A cluster randomised controlled trial of the efficacy of a brief walking intervention delivered in primary care: study protocol.
The aim of the present research is to conduct a fully powered explanatory trial to evaluate the efficacy of a brief self-regulation intervention to increase walking. The intervention will be delivered in primary care by practice nurses (PNs) and Healthcare Assistants (HCAs) to patients for whom increasing physical activity is a particular priority. The intervention has previously demonstrated efficacy with a volunteer population, and subsequently went through an iterative process of refinement in primary care, to maximise acceptability to both providers and recipients. This two arm cluster randomised controlled trial set in UK general practices will compare two strategies for increasing walking, assessed by pedometer, over six months. Patients attending practices randomised to the self-regulation intervention arm will receive an intervention consisting of behaviour change techniques designed to increase walking self-efficacy (confidence in ability to perform the behaviour), and to help people translate their "good" intentions into behaviour change by making plans. Patients attending practices randomised to the information provision arm will receive written materials promoting walking, and a short unstructured discussion about increasing their walking.The trial will recruit 20 PN/HCAs (10 per arm), who will be trained by the research team to deliver the self-regulation intervention or information provision control intervention, to 400 patients registered at their practices (20 patients per PN/HCA). This will provide 85% power to detect a mean difference of five minutes/day walking between the self-regulation intervention group and the information provision control group. Secondary outcomes include health services costs, and intervention effects in sub-groups defined by age, ethnicity, gender, socio-economic status, and clinical condition. A mediation analysis will investigate the extent to which changes in constructs specified by the Theory of Planned Behaviour lead to changes in objectively assessed walking behaviour. This trial addresses the current lack of evidence for interventions that are effective at increasing walking and that can be offered to patients in primary care. The intervention being evaluated has demonstrated efficacy, and has been through an extensive process of adaptation to ensure acceptability to both provider and recipient, thus optimising fidelity of intervention delivery and treatment receipt. It therefore provides a strong test of the hypothesis that a self-regulation intervention can help primary care patients increase their walking. Current Controlled Trials ISRCTN95932902.


Traumatic brain injury dysregulates microRNAs to modulate cell signaling in rat hippocampus.
Traumatic brain injury (TBI) is a common cause for cognitive and communication problems, but the molecular and cellular mechanisms are not well understood. Epigenetic modifications, such as microRNA (miRNA) dysregulation, may underlie altered gene expression in the brain, especially hippocampus that plays a major role in spatial learning and memory and is vulnerable to TBI. To advance our understanding of miRNA in pathophysiological processes of TBI, we carried out a time-course microarray analysis of microRNA expression profile in rat ipsilateral hippocampus and examined histological changes, apoptosis and synapse ultrastructure of hippocampus post moderate TBI. We found that 10 out of 156 reliably detected miRNAs were significantly and consistently altered from one hour to seven days after injury. Bioinformatic and gene ontology analyses revealed 107 putative target genes, as well as several biological processes that might be initiated by those dysregulated miRNAs. Among those differentially expressed microRNAs, miR-144, miR-153 and miR-340-5p were confirmed to be elevated at all five time points after TBI by quantitative RT-PCR. Western blots showed three of the predicated target proteins, calcium/calmodulin-dependent serine protein kinase (CASK), nuclear factor erythroid 2-related factor 2 (NRF2) and alpha-synuclein (SNCA), were concurrently down- regulated, suggesting that miR-144, miR-153 and miR-340-5p may play important roles collaboratively in the pathogenesis of TBI-induced cognitive and memory impairments. These microRNAs might serve as potential targets for progress assessment and intervention against TBI to mitigate secondary damage to the brain.


Dissection of the mechanism of manganese porphyrin-catalyzed chlorine dioxide generation.
Chlorine dioxide, an industrially important biocide and bleach, is produced rapidly and efficiently from chlorite ion in the presence of water-soluble, manganese porphyrins and porphyrazines at neutral pH under mild conditions. The electron-deficient manganese(III) tetra-(N,N-dimethyl)imidazolium porphyrin (MnTDMImP), tetra-(N,N-dimethyl)benzimidazolium (MnTDMBImP) porphyrin, and manganese(III) tetra-N-methyl-2,3-pyridinoporphyrazine (MnTM23PyPz) were found to be the most efficient catalysts for this process. The more typical manganese tetra-4-N-methylpyridiumporphyrin (Mn-4-TMPyP) was much less effective. Rates for the best catalysts were in the range of 0.24-32 TO/s with MnTM23PyPz being the fastest. The kinetics of reactions of the various ClO(x) species (e.g., chlorite ion, hypochlorous acid, and chlorine dioxide) with authentic oxomanganese(IV) and dioxomanganese(V)MnTDMImP intermediates were studied by stopped-flow spectroscopy. Rate-limiting oxidation of the manganese(III) catalyst by chlorite ion via oxygen atom transfer is proposed to afford a trans-dioxomanganese(V) intermediate. Both trans-dioxomanganese(V)TDMImP and oxoaqua-manganese(IV)TDMImP oxidize chlorite ion by 1-electron, generating the product chlorine dioxide with bimolecular rate constants of 6.30 × 10(3) M(-1) s(-1) and 3.13 × 10(3) M(-1) s(-1), respectively, at pH 6.8. Chlorine dioxide was able to oxidize manganese(III)TDMImP to oxomanganese(IV) at a similar rate, establishing a redox steady-state equilibrium under turnover conditions. Hypochlorous acid (HOCl) produced during turnover was found to rapidly and reversibly react with manganese(III)TDMImP to give dioxoMn(V)TDMImP and chloride ion. The measured equilibrium constant for this reaction (K(eq) = 2.2 at pH 5.1) afforded a value for the oxoMn(V)/Mn(III) redox couple under catalytic conditions (E' = 1.35 V vs NHE). In subsequent processes, chlorine dioxide reacts with both oxomanganese(V) and oxomanganese(IV)TDMImP to afford chlorate ion. Kinetic simulations of the proposed mechanism using experimentally measured rate constants were in agreement with observed chlorine dioxide growth and decay curves, measured chlorate yields, and the oxoMn(IV)/Mn(III) redox potential (1.03 V vs NHE). This acid-free catalysis could form the basis for a new process to make ClO(2).


Quantification of physical and biological uncertainty in the simulation of the yield of a tropical crop using present-day and doubled CO2 climates.
The impacts of climate change on crop productivity are often assessed using simulations from a numerical climate model as an input to a crop simulation model. The precision of these predictions reflects the uncertainty in both models. We examined how uncertainty in a climate (HadAM3) and crop General Large-Area Model (GLAM) for annual crops model affects the mean and standard deviation of crop yield simulations in present and doubled carbon dioxide (CO2) climates by perturbation of parameters in each model. The climate sensitivity parameter (gamma, the equilibrium response of global mean surface temperature to doubled CO2) was used to define the control climate. Observed 1966-1989 mean yields of groundnut (Arachis hypogaea L.) in India were simulated well by the crop model using the control climate and climates with values of gamma near the control value. The simulations were used to measure the contribution to uncertainty of key crop and climate model parameters. The standard deviation of yield was more affected by perturbation of climate parameters than crop model parameters in both the present-day and doubled CO2 climates. Climate uncertainty was higher in the doubled CO2 climate than in the present-day climate. Crop transpiration efficiency was key to crop model uncertainty in both present-day and doubled CO2 climates. The response of crop development to mean temperature contributed little uncertainty in the present-day simulations but was among the largest contributors under doubled CO2. The ensemble methods used here to quantify physical and biological uncertainty offer a method to improve model estimates of the impacts of climate change.


Endogenous and exogenous factors controlling temporal abundance patterns of tropical mosquitoes.
The growing demand for efficient and effective mosquito control requires a better understanding of vector population dynamics and how these are modified by endogenous and exogenous factors. A long-term (11-year) monitoring data set describing the relative abundance of the saltmarsh mosquito (Aedes vigilax) in the greater Darwin region, northern Australia, was examined in a suite of Gompertz-logistic (GL) models with and without hypothesized environmental correlates (high tide frequency, rainfall, and relative humidity). High tide frequency and humidity were hypothesized to influence saltmarsh mosquito abundance positively, and rainfall was hypothesized to correlate negatively by reducing the availability of suitable habitats (moist substrata) required by ovipositing adult female mosquitoes. We also examined whether environmental correlates explained the variance in seasonal carrying capacity (K) because environmental stochasticity is hypothesized to modify population growth rate (r), carrying capacity, or both. Current and lagged-time effects were tested by comparing alternative population dynamics models using three different information criteria (Akaike's Information Criterion [corrected; AIC(c)], Bayesian Information Criterion [BIC], and cross-validation [C-V]). The GL model with a two-month lag without environmental effects explained 31% of the deviance in population growth rate. This increased to > 70% under various model combinations of high tide frequency, rainfall, and relative humidity, of which, high tide frequency and rainfall had the highest contributions. Temporal variation in K was explained weakly by high tide frequency, and there was some evidence that the filling of depressions to reduce standing water availability has reduced Aedes vigilax carrying capacity over the study period. This study underscores the need to consider simultaneously both types of drivers (endogenous and exogenous) when predicting mosquito abundance and population growth patterns. This work also indicates that climate change, via continued increases in rainfall and higher expected frequencies and intensities of high tide events with sea level rise, will alter mosquito abundance trends in northern Australia.


When the optimal is not the best: parameter estimation in complex biological models.
The vast computational resources that became available during the past decade enabled the development and simulation of increasingly complex mathematical models of cancer growth. These models typically involve many free parameters whose determination is a substantial obstacle to model development. Direct measurement of biochemical parameters in vivo is often difficult and sometimes impracticable, while fitting them under data-poor conditions may result in biologically implausible values. We discuss different methodological approaches to estimate parameters in complex biological models. We make use of the high computational power of the Blue Gene technology to perform an extensive study of the parameter space in a model of avascular tumor growth. We explicitly show that the landscape of the cost function used to optimize the model to the data has a very rugged surface in parameter space. This cost function has many local minima with unrealistic solutions, including the global minimum corresponding to the best fit. The case studied in this paper shows one example in which model parameters that optimally fit the data are not necessarily the best ones from a biological point of view. To avoid force-fitting a model to a dataset, we propose that the best model parameters should be found by choosing, among suboptimal parameters, those that match criteria other than the ones used to fit the model. We also conclude that the model, data and optimization approach form a new complex system and point to the need of a theory that addresses this problem more generally.


Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.
The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.


Predictors of mortality in the prospective Dubbo study of Australian elderly.
A prospective study in non-institutionalised Australian elderly 60 years and over commenced in Dubbo, NSW in 1988. To examine clinical and socio-demographic predictors of all-causes mortality. The data were derived from a community-based sample comprising 1236 men and 1569 women followed for a median period of 62 months. Two hundred and thirty five men (19%) and 184 women (12%) died, 46% of male and 53% of female deaths respectively related to cardiovascular disease. In a proportional hazards model, the significant predictors of mortality were: older age, being married (relative risk [RR] = 0.71 for men, 0.74 for women), current smoking for men (RR = 3.11), taking more than three alcoholic drinks per day for men (RR = 0.37), prior coronary heart disease for men (RR = 1.36), severe hypertension for women (RR = 1.99), use of anti-hypertensive medication for men (RR = 1.74), diabetes for men (RR = 1.62), poor-fair self-rated health for women (RR = 1.74) and physical disability for men (RR = 1.72). Serum cholesterol was associated with mortality in a 'J-shaped' relationship in men and in a reciprocal relationship in women. Blood pressure predicted mortality in an incremental fashion below 75 years, but in older subjects lower pressure was associated with excess mortality. Some predictors of mortality in the well elderly have been identified and a more extended period of follow-up will possibly resolve contradictory findings in some areas.


The estrogen-occupied estrogen receptor functions as a negative regulator to inhibit cell proliferation induced by insulin/IGF-1: a cell context-specific antimitogenic action of estradiol on rat lactotrophs in culture.
Estrogens stimulate cell proliferation in typical estrogen-responsive tissues including the anterior pituitary gland. Here we report that 17-beta estradiol (E2) has estrogen receptor-mediated mitogenic and antimitogenic actions on rat lactotrophs in primary culture, depending on the cell context. E2 did not affect basal proliferation at 2 d after treatment, but it increased it at 4 d. Insulin markedly increased proliferative activity, which was inhibited by simultaneous treatment with E2, even after only 2 d of treatment. This antimitogenic action on insulin-induced proliferation was also observed with other estrogens but not with nonestrogenic steroids. Treatment with antiestrogens in combination with E2 antagonized both the mitogenic and antimitogenic actions of E2. Antiestrogen treatment alone inhibited basal proliferation, and it mimicked the inhibitory action of E2 on insulin-induced proliferation with less potency. In parallel with cell proliferation, an insulin-induced increase in the cell number of cyclin D1-immunoreactive lactotrophs was inhibited by E2 treatment. Although the antimitogenic action of E2 was seen with a wide range of doses of insulin or IGF-1, proliferation was stimulated rather than inhibited by E2 when cells were treated with serum or forskolin/isobutylmethylxanthine instead of insulin, indicating a mitogen-specific, but not proliferative activity-dependent, inhibition by E2. The results of estrogen-occupied estrogen receptors as negative regulators of proliferation suggest a novel interaction between estrogen and growth factors in the regulation of proliferation in estrogen-responsive cells.


Excitatory input onto hilar somatostatin interneurons is increased in a chronic model of epilepsy.
The density of somatostatin (SOM)-containing GABAergic interneurons in the hilus of the dentate gyrus is significantly decreased in both human and experimental temporal lobe epilepsy. We used the pilocarpine model of status epilepticus and temporal lobe epilepsy in mice to study anatomical and electrophysiological properties of surviving somatostatin interneurons and determine whether compensatory functional changes occur that might offset loss of other inhibitory neurons. Using standard patch-clamp techniques and pipettes containing biocytin, whole cell recordings were obtained in hippocampal slices maintained in vitro. Hilar SOM cells containing enhanced green fluorescent protein (EGFP) were identified with fluorescent and infrared differential interference contrast video microscopy in epileptic and control GIN (EGFP-expressing Inhibitory Neurons) mice. Results showed that SOM cells from epileptic mice had 1) significant increases in somatic area and dendritic length; 2) changes in membrane properties, including a small but significant decrease in resting membrane potential, and increases in time constant and whole cell capacitance; 3) increased frequency of slowly rising spontaneous excitatory postsynaptic currents (sEPSCs) due primarily to increased mEPSC frequency, without changes in the probability of release; 4) increased evoked EPSC amplitude; and 5) increased spontaneous action potential generation in cell-attached recordings. Results suggest an increase in excitatory innervation, perhaps on distal dendrites, considering the slower rising EPSCs and increased output of hilar SOM cells in this model of epilepsy. In sum, these changes would be expected to increase the inhibitory output of surviving SOM interneurons and in part compensate for interneuronal loss in the epileptogenic hippocampus.


Identifying physiological origins of baroreflex dysfunction in salt-sensitive hypertension in the Dahl SS rat.
Salt-sensitive hypertension is known to be associated with dysfunction of the baroreflex control system in the Dahl salt-sensitive (SS) rat. However, neither the physiological mechanisms nor the genomic regions underlying the baroreflex dysfunction seen in this rat model are definitively known. Here, we have adopted a mathematical modeling approach to investigate the physiological and genetic origins of baroreflex dysfunction in the Dahl SS rat. We have developed a computational model of the overall baroreflex heart rate control system based on known physiological mechanisms to analyze telemetry-based blood pressure and heart rate data from two genetic strains of rat, the SS and consomic SS.13(BN), on low- and high-salt diets. With this approach, physiological parameters are estimated, unmeasured physiological variables related to the baroreflex control system are predicted, and differences in these quantities between the two strains of rat on low- and high-salt diets are detected. Specific findings include: a significant selective impairment in sympathetic gain with high-salt diet in SS rats and a protection from this impairment in SS.13(BN) rats, elevated sympathetic and parasympathetic offsets with high-salt diet in both strains, and an elevated sympathetic tone with high-salt diet in SS but not SS.13(BN) rats. In conclusion, we have associated several important physiological parameters of the baroreflex control system with chromosome 13 and have begun to identify possible physiological mechanisms underlying baroreflex impairment and hypertension in the Dahl SS rat that may be further explored in future experimental and modeling-based investigation.


'I had a sort of epiphany!' An exploratory study of group mindfulness-based cognitive therapy for older people with depression.
Mindfulness-based cognitive therapy (MBCT) has been successful in reducing depressive symptoms in people with chronic-recurrent depression. However, the research evaluating the efficacy of this approach, and other innovative treatments for mood disorders, has mainly been with people under 65 years. This paper aims to help redress this imbalance by exploring older people's own reflections of their experience of MBCT. A qualitative approach was used to explore 13 participants' experiences of MBCT; participants were interviewed pre and post-intervention and again after six months. To see whether the standard course requires any adaptations for older participants, the two MBCT course facilitators were interviewed post-intervention. Thematic analysis identified five overarching themes and showed that older people reported positive changes in their mental health and well-being and reported being 'released from the past'. The facilitators reported that they needed to be aware of later life issues, such as loneliness and potential physical limitations, but otherwise only minor adaptations were needed to the standard MBCT course for older people. MBCT is an acceptable approach for people aged 65 years and over and further research should explore potential mechanisms of change including changes in meta-cognitive awareness and self-compassion.


Annexin V-Conjugated Mixed Micelles as a Potential Drug Delivery System for Targeted Thrombolysis.
To alleviate the hemorrhagic side effect of thrombolysis therapy, a thrombus targeted drug delivery system based on the specific affinity of Annexin V to phosphatidylserine exposed on the membrane surface of activated platelet was developed. The amphiphilic and biodegradable biomaterial, polycaprolactone-block-poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-hydroxyethyl methacrylate) (PCL-b-PDMAEMA-b-PHEMA (PCDH)) triblock polymer, was synthesized via ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) to use as the nanocarriers of thrombolytic drug. In order to conjugate Annexin V to the polymer, PCDH was modified by succinic anhydride via ring-opening reaction to introduce the carboxyl group (PCDH-COOH). After preparation of PCDH/PCDH-COOH (9/1, m/m) mixed micelles, Annexin V was coupled with the micelles using carbodiimide chemistry. The blood clot lysis assay in vitro confirmed that lumbrokinase-loaded targeted micelles (LKTM) had stronger thrombolysis potency than free lumbrokinase (LK) and LK-loaded nontargeted micelles (LKM, P < 0.05). In vivo thrombolytic assay, multispectral, optoacoustic tomography (MSOT) was used to assess the target ability of LKTM. The results of MSOT images indicated the fluorescence intensity of the LKTM group located in the blood clot position were significantly stronger than the LKM group. A 5 mm of carotid artery containing blood clot was cut out 24 h later after administration to assess the degree of thrombolysis. The results of thrombolytic assay in vivo were consistent with the assay in vitro, which the differences between LK, LKM, and LKTM groups were both statistically significant. All the results of thrombolysis assays above proved that the capacity of thrombolysis in the LKTM group was optimal. It suggested that Annexin V-conjugated micelles will be a potential drug delivery system for targeted thrombolysis.


American surgery and the Affordable Care Act.
The Affordable Care Act (ACA) attempts to change the way we finance and deliver health care by coordinating the delivery of primary, specialty, and hospital services in accountable care organizations. The ways in which accountable care organizations will develop and evolve is unclear; however, the effects on surgeons and their patients will be substantial. High-value care in the ACA emphasizes quality, safety, resource use and appropriateness, and the patient's experience of care. Payment will be linked to these principles. Department chairs overseeing a clinical enterprise in academic medical centers now must add financial and quality measures to the traditional missions of education, research, and clinical service. At a time when surgical training is in dramatic evolution, with work hour limitations for residents and an emphasis on quality, productivity, and increasing oversight of trainees for faculty, residency programs will need to meet the increasing demands of an aging population and newly insured patients under the ACA. The American College of Surgeons, with its century-long commitment to quality improvement, research-based standards, and performance measurement and verification, has begun its Inspiring Quality Campaign, is developing new educational tools, and is preparing proposals for payment reform based on surgeons' participation in quality programs.


Probing glycosaminoglycan spectral signatures in live cells and their conditioned media by Raman microspectroscopy.
Spectroscopic markers characteristic of reference glycosaminoglycan molecules were identified previously based on their vibrational signatures. Infrared spectral signatures of glycosaminoglycans in fixed cells were also recently demonstrated but probing live cells still remains challenging. Raman microspectroscopy is potentially interesting to perform studies under physiological conditions. The aim of the present work was to identify the Raman spectral signatures of GAGs in fixed and live cells and in their conditioned media. Biochemical and Raman analyses were performed on five cell types: chondrocytes, dermal fibroblasts, melanoma (SK-MEL-28), wild type CHO, and glycosaminoglycan-defective mutant CHO-745 cells. The biochemical assay of sulfated GAGs in conditioned media was only possible for chondrocytes, dermal fibroblasts, and wild type CHO due to the detection limit of the test. In contrast, Raman microspectroscopy allowed probing total glycosaminoglycan content in conditioned media, fixed and live cells and the data were analysed by principal component analysis. Our results showed that the Raman technique is sensitive enough to identify spectral markers of glycosaminoglycans that were useful to characterise the conditioned media of the five cell types. The results were confirmed at the single cell level on both live and fixed cells with a good differentiation between the cell types. Furthermore, the principal component loadings revealed prominent glycosaminoglycan-related spectral information. Raman microspectroscopy allows monitoring of the glycosaminoglycan profiles of single live cells and could therefore be developed for cell screening purposes and holds promise for identifying glycosaminoglycan signatures as a marker of cancer progression in tissues.


Structural diversification during glucosinolate breakdown: mechanisms of thiocyanate, epithionitrile and simple nitrile formation.
Secondary metabolism is characterized by an impressive structural diversity. Here, we have addressed the mechanisms underlying structural diversification upon damage-induced activation of glucosinolates, a group of thioglucosides found in the Brassicales. The classical pathway of glucosinolate activation involves myrosinase-catalyzed hydrolysis and rearrangement of the aglucone to an isothiocyanate. Plants of the Brassicaceae possess specifier proteins, i.e. non-heme iron proteins that promote the formation of alternative products by interfering with this reaction through unknown mechanisms. We have used structural information available for the thiocyanate-forming protein from Thlaspi arvense (TaTFP), to test the impact of loops protruding at one side of its β-propeller structure on product formation using the allylglucosinolate aglucone as substrate. In silico loop structure sampling and semiempirical quantum mechanical calculations identified a 3L2 loop conformation that enabled the Fe2+ cofactor to interact with the double bond of the allyl side chain. Only this arrangement enabled the formation of allylthiocyanate, a specific product of TaTFP. Simulation of 3,4-epithiobutane nitrile formation, the second known product of TaTFP, required an alternative substrate docking arrangement in which Fe2+ interacts with the aglucone thiolate. In agreement with these results, substitution of 3L2 amino acid residues involved in the conformational change as well as exchange of critical amino acid residues of neighboring loops affected the allylthiocyanate versus epithionitrile proportion obtained upon myrosinase-catalyzed allylglucosinolate hydrolysis in the presence of TaTFP in vitro. Based on these insights, we propose that specifier proteins are catalysts that might be classified as Fe2+ -dependent lyases.


Serving the Very Sick, Very Frail, and Very Old: Geriatrics, Palliative Care, and Clinical Ethics.
How can we provide the best care for growing numbers of very frail, very sick, or very old people? The disciplines of geriatrics, palliative care, and clinical ethics each have a good deal to offer to improve care for elders, yet each field is saddled with heavy historical baggage. Using a case as a springboard, we address specific strengths and shortcomings of each field, and what these disciplines can learn from each other. Geriatrics is currently largely focused on prevention of disability, cognitive impairment, and death; it should reorganize around a palliative approach to providing care for elders living with multiple chronic conditions, disability, and dementia. Palliative care, while paying some attention to the spectrum of advanced illness, concentrates primarily on cancer; it should expand its central purpose to include providing supportive care to elders with serious illness and their caregivers. Ethics committee members and consultants principally stress individual autonomy; they need to expand their approach and develop longitudinal relationships with patients and family members, routinely incorporating them in deliberations and the crafting of recommendations. However, improving these three disciplines will only go so far toward improving the care of very frail, very sick, or very old people. What is most needed is longitudinal care provided by interdisciplinary primary care teams steeped in the core principles of all three disciplines.


Dysregulation of B Cell Activity During Proliferative Kidney Disease in Rainbow Trout.
Proliferative kidney disease (PKD) is a widespread disease caused by the endoparasite Tetracapsuloides bryosalmonae (Myxozoa: Malacosporea). Clinical disease, provoked by the proliferation of extrasporogonic parasite stages, is characterized by a chronic kidney pathology with underlying transcriptional changes indicative of altered B cell responses and dysregulated T-helper cell-like activities. Despite the relevance of PKD to European and North American salmonid aquaculture, no studies, to date, have focused on further characterizing the B cell response during the course of this disease. Thus, in this work, we have studied the behavior of diverse B cell populations in rainbow trout (Oncorhynchus mykiss) naturally infected with T. bryosalmonae at different stages of preclinical and clinical disease. Our results show a clear upregulation of all trout immunoglobulins (Igs) (IgM, IgD, and IgT) demonstrated by immunohistochemistry and Western blot analysis, suggesting the alteration of diverse B cell populations that coexist in the infected kidney. Substantial changes in IgM, IgD, and IgT repertoires were also identified throughout the course of the disease further pointing to the involvement of the three Igs in PKD through what appear to be independently regulated mechanisms. Thus, our results provide strong evidence of the involvement of IgD in the humoral response to a specific pathogen for the first time in teleosts. Nevertheless, it was IgT, a fish-specific Ig isotype thought to be specialized in mucosal immunity, which seemed to play a prevailing role in the kidney response to T. bryosalmonae. We found that IgT was the main Ig coating extrasporogonic parasite stages, IgT+ B cells were the main B cell subset that proliferated in the kidney with increasing kidney pathology, and IgT was the Ig for which more significant changes in repertoire were detected. Hence, although our results demonstrate a profound dysregulation of different B cell subsets during PKD, they point to a major involvement of IgT in the immune response to the parasite. These results provide further insights into the pathology of PKD that may facilitate the future development of control strategies.


Lactobacillus paracasei comparative genomics: towards species pan-genome definition and exploitation of diversity.
Lactobacillus paracasei is a member of the normal human and animal gut microbiota and is used extensively in the food industry in starter cultures for dairy products or as probiotics. With the development of low-cost, high-throughput sequencing techniques it has become feasible to sequence many different strains of one species and to determine its "pan-genome". We have sequenced the genomes of 34 different L. paracasei strains, and performed a comparative genomics analysis. We analysed genome synteny and content, focussing on the pan-genome, core genome and variable genome. Each genome was shown to contain around 2800-3100 protein-coding genes, and comparative analysis identified over 4200 ortholog groups that comprise the pan-genome of this species, of which about 1800 ortholog groups make up the conserved core. Several factors previously associated with host-microbe interactions such as pili, cell-envelope proteinase, hydrolases p40 and p75 or the capacity to produce short branched-chain fatty acids (bkd operon) are part of the L. paracasei core genome present in all analysed strains. The variome consists mainly of hypothetical proteins, phages, plasmids, transposon/conjugative elements, and known functions such as sugar metabolism, cell-surface proteins, transporters, CRISPR-associated proteins, and EPS biosynthesis proteins. An enormous variety and variability of sugar utilization gene cassettes were identified, with each strain harbouring between 25-53 cassettes, reflecting the high adaptability of L. paracasei to different niches. A phylogenomic tree was constructed based on total genome contents, and together with an analysis of horizontal gene transfer events we conclude that evolution of these L. paracasei strains is complex and not always related to niche adaptation. The results of this genome content comparison was used, together with high-throughput growth experiments on various carbohydrates, to perform gene-trait matching analysis, in order to link the distribution pattern of a specific phenotype to the presence/absence of specific sets of genes.


Metabolite Profiling of Candidatus Liberibacter Infection in Hamlin Sweet Oranges.
Huanglongbing (HLB), also known as citrus greening disease, caused by Candidatus Liberibacter asiaticus (CLas), is considered the most serious citrus disease in the world. CLas infection has been shown to greatly affect metabolite profiles in citrus fruits. However, because of uneven distribution of CLas throughout the tree and a minimum bacterial titer requirement for polymerase chain reaction (PCR) detection, the infected trees may test false negative. To prevent this, metabolites of healthy Hamlin oranges (CLas-) obtained from the citrus undercover protection systems (CUPS) were investigated. Comparison of the metabolite profile of juice obtained from CLas- and CLas+ (asymptomatic and symptomatic) trees revealed significant differences in both volatile and nonvolatile metabolites. However, no consistent pattern could be observed in alcohols, esters, sesquiterpenes, sugars, flavanones, and limonoids as compared to previous studies. These results suggest that CLas may affect metabolite profiles of citrus fruits earlier than detecting infection by PCR. Citric acid, nobiletin, malic acid, and phenylalanine were identified as the metabolic biomarkers associated with the progression of HLB. Thus, the differential metabolites found in this study may serve as the biomarkers of HLB in its early stage, and the metabolite signature of CLas infection may provide useful information for developing a potential treatment strategy.


Exploring causal networks of bovine milk fatty acids in a multivariate mixed model context.
Knowledge regarding causal relationships among traits is important to understand complex biological systems. Structural equation models (SEM) can be used to quantify the causal relations between traits, which allow prediction of outcomes to interventions applied to such a network. Such models are fitted conditionally on a causal structure among traits, represented by a directed acyclic graph and an Inductive Causation (IC) algorithm can be used to search for causal structures. The aim of this study was to explore the space of causal structures involving bovine milk fatty acids and to select a network supported by data as the structure of a SEM. The IC algorithm adapted to mixed models settings was applied to study 14 correlated bovine milk fatty acids, resulting in an undirected network. The undirected pathway from C4:0 to C12:0 resembled the de novo synthesis pathway of short and medium chain saturated fatty acids. By using prior knowledge, directions were assigned to that part of the network and the resulting structure was used to fit a SEM that led to structural coefficients ranging from 0.85 to 1.05. The deviance information criterion indicated that the SEM was more plausible than the multi-trait model. The IC algorithm output pointed towards causal relations between the studied traits. This changed the focus from marginal associations between traits to direct relationships, thus towards relationships that may result in changes when external interventions are applied. The causal structure can give more insight into underlying mechanisms and the SEM can predict conditional changes due to such interventions.


Use of drinking protective behavioral strategies and sexual perceptions and behaviors in U.S. college students.
Alcohol use among college students is linked to an increased likelihood of engaging in risky sexual behaviors, including casual sex and unprotected sex. These behaviors increase college students' risks for negative social and health-related consequences. This study examined the relationship between drinking behaviors and protective behavioral strategies (PBS), expectancies and perceptions of sexual risk, and actual alcohol-related sexual behaviors and consequences. Sexually active college students completed Web-based self-report measures of drinking behaviors and use of PBS, alcohol expectancies and perceptions of risk, and sexual behaviors and related consequences (n = 524; 57.1% women). Findings indicated that PBS were related to lower expectancies of sexual risk and sexual disinhibition, and among lighter drinkers, lower expectancies of sexual enhancement from alcohol. PBS were also related to decreased perceptions of sexual-related risks, some alcohol-related sexual behaviors, including number of drinks before/during sex, and number of sexual consequences, but were not related to abstaining during sex, frequency of alcohol-related sexual behaviors, or general condom use. These findings demonstrate a disconnect between perceived and actual risks among college students, such that decreased perceptions of risk may not be associated with protective behaviors. Prevention and intervention implications are discussed.


Association of periodontitis with rheumatoid arthritis: a pilot study.
Similarities exist in the epidemiology and immunopathogenesis of periodontitis and rheumatoid arthritis (RA), but the associations between their respective disease activities and severities are less well documented. We evaluated the prevalence and severity of periodontitis in United States (U.S.) veterans with RA and their relationship to RA disease activity and severity. Patients with RA from an outpatient rheumatology clinic were eligible, and patients with osteoarthritis (OA) served as controls. Dentists, masked to the rheumatologic diagnoses, performed periodontal probing and examined dental panoramic radiographs to assess the presence and severity of periodontitis. Associations of periodontitis with RA were examined using multivariate regression, whereas the association of periodontitis with disease-severity measures in RA was examined using the chi(2) test. Sixty-nine patients with RA (57 males and 12 females) and 35 patients with OA (30 males and five females) were studied. Moderate to severe periodontitis was more prevalent in patients with RA (51%) than controls (26%) (P = 0.03), an association independent of age, race, smoking, diabetes mellitus, and gender. Patients with RA who were seropositive for rheumatoid factor (RF) were more likely to have moderate to severe periodontitis (59%) than patients who were RF negative (15%) (P = 0.02). Likewise, patients with RA who were positive for the anti-cyclic citrullinated peptide (CCP) antibodies were more likely to have moderate to severe periodontitis (56%) than patients who were anti-CCP negative (22%) (P = 0.01). There were no associations of periodontitis status with other measures of RA disease activity or severity. In a cohort of U.S. veterans, periodontitis was more common and severe in patients with RA compared to patients with OA. Although unrelated to disease activity, the presence of periodontitis in patients with RA was associated with seropositivity for RF and the anti-CCP antibody, which was highly relevant given the associations of these autoantibodies with poor outcomes and disease pathogenesis in RA.


Could increased axial wall stress be responsible for the development of atheroma in the proximal segment of myocardial bridges?
A recent model describing the mechanical interaction between a stenosis and the vessel wall has shown that axial wall stress can considerably increase in the region immediately proximal to the stenosis during the (forward) flow phases, so that abnormal biological processes and wall damages are likely to be induced in that region. Our objective was to examine what this model predicts when applied to myocardial bridges. The model was adapted to the hemodynamic particularities of myocardial bridges and used to estimate by means of a numerical example the cyclic increase in axial wall stress in the vessel segment proximal to the bridge. The consistence of the results with reported observations on the presence of atheroma in the proximal, tunneled, and distal vessel segments of bridged coronary arteries was also examined. 1) Axial wall stress can markedly increase in the entrance region of the bridge during the cardiac cycle. 2) This is consistent with reported observations showing that this region is particularly prone to atherosclerosis. The proposed mechanical explanation of atherosclerosis in bridged coronary arteries indicates that angioplasty and other similar interventions will not stop the development of atherosclerosis at the bridge entrance and in the proximal epicardial segment if the decrease of the lumen of the tunneled segment during systole is not considerably reduced.


Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides.
Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate.


Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression.
Gastric carcinoma is one of the most common malignancies and a lethal cancer in the world. Notch signaling and transcription factors STAT3 (signal transducer and activator of transcription 3) and Twist regulate tumor development and are critical regulators of gastric cancer progression. Herein, the relationship among Notch, STAT3 and Twist pathways in the control of gastric cancer progression was studied. We found that Twist and phosphorylated STAT3 levels were promoted by the activated Notch1 receptor in human stomach adenocarcinoma SC-M1, embryonic kidney HEK293 and erythroleukemia K562 cells. Notch1 signaling dramatically induced Twist promoter activity through a C promoter binding factor-1-independent manner and STAT3 phosphorylation. Overexpression of Notch1 receptor intracellular domain (N1IC) enhanced the interaction between nuclear STAT3 and Twist promoter in cells. Gastric cancer progression of SC-M1 cells was promoted by N1IC through STAT3 phosphorylation and Twist expression including colony formation, migration and invasion. STAT3 regulated gastric cancer progression of SC-M1 cells via Twist. N1IC also elevated the progression of other gastric cancer cells such as AGS and KATO III cells through STAT3 and Twist. The N1IC-promoted tumor growth and lung metastasis of SC-M1 cells in mice were suppressed by the STAT3 inhibitor JSI-124 and Twist knockdown. Furthermore, Notch1 and Notch ligand Jagged1 expressions were significantly associated with phosphorylated STAT3 and Twist levels in gastric cancer tissues of patients. Taken together, these results suggest that Notch1/STAT3/Twist signaling axis is involved in progression of human gastric cancer and modulation of this cascade has potential for the targeted combination therapy.


Efficacy and limitation of a chlorhexidine-based decolonization strategy in preventing transmission of methicillin-resistant Staphylococcus aureus in an intensive care unit.
Surface-active antiseptics, such as chlorhexidine, are increasingly being used as part of intervention programs to prevent methicillin-resistant Staphylococcus aureus (MRSA) transmission, despite limited evidence and potential for resistance. We report on the effect of an antiseptic protocol on acquisition of both endemic MRSA and an outbreak strain of MRSA sequence type 239 (designated TW). Interrupted time-series data on MRSA acquisitions in two 15-bed intensive care units were analyzed using segmented regression models to estimate the effects of sequential introduction of an educational campaign, cohorting, and a chlorhexidine-based antiseptic protocol on transmission of TW and non-TW MRSA strains. Representative TW and non-TW MRSA strains were assessed for carriage of qacA/B genes and antiseptic susceptibility. The antiseptic protocol was associated with a highly significant, immediate 70% reduction in acquisition of non-TW MRSA strains (estimated model-averaged incidence rate ratio, 0.3; 95% confidence interval, 0.19-0.47) and an increase in acquisition of TW MRSA strains (estimated model-averaged incidence rate ratio, 3.85; 95% confidence interval, 0.80-18.59). There was only weak evidence of an effect of other interventions on MRSA transmission. All TW MRSA strains (21 of 21 isolates) and <5% (1 of 21 isolates) of non-TW MRSA strains tested carried the chlorhexidine resistance loci qacA/B. In vitro chlorhexidine minimum bactericidal concentrations of TW strains were 3-fold higher than those of non-TW MRSA strains, and in vivo, only patients with non-TW MRSA demonstrated a reduction in the number of colonization sites in response to chlorhexidine treatment. A chlorhexidine-based surface antiseptic protocol can interrupt transmission of MRSA in the intensive care unit, but strains carrying qacA/B genes may be unaffected or potentially spread more rapidly.


Current epidemiology of mild cognitive impairment and other predementia syndromes.
A variety of clinically-defined predementia syndromes, with differing diagnostic criteria and nomenclature, have been proposed to describe nondisabling symptomatic cognitive deficits arising in elderly persons. Incidence and prevalence of different predementia syndromes vary as a result of different diagnostic criteria, sampling, and assessment procedures. The incidence rates of all predementia syndromes increase with age and are higher in subjects with less education; but age, educational background, and gender are not consistently related to prevalence rates. There is particular interest in "Mild Cognitive Impairment (MCI)" because this predementia syndrome is thought to be a prodromal phase of Alzheimer disease (AD). Several studies have suggested that most patients who meet MCI criteria will progress to AD, but rates of conversion to AD and dementia vary widely among studies. Furthermore, MCI definition is less consistent in population-based studies than clinical studies, in which progression to AD is also more consistent. To clarify the sources of discrepant findings in the literature, this review summarizes existing epidemiological studies of the defined clinical predementia syndromes and their progression to dementia.


The LAILAPS search engine: relevance ranking in life science databases.
Search engines and retrieval systems are popular tools at a life science desktop. The manual inspection of hundreds of database entries, that reflect a life science concept or fact, is a time intensive daily work. Hereby, not the number of query results matters, but the relevance does. In this paper, we present the LAILAPS search engine for life science databases. The concept is to combine a novel feature model for relevance ranking, a machine learning approach to model user relevance profiles, ranking improvement by user feedback tracking and an intuitive and slim web user interface, that estimates relevance rank by tracking user interactions. Queries are formulated as simple keyword lists and will be expanded by synonyms. Supporting a flexible text index and a simple data import format, LAILAPS can easily be used both as search engine for comprehensive integrated life science databases and for small in-house project databases. With a set of features, extracted from each database hit in combination with user relevance preferences, a neural network predicts user specific relevance scores. Using expert knowledge as training data for a predefined neural network or using users own relevance training sets, a reliable relevance ranking of database hits has been implemented. In this paper, we present the LAILAPS system, the concepts, benchmarks and use cases. LAILAPS is public available for SWISSPROT data at http://lailaps.ipk-gatersleben.de.


The effects of enriched carbon dioxide atmospheres on plant--insect herbivore interactions.
Little is known about the effects of enriched CO(2) atmospheres, which may exist in the next century, on natural plant-insect herbivore interactions. Larvae of a specialist insect herbivore, Junonia coenia (Lepidoptera: Nymphalidae), were reared on one of its host plants, Plantago lanceolata (Plantaginaceae), grown in either current low (350 parts per million) or high (700 ppm) CO(2) environments. Those larvae raised on high-CO(2) foliage grew more slowly and experienced greater mortality, especially in early instars, than those raised on low-CO(2) foliage. Poor larval performance on high-CO(2) foliage was probably due to the reduced foliar water and nitrogen concentrations of those plants and not to changes in the concentration of the defensive compounds, iridoid glycosides. Adult pupal weight and female fecundity were not affected by the CO(2) environment of the host plant. These results indicate that interactions between plants and herbivorous insects will be modified under the predicted CO(2) conditions of the 21st century.


Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression.
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a(+) LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-beta1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-beta1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis.


Global, regional, and national burden of brain and other CNS cancer, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Brain and CNS cancers (collectively referred to as CNS cancers) are a source of mortality and morbidity for which diagnosis and treatment require extensive resource allocation and sophisticated diagnostic and therapeutic technology. Previous epidemiological studies are limited to specific geographical regions or time periods, making them difficult to compare on a global scale. In this analysis, we aimed to provide a comparable and comprehensive estimation of the global burden of brain cancer between 1990 and 2016. We report means and 95% uncertainty intervals (UIs) for incidence, mortality, and disability-adjusted life-years (DALYs) estimates for CNS cancers (according to the International Classification of Diseases tenth revision: malignant neoplasm of meninges, malignant neoplasm of brain, and malignant neoplasm of spinal cord, cranial nerves, and other parts of CNS) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. Data sources include vital registration and cancer registry data. Mortality was modelled using an ensemble model approach. Incidence was estimated by dividing the final mortality estimates by mortality to incidence ratios. DALYs were estimated by summing years of life lost and years lived with disability. Locations were grouped into quintiles based on the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate. In 2016, there were 330 000 (95% UI 299 000 to 349 000) incident cases of CNS cancer and 227 000 (205 000 to 241 000) deaths globally, and age-standardised incidence rates of CNS cancer increased globally by 17·3% (95% UI 11·4 to 26·9) between 1990 and 2016 (2016 age-standardised incidence rate 4·63 per 100 000 person-years [4·17 to 4·90]). The highest age-standardised incidence rate was in the highest quintile of SDI (6·91 [5·71 to 7·53]). Age-standardised incidence rates increased with each SDI quintile. East Asia was the region with the most incident cases of CNS cancer for both sexes in 2016 (108 000 [95% UI 98 000 to 122 000]), followed by western Europe (49 000 [37 000 to 54 000]), and south Asia (31 000 [29 000 to 37 000]). The top three countries with the highest number of incident cases were China, the USA, and India. CNS cancer was responsible for 7·7 million (95% UI 6·9 to 8·3) DALYs globally, a non-significant change in age-standardised DALY rate of -10·0% (-16·4 to 2·6) between 1990 and 2016. The age-standardised DALY rate decreased in the high SDI quintile (-10·0% [-27·1 to -0·1]) and high-middle SDI quintile (-10·5% [-18·4 to -1·4]) over time but increased in the low SDI quintile (22·5% [11·2 to 50·5]). CNS cancer is responsible for substantial morbidity and mortality worldwide, and incidence increased between 1990 and 2016. Significant geographical and regional variation in the incidence of CNS cancer might be reflective of differences in diagnoses and reporting practices or unknown environmental and genetic risk factors. Future efforts are needed to analyse CNS cancer burden by subtype. Bill & Melinda Gates Foundation.


Characteristics of a prevalent vertebral deformity predict subsequent vertebral fracture: results from the European Prospective Osteoporosis Study (EPOS).
The presence of a prevalent vertebral deformity increases the risk of a future vertebral fracture. The aim of this study was to determine whether certain characteristics of the prevalent deformity, including its shape and location in the spine, influenced this effect. The 3100 men and 3500 women who took part in this analysis were recruited from population registers for participation in the European Prospective Osteoporosis Study (EPOS). Subjects had lateral thoracic and lumbar spine x-rays at baseline, and again after a mean interval of 3.8 years. Prevalent morphometric vertebral deformities on the baseline film were identified by the McCloskey-Kanis method. Incident fractures were defined as vertebrae that also satisfied the McCloskey-Kanis criterion for prevalent deformities on the follow-up film, and in addition had at least one height (anterior, mid, or posterior) which had reduced by at least 20% between films. Poisson regression was used to assess the association between various characteristics of the prevalent deformity and the risk of an incident vertebral fracture, with generalised estimating equations used to allow for the fact that each subject contributed several vertebrae to the analysis. The risk of an incident fracture increased with the number of prevalent deformities: relative risk (RR) for one prevalent deformity 3.2 (95% confidence interval (CI); 2.1, 4.8); 9.8 (95% CI;6.1, 15.8) for 2; and 23.3 (95% CI;15.3, 35.4) for 3 or more. Relative risks differed significantly according to the shape of the prevalent deformity, ranging from 5.9 (95% CI; 4.1, 8.6) if the anterior and mid heights were reduced to 1.6 (95% CI;0.8, 3.2) if the posterior and mid heights were reduced. Risks varied also according to the severity of the deformity. There were fivefold differences in relative risk of incident fracture depending on the location of the prevalent deformity within the spine. Compared to vertebrae in subjects with no deformities at baseline, the relative risk of an incident fracture within three vertebrae of a prevalent deformity was greater (7.7 (95% CI;5.6, 10.5)) than the risk in more distant vertebrae (4.0 (95% CI;2.6, 6.0)). In summary, the risk of a subsequent vertebral fracture in individuals with preexisting deformities is importantly influenced by the characteristics of these deformities.


Consumption of fermented milk product with probiotic modulates brain activity.
Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.


First Occurrence of Downy Mildew on Boxleaf Veronica Caused by Peronospora grisea in Italy.
Boxleaf veronica (Hebe buxifolia (Benth.) Cockayne & Allan), native to New Zealand, is an annual or perennial shrub widely cultivated in Mediterranean zones. During late spring 2003, after seasonably wet and cool weather, a downy mildew epidemic occurred on potted, overhead irrigated, 1-year-old seedlings at a commercial nursery in eastern Sicily (southern Italy). Infections affected boxleaf veronica at first, but spread to variegated boxleaf (H. buxifolia cv. variegata). Initial symptoms on the upper side of leaves were small, gray brown patches that gradually spread, eventually resulting in necrosis in the center of infected areas. At that point, brown patches were evident on both sides of the leaves. Lesions on the lower leaf surface became covered with a fairly dense, pale gray-to-brown layer of conidia and conidiophores. As the disease progressed, these spots coalesced into large and conspicuous brown lesions. The youngest, most succulent shoots withered and died. The large brown lesions on the leaves were disfiguring and affected 95 to 100% of plants in the nursery. All diseased nursery stock had to be discarded. Oospores were not observed in leaf tissues. The fungus recovered from leaves with abundant gray brown sporulation was identified as Peronospora grisea (Unger) Unger. Microscopic observations revealed conidiophores that branched dichotomously five to seven times with branch ends 6 to 10 × 2 to 3 μm, slightly curved, and tapered to a blunt apex. Hyaline conidia were ellipsoid, brownish when mature, and measured 23 to 27 × 15 to 18 μm (mean = 25.2 × 17.1 μm), falling within the range of those reported for P. grisea (1). Pathogenicity was confirmed by inoculating 10 1-yr-old seedlings (10 cm tall) by gently pressing infected leaves with abundant sporulation onto healthy leaves and maintaining inoculated plants in a humid chamber at 21°C. An equal number of noninoculated plants served as controls. After 9 to 11 days, symptoms similar to those originally observed developed onto inoculated plants, and after 12 to 15 days, grayish mildew grew on leaves. Microscopic examination of the developing mycelium confirmed that leaves were infected with P. grisea. Uninoculated control plants did not develop any symptoms. The disease was also confirmed in this way on variegated boxleaf veronica (H. buxifolia cv. variegata). Downy mildew of Hebe spp. has been recorded in New Zealand, Britain, France, Germany, and more recently, West Sussex (2). Heavy rainfall during the spring of 2003 in eastern Sicily could have favored disease development. To our knowledge, this is the first report of downy mildew of boxleaf veronica and variegated boxleaf veronica caused by P. grisea in Italy. References: (1) S. M. Francis and A. M. Berrie. Peronospora grisea. No. 766 in: Descriptions of pathogenic fungi and bacteria. CMI, Kew, Surrey, UK. 1983. (2) J. M. Whipps and C. A. Linfield. Plant Pathol. 36:216, 1987.


Transcriptomic analysis of longitudinal Burkholderia pseudomallei infecting the cystic fibrosis lung.
The melioidosis bacterium, Burkholderia pseudomallei, is increasingly being recognised as a pathogen in patients with cystic fibrosis (CF). We have recently catalogued genome-wide variation of paired, isogenic B. pseudomallei isolates from seven Australasian CF cases, which were collected between 4 and 55 months apart. Here, we extend this investigation by documenting the transcriptomic changes in B. pseudomallei in five cases. Following growth in an artificial CF sputum medium, four of the five paired isolates exhibited significant differential gene expression (DE) that affected between 32 and 792 genes. The greatest number of DE events was observed between the strains from patient CF9, consistent with the hypermutator status of the latter strain, which is deficient in the DNA mismatch repair protein MutS. Two patient isolates harboured duplications that concomitantly increased expression of the β-lactamase-encoding gene penA, and a 35 kb deletion in another abolished expression of 29 genes. Convergent expression profiles in the chronically-adapted isolates identified two significantly downregulated and 17 significantly upregulated loci, including the resistance-nodulation-division (RND) efflux pump BpeEF-OprC, the quorum-sensing hhqABCDE operon, and a cyanide- and pyocyanin-insensitive cytochrome bd quinol oxidase. These convergent pathoadaptations lead to increased expression of pathways that may suppress competing bacterial and fungal pathogens, and that enhance survival in oxygen-restricted environments, the latter of which may render conventional antibiotics less effective in vivo. Treating chronically adapted B. pseudomallei infections with antibiotics designed to target anaerobic infections, such as the nitroimidazole class of antibiotics, may significantly improve pathogen eradication attempts by exploiting this Achilles heel.


A Detailed Dosimetric Analysis of Spinal Cord Tolerance in High-Dose Spine Radiosurgery.
Dose-volume tolerance of the spinal cord (SC) in spinal stereotactic radiosurgery (SRS) is difficult to define because radiation myelitis rates are low, and published reports document cases of myelopathy but do not account for the total number of patients treated at given dose-volume combinations who do not have myelitis. This study reports SC toxicity from single-fraction spinal SRS and presents a comprehensive atlas of the incidence of adverse events to examine dose-volume predictors. A prospective database of all patients undergoing single-fraction spinal SRS at our institution between 2004 and 2011 was reviewed. SC toxicity was defined by clinical myelitis with accompanying magnetic resonance imaging (MRI) signal changes that were not attributable to tumor progression. Dose-volume histogram (DVH) atlases were created for these endpoints. Rates of adverse events with 95% confidence limits and probabilities that rates of adverse events were <2% and <5% for myelitis were determined as functions of dose and absolute volume. Information about DVH and myelitis was available for 228 patients treated at 259 sites. The median follow-up time was 14.6 months (range, 0.1-138.3 months). The median prescribed dose to the planning treatment volume was 24 Gy (range, 18-24 Gy). There were 2 cases of radiation myelitis (rate r=0.7%) with accompanying MRI signal changes. Myelitis occurred in 2 patients, with Dmax >13.33 Gy, and minimum doses to the hottest 0.1, 0.2, 0.5, and 1 cc were >10.66, 10.9, and 8 Gy, respectively; however, both myelitis cases occurred below the 34th percentile for Dmax and there were 194 DVHs in total with Dmax >13.33 Gy. A median SC Dmax of 13.85 Gy is safe and supports that a Dmax limit of 14 Gy carries a low <1% rate of myelopathy. No dose-volume thresholds or relationships between SC dose and myelitis were apparent. This is the largest study examining dosimetric data and radiation-induced myelitis in de novo spine SRS.


Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.
The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.


Antimicrobials for bacterial bioterrorism agents.
The limitations of current antimicrobials for highly virulent pathogens considered as potential bioterrorism agents drives the requirement for new antimicrobials that are suitable for use in populations in the event of a deliberate release. Strategies targeting bacterial virulence offer the potential for new countermeasures to combat bacterial bioterrorism agents, including those active against a broad spectrum of pathogens. Although early in the development of antivirulence approaches, inhibitors of bacterial type III secretion systems and cell division mechanisms show promise for the future.


Investigating gender and ethnicity differences in proximal humeral morphology using a statistical shape model.
Morphological variability in the shoulder influences the joint biomechanics and is an important consideration in arthroplasty and implant design. The objectives of this study were to quantify cortical and cancellous proximal humeral morphology and to assess whether shape variation was influenced by gender and ethnicity, with the overarching goal of informing implant design and treatment. A statistical shape model of the proximal humeral cortical and cancellous regions was developed for a training set of 84 subjects of both genders and different ethnicities. Cortical and cancellous bone geometries were reconstructed from CT scans, meshed with triangular elements, and registered to a template. Principal component analysis was applied to quantify modes of variation. Anatomical measurements were computed on the registered geometries to assess correlation with modes of variation. Parallel analysis identified six significant modes of variation, which accounted for 93% of variation in the training set and described scaling (Mode 1), inclination of the head (Modes 2 and 5), and shape of the greater tuberosity and neck region (Modes 3, 4, and 6). Size differences as described by Mode 1 were statistically significant for gender and ethnicity, where female and Asian subjects were smaller than male and Caucasian subjects, respectively; however, differences in other modes were not significant. Cortical thickness of the shaft after normalization by outer diameter was significantly larger for Asian subjects compared to Caucasian subjects. The statistical shape model quantified cortical and cancellous humeral morphology considering gender and ethnicity, providing descriptive data to support surgical planning, and implant design. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3043-3052, 2018.


Development and Validation of a Deep Learning Algorithm for Detection of Diabetic Retinopathy in Retinal Fundus Photographs.
Deep learning is a family of computational methods that allow an algorithm to program itself by learning from a large set of examples that demonstrate the desired behavior, removing the need to specify rules explicitly. Application of these methods to medical imaging requires further assessment and validation. To apply deep learning to create an algorithm for automated detection of diabetic retinopathy and diabetic macular edema in retinal fundus photographs. A specific type of neural network optimized for image classification called a deep convolutional neural network was trained using a retrospective development data set of 128 175 retinal images, which were graded 3 to 7 times for diabetic retinopathy, diabetic macular edema, and image gradability by a panel of 54 US licensed ophthalmologists and ophthalmology senior residents between May and December 2015. The resultant algorithm was validated in January and February 2016 using 2 separate data sets, both graded by at least 7 US board-certified ophthalmologists with high intragrader consistency. Deep learning-trained algorithm. The sensitivity and specificity of the algorithm for detecting referable diabetic retinopathy (RDR), defined as moderate and worse diabetic retinopathy, referable diabetic macular edema, or both, were generated based on the reference standard of the majority decision of the ophthalmologist panel. The algorithm was evaluated at 2 operating points selected from the development set, one selected for high specificity and another for high sensitivity. The EyePACS-1 data set consisted of 9963 images from 4997 patients (mean age, 54.4 years; 62.2% women; prevalence of RDR, 683/8878 fully gradable images [7.8%]); the Messidor-2 data set had 1748 images from 874 patients (mean age, 57.6 years; 42.6% women; prevalence of RDR, 254/1745 fully gradable images [14.6%]). For detecting RDR, the algorithm had an area under the receiver operating curve of 0.991 (95% CI, 0.988-0.993) for EyePACS-1 and 0.990 (95% CI, 0.986-0.995) for Messidor-2. Using the first operating cut point with high specificity, for EyePACS-1, the sensitivity was 90.3% (95% CI, 87.5%-92.7%) and the specificity was 98.1% (95% CI, 97.8%-98.5%). For Messidor-2, the sensitivity was 87.0% (95% CI, 81.1%-91.0%) and the specificity was 98.5% (95% CI, 97.7%-99.1%). Using a second operating point with high sensitivity in the development set, for EyePACS-1 the sensitivity was 97.5% and specificity was 93.4% and for Messidor-2 the sensitivity was 96.1% and specificity was 93.9%. In this evaluation of retinal fundus photographs from adults with diabetes, an algorithm based on deep machine learning had high sensitivity and specificity for detecting referable diabetic retinopathy. Further research is necessary to determine the feasibility of applying this algorithm in the clinical setting and to determine whether use of the algorithm could lead to improved care and outcomes compared with current ophthalmologic assessment.


Electronic Effect on the Molecular Motion of Aromatic Amides: Combined Studies Using VT-NMR and Quantum Calculations.
Rotational barrier energy studies to date have focused on the amide bond of aromatic compounds from a kinetic perspective using quantum calculations and nuclear magnetic resonance (NMR). These studies provide valuable information, not only regarding the basic conformational properties of amide bonds but also the molecular gear system, which has recently gained interest. Thus, we investigate the precise motion of the amide bonds of two aromatic compounds using an experimental rotational barrier energy estimation by NMR experiments and a theoretical evaluation of the density functional theory calculation. The theoretical potential energy surface scan method combined with the quadratic synchronous transit 3 method and consideration of additional functional group rotation with optimization and frequency calculations support the results of the variable temperature ¹H NMR, with deviations of less than 1 kcal/mol. This detailed experimental and theoretical research strongly supports molecular gear motion in the aromatic amide system, and the difference in kinetic energy indicates that the electronic effect from the aromatic structure has a key role in conformational movements at different temperatures. Our study provides an enhanced basis for future amide structural dynamics research.


Role of neutrophil elastase in hypersecretion in asthma.
Goblet cell (GC) hyperplasia and mucous plugging are common in patients with acute asthma. These patients also show neutrophil recruitment into the airways. Neutrophils contain elastase, a potent secretagogue in airways. Therefore, it was reasoned that neutrophil recruitment, by releasing elastase, could result in GC hypersecretion. When neutrophil chemoattractants were instilled in the airways of guinea-pigs, time-dependent neutrophil recruitment and GC degranulation occurred. An inhibitor of leukocyte infiltration (NPC15669) prevented both responses, implicating neutrophils. An inhibitor of neutrophil elastase (ICI 200,355) abolished GC degranulation, implicating elastase. Further studies implicate movement of elastase from cytoplasmic granules to the neutrophil surface, and they suggest a role for adhesion molecules on neutrophils and on GCs in neutrophil-dependent GC degranulation. Similarly, instillation of ovalbumin (OVA) into airways of OVA-sensitized guinea-pigs caused early recruitment of neutrophils and GC degranulation. GC degranulation was prevented by pretreatment with NPC15669 or ICI 200,355. These results implicate neutrophil release of elastase in allergen-induced hypersecretion. The results suggest a mechanism for the mucous plugging that occurs in acute asthma; prevention of neutrophil recruitment, prevention of neutrophil-GC adhesion, or inhibition of elastase activity could provide effective therapy for this serious pathophysiological abnormality.


Occurrence of colistin-resistant hypervirulent Klebsiella variicola.
A colistin-resistant mucoid Klebsiella strain was recovered from the blood of a patient in China. Hypervirulence has been reported in Klebsiella pneumoniae, but not in other Klebsiella spp. The strain was suspected to be hypervirulent and was therefore characterized. The strain was subjected to genome sequencing using both the short-read Illumina HiSeq X10 Sequencer and the long-read MinION sequencer. Precise species identification was established using average nucleotide identity based on genome sequences. Virulence and antimicrobial resistance genes were identified using ResFinder and the bigsdb database. Conjugation experiments were performed. Virulence was assessed using wax moth (Galleria mellonella) larvae with control Klebsiella strains of low virulence and hypervirulence. The strain had a 5 553 341 bp circular chromosome and a 236 355 bp large plasmid. It was identified as Klebsiella variicola. The strain had multiple virulence genes encoding mucoid phenotype regulator (rmpA and rmpA2), aerobactin (iucABCD-iutA), salmochelin (iroBCDN) and yersiniabactin (irp1-2 and ybtAEPQSTUX) on the plasmid, which was not self-transmissible. It exhibited enhanced virulence in the larvae model, suggesting that the strain was hypervirulent. It was resistant to colistin (MIC = 8 mg/L) but was susceptible to amikacin, aztreonam, cefotaxime, ceftazidime, gentamicin, imipenem, meropenem, moxifloxacin, piperacillin/tazobactam, trimethoprim/sulfamethoxazole and tigecycline. The D150G substitution in PhoP, part of the PhoP-Q two-component system, which is known to mediate colistin resistance, was present in the strain. Hypervirulence is not restricted to K. pneumoniae; it is also seen in other Klebsiella spp. The convergence of colistin resistance and hypervirulence in K. variicola represents a new challenge for health.


Statistical methods for examining genetic influences of resistance to anti-epileptic drugs.
It is generally accepted that genetics may be an important factor in explaining the variation between patients' responses to certain drugs. However, identification and confirmation of the responsible genetic variants is proving to be a challenge in many cases. A number of difficulties that may be encountered in pursuit of these variants, such as nonreplication of a true effect, population structure and selection bias, can be mitigated or at least reduced by appropriate statistical methodology. Another major statistical challenge facing pharmacogenetic studies is the detection of possible small polygenic effects using large volumes of genetic data, while controlling the number of false-positive signals. Here, we review statistical design and analysis options available for investigations of genetic resistance to anti-epileptic drugs.


Potassium magnesium supplementation for four weeks improves small distal artery compliance and reduces blood pressure in patients with essential hypertension.
It has been postulated that the loss of arterial compliance may precede cardiovascular diseases, and that arterial compliance is an important parameter to consider when evaluating arterial diseases such as essential hypertension (EH) and the effects of antihypertensive treatment. In all, 133 EH patients and 147 healthy subjects were enrolled in this study. Large arterial compliance (C1) and small arterial compliance (C2) were measured by the CVProfilor DO-2020 CardioVascular Profiling System. Thirty-five patients randomly received magnesium potassium supplementation (magnesium, 70.8 mg/d; potassium, 217.2 mg/d) for four weeks, and 32 patients received lacidipin (4 mg/d) as a control. Before and after the four weeks, blood pressure, C1, and C2 were measured. It was found that arterial compliance was significantly lower in EH patients compared with healthy subjects (C1: 12.53 +/- 0.33 vs. 15.63 +/- 0.30 ml/mmHg x 10, p < 0.01;C2: 3.79 +/- 0.17 vs. 5.69 +/- 0.25 ml/mmHg x 100, p < 0.01). On lacidipine, systolic and diastolic BP decreased 13.27 +/- 1.76 mm Hg and 6.33 +/- 1.55 mm Hg, and C1 and C2 compliance values increased 25.05% +/- 4.49% and 34.50% +/- 7.40%, respectively. On K+ and Mg2+ supplementation, systolic and diastolic BP decreased 7.83 +/- 1.87 mm Hg and 3.67 +/- 1.03 mm Hg, and C1 and C2 compliance values increased 12.44% +/- 4.43% and 45.25% +/- 6.67%, respectively. Decreases in systemic vascular resistance (mean arterial pressure divided by cardiac output) by 11.9% and 16.6 % (p < 0.01) were seen between the drug-induced changes, respectively. Both large arterial compliance and small arterial compliance were decreased in essential hypertension patients. In essential hypertension patients, magnesium and potassium supplementation could improve small arterial compliance, while lacidipine improved large arterial compliance significantly.


Epigenetics of autism-related impairment: copy number variation and maternal infection.
Epidemiological data have suggested maternal infection and fever to be associated with increased risk of autism spectrum disorder (ASD). Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated copy number variants (CNVs) and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings. We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array comparative genomic hybridization screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-reported interview and questionnaires. We found significant interactive effects between the presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD. Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes and suggest that these effects are specific to ASD rather than to global neurodevelopment.


Effects of publicly funded and quality of life on attendance rate among methadone maintenance treatment patients in Taiwan: an 18-month follow-up study.
Methadone maintenance treatment programs (MMTPs) are important public health intervention to control the human immunodeficiency virus (HIV) and the drug use problems. For expanding treatment coverage, publicly funded programs may be necessary for heroin users with low socio-economic status. We evaluated the difference of demographics, clinical features, and quality of life (QoL) of heroin users enrolled in publicly funded and self-paid MMTP and explored determinants influencing their attendance rate, respectively, for these two groups. A total of 234 heroin users enrolled in MMTP (129 in publicly funded and 105 in self-paid) between 2006 and 2008 self-reported the Taiwan version of the World Health Organization Quality of Life Instrument, Brief Version (WHOQOL-BREF) at baseline. Data regarding demographic and clinical features were collected during baseline interview. Methadone per 3-month attendance rates up to 18 months were conducted for each participant beginning from the index date. Self-paid group had a better QoL but lower treatment adherence than did the publicly funded group. Male and living alone were positive predictors on attendance rate for publicly funded group, and age of first heroin use and hepatitis C virus (HCV) seropositive were negative predictors. However, predictors on attendance rate for self-paid group were different from publicly funded group: HCV seropositive was a positive predictor and social QoL was a negative predictor. Findings of this study should be concerned with modifying original funding eligibility. Additional measures to explore what could impede treatment adherence are needed.


Semantic Representations for NLP Using VerbNet and the Generative Lexicon.
The need for deeper semantic processing of human language by our natural language processing systems is evidenced by their still-unreliable performance on inferencing tasks, even using deep learning techniques. These tasks require the detection of subtle interactions between participants in events, of sequencing of subevents that are often not explicitly mentioned, and of changes to various participants across an event. Human beings can perform this detection even when sparse lexical items are involved, suggesting that linguistic insights into these abilities could improve NLP performance. In this article, we describe new, hand-crafted semantic representations for the lexical resource VerbNet that draw heavily on the linguistic theories about subevent semantics in the Generative Lexicon (GL). VerbNet defines classes of verbs based on both their semantic and syntactic similarities, paying particular attention to shared diathesis alternations. For each class of verbs, VerbNet provides common semantic roles and typical syntactic patterns. For each syntactic pattern in a class, VerbNet defines a detailed semantic representation that traces the event participants from their initial states, through any changes and into their resulting states. The Generative Lexicon guided the structure of these representations. In GL, event structure has been integrated with dynamic semantic models in order to represent the attribute modified in the course of the event (the location of the moving entity, the extent of a created or destroyed entity, etc.) as a sequence of states related to time points or intervals. We applied that model to VerbNet semantic representations, using a class's semantic roles and a set of predicates defined across classes as components in each subevent. We will describe in detail the structure of these representations, the underlying theory that guides them, and the definition and use of the predicates. We will also evaluate the effectiveness of this resource for NLP by reviewing efforts to use the semantic representations in NLP tasks.


The 'human revolution' in lowland tropical Southeast Asia: the antiquity and behavior of anatomically modern humans at Niah Cave (Sarawak, Borneo).
Recent research in Europe, Africa, and Southeast Asia suggests that we can no longer assume a direct and exclusive link between anatomically modern humans and behavioral modernity (the 'human revolution'), and assume that the presence of either one implies the presence of the other: discussions of the emergence of cultural complexity have to proceed with greater scrutiny of the evidence on a site-by-site basis to establish secure associations between the archaeology present there and the hominins who created it. This paper presents one such case study: Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 in the West Mouth of the Great Cave of a modern human skull, the 'Deep Skull,' controversially associated with radiocarbon dates of ca. 40,000 years before the present. A new chronostratigraphy has been developed through a re-investigation of the lithostratigraphy left by the earlier excavations, AMS-dating using three different comparative pre-treatments including ABOX of charcoal, and U-series using the Diffusion-Absorption model applied to fragments of bones from the Deep Skull itself. Stratigraphic reasons for earlier uncertainties about the antiquity of the skull are examined, and it is shown not to be an 'intrusive' artifact. It was probably excavated from fluvial-pond-desiccation deposits that accumulated episodically in a shallow basin immediately behind the cave entrance lip, in a climate that ranged from times of comparative aridity with complete desiccation, to episodes of greater surface wetness, changes attributed to regional climatic fluctuations. Vegetation outside the cave varied significantly over time, including wet lowland forest, montane forest, savannah, and grassland. The new dates and the lithostratigraphy relate the Deep Skull to evidence of episodes of human activity that range in date from ca. 46,000 to ca. 34,000 years ago. Initial investigations of sediment scorching, pollen, palynomorphs, phytoliths, plant macrofossils, and starch grains recovered from existing exposures, and of vertebrates from the current and the earlier excavations, suggest that human foraging during these times was marked by habitat-tailored hunting technologies, the collection and processing of toxic plants for consumption, and, perhaps, the use of fire at some forest-edges. The Niah evidence demonstrates the sophisticated nature of the subsistence behavior developed by modern humans to exploit the tropical environments that they encountered in Southeast Asia, including rainforest.


Developing the National Usability-Focused Health Information System Scale for Physicians: Validation Study.
Problems in the usability of health information systems (HISs) are well acknowledged, but research still lacks a validated questionnaire for measuring and monitoring different dimensions of usability of HISs. Such questionnaires are needed not only for research but also for developing usability of HISs from the viewpoint of end-user experiences. This study aimed to develop and test the validity of the questionnaire measuring the National Usability-Focused HIS-Scale (NuHISS) among a nationally representative sample of Finnish physicians. We utilized 2 cross-sectional data collected from a random sample of Finnish physicians in 2014 (N=3781; of which 2340 [61.9%] were women) and 2017 (N=4018; of which 2604 [64.8%] were women). Exploratory and confirmatory factor analyses (structural equation modeling [SEM]) were applied to test the structural validity of the NuHISS. As the concurrent validity measure, we used the self-reported overall quality of the electronic health record system (school grade) provided by the participants using marginal structural models. The exploratory factor analyses with Varimax rotation suggested that the 7-factor solution did offer a good fit to the data in both samples (C2=2136.14 in 2014 and C2=2109.83 in 2017, both P<.001). Moreover, structural equation modelling analyses, using comparative fit index (CFI), Tucker-Lewis Index (TLI), Normed Fit Index (NFI), root mean squared error of approximation (RMSEA), and Standardized Root Mean square Residual (SRMR), showed that the 7-factor solution provided an acceptable fit in both samples (CFI=0.92/0.91, TLI=0.92/0.91, NFI=0.92/0.91, RMSEA=0.048/0.049, and SRMR=0.040/0.039). In addition, concurrent validity of this solution was shown to be acceptable. Ease of use, but also all other dimensions, was especially associated with overall quality reports independent of measured confounders. The 7-factor solution included dimensions of technical quality, information quality, feedback, ease of use, benefits, internal collaboration, and cross-organizational collaboration. NuHISS provides a useful tool for measuring usability of HISs among physicians and offers a valid measure for monitoring the long-term development of HISs on a large scale. The relative importance of items needs to be assessed against national electronic health policy goals and complemented with items that have remained outside the NuHISS from the questionnaire when appropriate.


Cardiovascular risk factors in men: The role of gonadal steroids and sex hormone-binding globulin.
Males have higher risk of cardiovascular disease (CVD) than premenopausal females. Gonadal steroids are probably involved in the gender difference in CVD, but previous results have been conflicting. We investigated the associations between CVD risk factors and sex hormones in a cross-sectional designed study of 508 healthy males, aged 41 to 72 years. We determined total testosterone (T), sex hormone-binding globulin (SHBG), free androgen index (FAI), and estradiol (E2) and studied their relationship to body fat mass (BF), blood pressure (BP), aortic compliance, left ventricular mass (LVM), and plasma lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], very--low-density lipoprotein [VLDL], and triglycerides). In quartile analyses after adjustment for confounders (age, body mass index [BMI], alcohol consumption, and smoking), SHBG and E2 were positively associated with HDL, while FAI was negatively associated with HDL. T and SHBG were negatively associated with VLDL and triglycerides, while FAI was positively associated with VLDL and triglycerides. T and SHBG were negatively associated with BMI and BF, while FAI and E2 were positively associated with BMI and BF. E2 was negatively associated with LVM. No hormone varied with total cholesterol, LDL, BP, and aortic compliance in the adjusted analyses. In multiple regression analyses, SHBG was the main predictive variable of HDL, VLDL, and triglycerides explaining 12%, 17%, and 17% of the variation, respectively. No other hormones were selected as predictive variables for VLDL and triglycerides, but E2, T, and FAI were selected in the HDL regression, explaining 3%, 2%, and less than 1%, respectively. Our regression analyses illustrate the diverging results when investigating associations between gonadal steroids and lipids with and without SHBG adjustment. Atherogenic lipid profile in males is associated with low SHBG, low T levels, and a high FAI. Males with high E2 levels may have a less atherogenic lipid profile and lower LVM. SHBG is a key hormone in the association between sex hormones and plasma lipids. We suggest that conflicting results of cross-sectional and intervention studies of sex hormones and lipids, in part, may be explained by interindividual differences or changes in SHBG. Thus, further studies on the potential role of SHBG in the development of ischemic heart disease (IHD) should be performed.


A Blueprint for Social Cognitive Development.
The field of social cognitive development (SCD) has historically failed to emerge as a dominant approach in developmental psychology. We take this opportunity to articulate the assumptions, goals, and contributions of SCD with the aim of invigorating research from this perspective. We begin by describing the current landscape of social and cognitive development, suggesting what they have and have not given us. We then outline major goals of the social cognitive developmental approach and walk through examples of successful SCD research. Finally, we examine the unique potential of the social cognitive approach to cross-fertilize social and cognitive development (as well as related fields such as social psychology and neuroscience) and to answer new questions about development.