viewed by a fixed observer, if there are random variations in its direction of propagation.


Bed-nets (mosquito-nets) and morbidity from malaria.
A study was undertaken in the Farafenni area of The Gambia to determine the relation between morbidity from malaria in children and the use of bed-nets (mosquito-nets). From comparisons of parasite and spleen rates in bed-net users and in non-users it seemed that bed-nets had a strong protective effect. However, the prevalence of malaria in the study population was also influenced by ethnic group and place of residence, and the association of bed-net use with these two confounding factors accounted for some of the differences observed between bed-net users and non-users. Nevertheless, a significant inverse correlation between splenomegaly and the use of bed-nets remained. This suggests that bed-nets give Gambian children some protection against malaria and that the use of bed-nets, either untreated or treated with an insecticide such as permethrin, should be investigated further as a means of malaria control in Africa.


Dutch patients, retail chicken meat and poultry share the same ESBL genes, plasmids and strains.
Intestinal carriage of extended-spectrum beta-lactamase (ESBL) -producing bacteria in food-producing animals and contamination of retail meat may contribute to increased incidences of infections with ESBL-producing bacteria in humans. Therefore, distribution of ESBL genes, plasmids and strain genotypes in Escherichia coli obtained from poultry and retail chicken meat in the Netherlands was determined and defined as 'poultry-associated' (PA). Subsequently, the proportion of E. coli isolates with PA ESBL genes, plasmids and strains was quantified in a representative sample of clinical isolates. The E. coli were derived from 98 retail chicken meat samples, a prevalence survey among poultry, and 516 human clinical samples from 31 laboratories collected during a 3-month period in 2009. Isolates were analysed using an ESBL-specific microarray, sequencing of ESBL genes, PCR-based replicon typing of plasmids, plasmid multi-locus sequence typing (pMLST) and strain genotyping (MLST). Six ESBL genes were defined as PA (bla(CTX-M-1) , bla(CTX-M-2) , bla(SHV-2) , bla(SHV-12) , bla(TEM-20) , bla(TEM-52) ): 35% of the human isolates contained PA ESBL genes and 19% contained PA ESBL genes located on IncI1 plasmids that were genetically indistinguishable from those obtained from poultry (meat). Of these ESBL genes, 86% were bla(CTX-M-1) and bla(TEM-52) genes, which were also the predominant genes in poultry (78%) and retail chicken meat (75%). Of the retail meat samples, 94% contained ESBL-producing isolates of which 39% belonged to E. coli genotypes also present in human samples. These findings are suggestive for transmission of ESBL genes, plasmids and E. coli isolates from poultry to humans, most likely through the food chain.


A 0-Hour/1-Hour Protocol for Safe, Early Discharge of Chest Pain Patients.
Guidelines recommend a 0-hour/1-hour high-sensitivity cardiac troponin T (hs-cTnT) diagnostic strategy in acute chest pain patients. There are, however, little data on the performance of this strategy when combined with clinical risk stratification. We aimed to evaluate the diagnostic accuracy of an accelerated diagnostic protocol (ADP) using the 0-hour/1-hour hs-cTnT strategy together with an adapted Thrombolysis In Myocardial Infarction (TIMI) score and electrocardiogram (ECG) for ruling out major adverse cardiac events (MACE) within 30 days. This prospective observational study enrolled consecutive emergency department (ED) chest pain patients. TIMI score variables, ED physicians' assessments of the ECG, and 0- and 1-hour hs-cTnT were collected. Thirty-day MACE was defined as acute myocardial infarction (AMI), unstable angina (UA), cardiogenic shock, ventricular arrhythmia, atrioventricular block, cardiac arrest, or death of cardiac or unknown cause. A total of 1,020 patients were included in the final analysis. The combination of an adapted TIMI score ≤1, a nonischemic ECG, and either a 0-hour hs-cTnT < 5 ng/L or a 0-hour hs-cTnT < 12 ng/L combined with a 1-hour increase < 3 ng/L identified 432 (42.4%) patients as very low risk with a negative predictive value of 99.5% (95% confidence interval [CI] = 98.3%-99.9%) and a negative likelihood ratio of 0.04 (95% CI = 0.01-0.14) for 30-day MACE. The ADP missed only two patients with UA and no patients with AMI or other forms of MACE. An ADP using the guideline recommended 0-hour/1-hour hs-cTnT strategy rapidly identified patients with a very low risk of 30-day MACE including UA where no further cardiac testing would be needed. This could potentially allow safe early discharge of about 40% of ED chest pain patients.