The influence of a sense of time on human development.
The subjective sense of future time plays an essential role in human motivation. Gradually, time left becomes a better predictor than chronological age for a range of cognitive, emotional, and motivational variables. Socioemotional selectivity theory maintains that constraints on time horizons shift motivational priorities in such a way that the regulation of emotional states becomes more important than other types of goals. This motivational shift occurs with age but also appears in other contexts (for example, geographical relocations, illnesses, and war) that limit subjective future time.


Extracting Various Classes of Data From Biological Text Using the Concept of Existence Dependency.
One of the key goals of biological natural language processing (NLP) is the automatic information extraction from biomedical publications. Most current constituency and dependency parsers overlook the semantic relationships between the constituents comprising a sentence and may not be well suited for capturing complex long-distance dependences. We propose in this paper a hybrid constituency-dependency parser for biological NLP information extraction called EDCC. EDCC aims at enhancing the state of the art of biological text mining by applying novel linguistic computational techniques that overcome the limitations of current constituency and dependency parsers outlined earlier, as follows: 1) it determines the semantic relationship between each pair of constituents in a sentence using novel semantic rules; and 2) it applies a semantic relationship extraction model that extracts information from different structural forms of constituents in sentences. EDCC can be used to extract different types of data from biological texts for purposes such as protein function prediction, genetic network construction, and protein-protein interaction detection. We evaluated the quality of EDCC by comparing it experimentally with six systems. Results showed marked improvement.


Health worker posting and transfer at primary level in Tamil Nadu: Governance of a complex health system function.
Posting and transfer (PT) of health personnel - placing the right health workers in the right place at the right time - is a core function of any large-scale health service. In the context of government health services, this may be seen as a simple process of bureaucratic governance and implementation of the rule of law. However the literature from India and comparable low and middle-income country health systems suggests that in reality PT is a contested domain, driven by varied expressions of private and public interest throughout the chain of implementation. To investigate policymaking for PT in the government health sector and implementation of policies as experienced by different health system actors and stakeholders at primary health care level. We undertook an empirical case study of a PT reform policy at primary health care level in Tamil Nadu State, to understand how different groups of health systems actors experience PT. In-depth qualitative methods were undertaken to study processes of implementation of PT policies enacted through 'counselling' of health workers (individualized consultations to determine postings and transfers). PT emerges as a complex phenomenon, shaped partially by the laws of the state and partially as a parallel system of norms and incentives requiring consideration and coordination of the interests of different groups. Micro-practices of governance represent homegrown coping mechanisms of health administrators that reconcile public and private interests and sustain basic health system functions. Beyond a functional perspective of PT, it also reflects justice and fairness as it plays out in the health system. It signifies how well a system treats its employees, and by inference, is an index of the overall health of the system. For a complex governance function such as PT, the roles of private actors and private interests are not easily separable from the public, but rather are intertwined within the complexities of delivery of a public service. This complexity blurs conventional boundaries of private and public ownership and behaviour, and raises critical questions for the interpretation of coordinated governance. Hence, the imperative of enforcing rules may need to be complemented with bottom-up policy approaches, including treating PT not merely as system dysfunction, but also as a potential instrument of governance innovations, procedural justice and the accountability of health services to communities they seek to serve.


Koinophilia replaces random mating in populations subject to mutations with randomly varying fitnesses.
Koinophilia, the avoidance of sexual mates bearing strange phenotypic features, or displaying odd behaviour, would, if it evolved, profoundly influence the evolutionary process. A stochastic computer model was therefore devised to investigate the evolution of an initially rare koinophilic trait in panmictic populations, subject to mutations with randomly varying fitnesses. Individual genomes consisted of 50 genes. Mutations occurred at a rate of 0.005, 0.01 or 0.02 per gene per generation. The mean and maximum fitness of mutations could be varied, as could the proportion of beneficial mutations. The carriers of the koinophilic trait avoided, with adjustable degrees of intensity, mates displaying unusual phenotypic features (traits with population frequencies < 0.5); panmictic individuals mated randomly. The results show that koinophilia tends to replace panmixis whenever the preference for common phenotypic traits is strongly expressed, when few mutations are beneficial (1% instead of 10%), or when the maximum fitness of mutations is low (1.2 instead of 2.0). The mutation rate and mean fitness of mutations had only minor effects on the relative advantage of koinophilia.


Fluid management in acute kidney injury.
Acute kidney injury (AKI) and fluids are closely linked through oliguria, which is a marker of the former and a trigger for administration of the latter. Recent progress in this field has challenged the physiological and clinical rational of using oliguria as a trigger for the administration of fluid and brought attention to the delicate balance between benefits and harms of different aspects of fluid management in critically ill patients, in particular those with AKI. This narrative review addresses various aspects of fluid management in AKI outlining physiological aspects, the effects of crystalloids and colloids on kidney function and the effect of various resuscitation and de-resuscitation strategies on the course and outcome of AKI.


Celiac disease risk varies between birth cohorts, generating hypotheses about causality: evidence from 36 years of population-based follow-up.
Celiac disease (CD) is a major public health problem with estimated 1-3% prevalence in the general population. In recent years an increase in CD prevalence has been reported both in Sweden and worldwide. This study aimed at examining the annual incidence rate of biopsy-proven celiac disease among children in Sweden over a 36-year period, to assess variations by age, sex and birth cohort, and to assess the clinical impact of these changes. The National Swedish Childhood CD Register was used to identify 9107 children aged 0-14.9 years who were diagnosed with CD during the period 1973 to 2009. From 1973 to 1990 the register covered 15% of the nation, this increased to 40% during 1991-1997; a full national coverage was obtained from 1998 onwards. Estimations for the annual incidence rate, cumulative incidence and clinical impact by age groups, calendar month and birth cohorts were made. CD incidence is continuing to increase in the child population aged 2-14.9 years. A continued variation in CD incidence was observed in children aged 0-1.9 years, characterized by a marked decrease in most recent years. The median age at diagnosis has increased from 1.0 year in the 1970s to 6.8 years in 2009. The average number of new cases has risen from ~200 during 1973-1983 to ~600 during 2004-2009. In the birth cohorts of 2000-2002 the cumulative incidence even exceeded that of the epidemic cohorts at comparable ages. The highest cumulative incidence was observed in the birth cohorts of 1985-1995 and 2000-2002. CD risk varies between birth cohorts, suggesting cyclic environmental and/or lifestyle risk factors in CD etiology. More research on underlying risk factors is required in order to move forward with preventive strategies.


The use of the autism diagnostic interview-revised with a latino population of adolescents and adults with autism.
Research shows that Latinos are less likely to be diagnosed with autism than their non-Latino counterparts. One factor that may contribute to these differences is that autism diagnostic instruments have not been adapted for the Latino population. The present study compared scores from the Autism Diagnostic Interview-Revised for two groups: 48 Latino adolescents and adults with autism and a matched sample of 96 non-Latino Whites. There were no significant differences between the two groups in total impairments in social reciprocity or communication. However, lower levels of restrictive-and-repetitive behaviors were found among Latino adolescents and adults with autism compared to Whites. Findings suggest that there may be cultural equivalency in some domains, but others may warrant further exploration.


Quantitative Assessment of Bone Metastasis in Prostate Cancer Using Synthetic Magnetic Resonance Imaging.
The aims of this study were to evaluate the feasibility of quantitative synthetic magnetic resonance imaging (SyMRI) for characterizing bone lesions in prostate cancer and to discriminate viable progressive osteoblastic bone metastasis from nonviable bone metastases with treatment-induced sclerosis during the treatment course. This institutional review board-approved prospective study included 96 consecutive prostate cancer patients who underwent whole-body MRI including diffusion-weighted imaging at the time of staging at diagnosis or starting a new line of anticancer treatment. Additional synthetic MRI of the lumbosacral spine, pelvis, and proximal femurs was performed. A region of interest of 1.0 cm in diameter was set in each bone lesion by 2 independent readers who were blinded to bone lesions' diagnosis. Differences in SyMRI variables between the different bone lesions were compared with the Wilcoxon rank sum test, and associations of SyMRI variables with active disease were analyzed with logistic regression analysis. Performance of T1, T2, and proton density (PD) for diagnosing active disease was assessed using the area under the receiver operating characteristic curve. Ninety-three bone lesions were eligible for analysis. The PD values of active (viable) bone metastatic lesions were significantly higher than those of inactive (nonviable) bone metastatic lesions without sclerosis and those of red bone marrow (P < 0.001 for both readers). The PD values of inactive bone metastatic lesions with sclerosis were significantly lower than those of inactive bone metastatic lesions without sclerosis and red bone marrow (P < 0.001 for both readers). The PD value proved to be an independent significant indicator (P < 0.001) for differentiating bone lesions. The areas under the curve of T1/T2/PD for identifying active disease were 0.81/0.69/0.93 for reader 1 and 0.78/0.70/0.92 for reader 2, respectively. Signal quantification on SyMRI provides objective assessment of bone lesions in the lower trunk. The PD value can be useful to determine the viability of bone metastases in prostate cancer.


Is household food insecurity a determinant of weight status in patients with type 2 diabetes in rural areas?
Background: There is mixed evidence about food insecurity and overweight/obesity coexisting, however it is unclear about association between food insecurity and weight status in people with type 2 diabetes. Therefore, the aim of this study was to evaluate the relationship between food insecurity and weight status in individuals with type 2 diabetes in rural areas in Iran. Methods: 1847 patients with type 2 diabetes who were residence in rural areas completed Household Food Security Scale (six-item short questionnaire). Logistic regression model was applied to assess the independent effect of food insecurity on weight status. Results: Mean age of the study population was 62.6±11.8 years, and the majority of them were female (70.4%). Most of the study population (70.4%) had unhealthy weight status. Food insecurity affected more than 46% (n=852) of the households of the study population. According to weight status, more than 40% (n=565) of overweight and obese subjects and 60% (n=18) of underweight subjects lived in households with food insecurity. The results of multiple logistic regression model showed that food insecurity was not an independent significant predictor of overweight or obesity in patients with type 2 diabetes. However, low food security (LFS) was an independent significant predictor for underweight in patients with type 2 diabetes (OR=2.35, P=0.041). Conclusion: It is concluded that food insecurity was frequent in all levels of weight status of patients with type 2 diabetes in rural regions. However this association observed in underweight individuals but there was no significant overall relationship between household food insecurity and in overweight and obesity in this group of patients.


Plant-soil interactions in Mediterranean forest and shrublands: impacts of climatic change.
In the Mediterranean climate, plants have evolved under conditions of low soil-water and nutrient availabilities and have acquired a series of adaptive traits that, in turn exert strong feedback on soil fertility, structure, and protection. As a result, plant-soil systems constitute complex interactive webs where these adaptive traits allow plants to maximize the use of scarce resources. It is necessary to review the current bibliography to highlight the most know characteristic mechanisms underlying Mediterranean plant-soil feed-backs and identify the processes that merit further research in order to reach an understanding of the plant-soil feed-backs and its capacity to cope with future global change scenarios. In this review, we characterize the functional and structural plant-soil relationships and feedbacks in Mediterranean regions. We thereafter discuss the effects of global change drivers on these complex interactions between plants and soil. The large plant diversity that characterizes Mediterranean ecosystems is associated to the success of coexisting species in avoiding competition for soil resources by differential exploitation in space (soil layers) and time (year and daily). Among plant and soil traits, high foliar nutrient re-translocation and large contents of recalcitrant compounds reduce nutrient cycling. Meanwhile increased allocation of resources to roots and soil enzymes help to protect against soil erosion and to improve soil fertility and capacity to retain water. The long-term evolutionary adaptation to drought of Mediterranean plants allows them to cope with moderate increases of drought without significant losses of production and survival in some species. However, other species have proved to be more sensitive decreasing their growth and increasing their mortality under moderate rising of drought. All these increases contribute to species composition shifts. Moreover, in more xeric sites, the desertification resulting from synergic interactions among some related process such as drought increases, torrential rainfall increases and human driven disturbances is an increasing concern. A research priority now is to discern the effects of long-term increases in atmospheric CO2 concentrations, warming, and drought on soil fertility and water availability and on the structure of soil communities (e.g. shifts from bacteria to fungi) and on patching vegetation and root-water uplift (from soil to plant and from soil deep layers to soil superficial layers) roles in desertification.


Synaptic pruning by microglia is necessary for normal brain development.
Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.


Definition of adenovirus type 5 functions involved in the induction of chromosomal aberrations in human cells.
Infection of human embryonic kidney cells with adenovirus type 5 (Ad5) induces aberrations (gaps and breaks) in the cell chromosomes. We have conducted a study utilizing a large number of Ad5 mutants to identify the viral functions that are responsible for the occurrence of cytogenetic damage. The results of our investigation have indicated that expression of the gene products of the Ad5 early region 1A (E1A) is necessary for the induction of chromosomal aberrations and that other early viral gene products do not appear to contribute to this phenotype. We have also shown that expression of both the major E1A gene products, the 243 amino acid and the 289 amino acid proteins, is required for induction of damage at wild-type levels, although the 289 amino acid protein appears to retain detectable activity on its own. Lastly, we have observed that deletions in the amino-terminal region of the E1A proteins and in the transactivating domain of the 289 amino acid protein prevent the occurrence of cytogenetic damage, whereas mutations elsewhere in the proteins do not affect this process.


Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma.
Sarcomas contain a subpopulation of tumor-propagating cells (TPCs) with enhanced tumor-initiating and self-renewal properties. However, it is unclear whether the TPC phenotype in sarcomas is stable or a dynamic cell state that can derive from non-TPCs. In this study, we utilized a mouse model of undifferentiated pleomorphic sarcoma (UPS) to trace the lineage relationship between sarcoma side population (SP) cells that are enriched for TPCs and non-SP cells. By cotransplanting SP and non-SP cells expressing different endogenous fluorescent reporters, we show that non-SP cells can give rise to SP cells with enhanced tumor-propagating potential in vivo. Lineage trajectory analysis using single-cell RNA sequencing from SP and non-SP cells supports the notion that non-SP cells can assume the SP cell phenotype de novo. To test the effect of eradicating SP cells on tumor growth and self-renewal, we generated mouse sarcomas in which the diphtheria toxin receptor is expressed in the SP cells and their progeny. Ablation of the SP population using diphtheria toxin did not impede tumor growth or self-renewal. Altogether, we show that the sarcoma SP represent a dynamic cell state and targeting TPCs alone is insufficient to eliminate tumor progression.


Compounds from Syzygium aromaticum possessing growth inhibitory activity against oral pathogens.
A crude MeOH extract of Syzygium aromaticum (clove) exhibited preferential growth-inhibitory activity against Gram-negative anaerobic periodontal oral pathogens, including Porphyromonas gingivalis and Prevotella intermedia. By means of bioassay-directed chromatographic fractionation, eight active compounds were isolated from this extract and were identified as 5,7-dihydroxy-2-methylchromone 8-C-beta-D-glucopyranoside, biflorin, kaempferol, rhamnocitrin, myricetin, gallic acid, ellagic acid, and oleanolic acid, based on spectroscopic evidence. The antibacterial activity of these pure compounds was determined against Streptococcus mutans, Actinomyces viscosus, P. gingivalis, and P. intermedia. The flavones, kaempferol and myricetin, demonstrated potent growth-inhibitory activity against the periodontal pathogens P. gingivalis and P. intermedia.


Trends in contraceptive prevalence rates in sub-Saharan Africa since the 2012 London Summit on Family Planning: results from repeated cross-sectional surveys.
The Family Planning 2020 (FP2020) initiative, launched at the 2012 London Summit on Family Planning, aims to enable 120 million additional women to use modern contraceptive methods by 2020 in the world's 69 poorest countries. It will require almost doubling the pre-2012 annual growth rate of modern contraceptive prevalence rates from an estimated 0·7 to 1·4 percentage points to achieve the goal. We examined the post-Summit trends in modern contraceptive prevalence rates in nine settings in eight sub-Saharan African countries (Burkina Faso; Kinshasa, DR Congo; Ethiopia; Ghana; Kenya; Niamey, Niger; Kaduna, Nigeria; Lagos, Nigeria; and Uganda). These settings represent almost 73% of the population of the 18 initial FP2020 commitment countries in the region. We used data from 45 rounds of the Performance Monitoring and Accountability 2020 (PMA2020) surveys, which were all undertaken after 2012, to ascertain the trends in modern contraceptive prevalence rates among all women aged 15-49 years and all similarly aged women who were married or cohabitating. The analyses were done at the national level in five countries (Burkina Faso, Ethiopia, Ghana, Kenya, and Uganda) and in selected high populous regions for three countries (DR Congo, Niger, and Nigeria). We included the following as modern contraceptive methods: oral pills, intrauterine devices, injectables, male and female sterilisations, implants, condom, lactational amenorrhea method, vaginal barrier methods, emergency contraception, and standard days method. We fitted design-based linear and quadratic logistic regression models and estimated the annual rate of changes in modern contraceptive prevalence rates for each country setting from the average marginal effects of the fitted models (expressed in absolute percentage points). Additionally, we did a random-effects meta-analysis to summarise the overall results for the PMA2020 countries. The annual rates of changes in modern contraceptive prevalence rates among all women of reproductive age (15-49 years) varied from as low as 0·77 percentage points (95% CI -0·73 to 2·28) in Lagos, Nigeria, to 3·64 percentage points (2·81 to 4·47) in Ghana, according to the quadratic model. The rate of change was also high (>1·4 percentage points) in Burkina Faso, Kinshasa (DR Congo), Kaduna (Nigeria), and Uganda. Although contraceptive use was rising rapidly in Ethiopia during the pre-Summit period, our results suggested that the yearly growth rate stalled recently (0·92 percentage points, 95% CI -0·23 to 2·07) according to the linear model. From the meta-analysis, the overall weighted average annual rate of change in modern contraceptive prevalence rates in all women across all nine settings was 1·92 percentage points (95% CI 1·14 to 2·70). Among married or cohabitating women, the annual rates of change were higher in most settings, and the overall weighted average was 2·25 percentage points (95% CI 1·37-3·13). Overall, the annual growth rates exceeded the 1·4 percentage points needed to achieve the FP2020 goal of 120 million additional users of modern contraceptives by 2020 in the select study settings. Local programme experiences can be studied for lessons to be shared with other countries aiming to respond to unmet demands for family planning. The findings of this study have implications for the way progress is tracked toward achieving the FP2020 goal. The Bill & Melinda Gates Foundation.


Death due to combined intake of ethanol and toluene: a case report.
Toluene is a commonly used volatile organic chemical in industry and is the most often chosen illicit substance among volatile substance abusers. Studies involving healthy volunteers suggest that ethanol consumption inhibits toluene metabolism, thus increasing its blood levels. In this study, a lethal case of combined ethanol consumption and toluene inhalation has been reported. Our case was a 30-year-old male who had used volatile substance for 15 years. The autopsy revealed no abnormal findings. Toxicological analysis revealed alcohol and toluene in the blood and the cause of death was considered as toxicity due to acute combined intake of alcohol and toluene. Lethal combined ethanol and toluene intake is rarely reported in the literature. Experimental studies indicate that toluene increases the risk of ethanol dependence and each substance increases the toxic effects of the other.


Proportionally constant quantitative transmission of nucleolin and protein B23 in cycling cancer cells.
Objective-To investigate whether and to what extent the two major AgNOR proteins, nucleolin and protein B23, are maintained after one cell division in proliferating cells.Design-Using three asynchronously growing human cancer cell lines, TG, SJNKP, and CHP 212 cells, nucleolin and protein B23 were first identified on SDS-polyacrylamide separated nucleolar proteins, transferred to nitrocellulose and silver stained for AgNOR proteins. Measurement of doubling time indicated a period very close to 24h for each of the cell lines. To quantify the percentage of nucleolin and protein B23 maintained in daughter cells after duplication, cells were labelled with [(35)S]-methionine and a 24h cold chase performed. Nucleolin and protein B23 labelling was evaluated by densitometric analysis on nitrocellulose autoradiograms.Results-The radioactivity relative to nucleolin and protein B23 bands maintained in the daughter cells was a constant fraction of that present before cell duplication. In the three cell lines the percentage of residual radioactivity measured in the nucleolin bands was 42.2, 40.6, and 41.2 and in protein B23 bands 48.0, 46.2, and 44.1.Conclusions-After one cell division the nucleolin and protein B23 quantity present in cells may be highly variable, depending on the amount of the two proteins present in the mother cell. This is important in relation to the correct utilisation of AgNOR protein quantity as an index for evaluating cell kinetics.


Differential effects of MDMA and methylphenidate on social cognition.
Social cognition is important in everyday-life social interactions. The social cognitive effects of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate (both used for neuroenhancement and as party drugs) are largely unknown. We investigated the acute effects of MDMA (75 mg), methylphenidate (40 mg) and placebo using the Facial Emotion Recognition Task, Multifaceted Empathy Test, Movie for the Assessment of Social Cognition, Social Value Orientation Test and the Moral Judgment Task in a cross-over study in 30 healthy subjects. Additionally, subjective, autonomic, pharmacokinetic, endocrine and adverse drug effects were measured. MDMA enhanced emotional empathy for positive emotionally charged situations in the MET and tended to reduce the recognition of sad faces in the Facial Emotion Recognition Task. MDMA had no effects on cognitive empathy in the Multifaceted Empathy Test or social cognitive inferences in the Movie for the Assessment of Social Cognition. MDMA produced subjective 'empathogenic' effects, such as drug liking, closeness to others, openness and trust. In contrast, methylphenidate lacked such subjective effects and did not alter emotional processing, empathy or mental perspective-taking. MDMA but not methylphenidate increased the plasma levels of oxytocin and prolactin. None of the drugs influenced moral judgment. Effects on emotion recognition and emotional empathy were evident at a low dose of MDMA and likely contribute to the popularity of the drug.


Gap junction disappearance in astrocytes and leptomeningeal cells as a consequence of protozoan infection.
Trypanosoma cruzi and Toxoplasma gondii are protozoan parasites capable of causing infections of the nervous system. In order to determine effects of infection by these organisms on intercellular communication in the brain, dye coupling and connexin abundance and distribution were examined in leptomeningeal cells and astrocytes infected with T. cruzi or T. gondii. For both cell types infected with either type of protozoan parasite, intercellular diffusion of intracellularly injected Lucifer Yellow was dramatically reduced. Immunocytochemistry with antibodies specific for connexin43 (in astrocytes) or both connexin43 and connexin26 (for leptomeningeal cells) demonstrated that punctate gap junctional staining was much reduced in infected cells, although uninfected neighbors could display normal connexin abundance and distribution. Western blot analyses revealed that connexin43 abundance in both cell types infected with either parasite was similar to that in uninfected cells. Phosphorylation state of connexin43 (inferred from electrophoretic mobility of connexin43 isoforms) was not significantly affected by the infection process. Immunocytochemistry of whole brains from animals acutely infected with either parasite also showed a marked reduction in connexin43 expression. We conclude that infection of both types of brain cells with either protozoan parasite results in a loss of intercellular communication and organized gap junction plaques without affecting expression levels or posttranslational processing of gap junction proteins. Presumably, these changes in gap junction distribution result from altered targeting of the junctional protein to the plasma membrane, and/or from changes in assembly of subunits into functional channels.


Pulmonary model to predict the effects of series ventricular interaction.
To fully describe the mechanisms of diastolic interaction between the right ventricle and left ventricle, it is necessary to understand how a change in right ventricular output (Qrvo) is transmitted across the pulmonary circulation. This series ventricular interaction is manifest as the temporal response in left ventricular filling (Qlvf) to a change in Qrvo. To quantify series interaction we used a three-element, two-parameter model of the pulmonary circulation. The parameters represented the pulmonary arterial and venous resistance and pulmonary vascular compliance. Using beat-to-beat values of mean pressure and flow measured at the input and output of the pulmonary circulation during the transient response to caval or pulmonary artery occlusion, we estimated the parameters for this model in eight open-chest dogs under control conditions, after autonomic blockade, and after fully opening the pericardium. From 110 separate data episodes, the average values of the pulmonary arterial and venous resistance and pulmonary vascular compliance were 0.14 +/- 0.08 mm Hg.sec/ml and 4.81 +/- 3.17 ml/mm Hg (+/- SD). These estimates were insensitive to the simultaneous effects of autonomic reflexes and direct ventricular interaction, so they uniquely measure the bulk transport properties of the pulmonary circulation. The time constant, which measures the response of Qlvf to a change in Qrvo, averaged 0.26 +/- 0.15 second, which implies that effects of series interaction on Qlvf are manifest within one beat. The model was also able to predict the dynamic response of Qlvf to changes in Qrvo and thus can be used to measure and predict the effects of series interaction in the intact cardiopulmonary system.


A model nurse practitioner-managed smoking cessation clinic.
To describe an intensive nurse practitioner (NP)-managed smoking cessation clinic that evolved from a primary-care quality-management initiative. Published articles, abstracts, books, clinical experience, and clinical data. Smoking continues to be the leading cause of preventable deaths in the United States and accounts for 87% of all lung cancers. Although smoking is responsible for nearly 30% of all cancer deaths, smoking prevalence rates remain stagnant in adults and are continuing to increase in adolescents. Twenty-five percent of all Americans smoke. An NP-managed clinic was developed within a large teaching hospital located in the southeastern United States based on the Agency for Health Care Policy and Research guideline for smoking cessation. The clinic provided effective smoking cessation interventions that can be replicated by experienced nurses with a smoking cessation background. All nurses have opportunities to assist patients to stop smoking through brief counseling and minimum interventions. Nurses can effectively manage an intensive smoking cessation clinic that is utilized by the interdisciplinary team to treat referrals. Cessation rates were high because therapies combined intensive behavioral sessions and pharmacologic approaches rather than either single modality. Nurses can replicate this practice in a variety of healthcare settings. Innovations in clinical practice often facilitate research studies to further define effective approaches for smoking cessation. Nurses need to identify and target smoking as the serious health problem it is and conduct much-needed research on cessation approaches within the inpatient and outpatient settings.


Costs of resistance in insect-parasite and insect-parasitoid interactions.
Most, if not all, organisms face attack by natural enemies and will be selected to evolve some form of defence. Resistance may have costs as well as its obvious benefits. These costs may be associated with actual defence or with the maintenance of the defensive machinery irrespective of whether a challenge occurs. In this paper, the evidence for costs of resistance in insect-parasite and insect-parasitoid systems is reviewed, with emphasis on two host-parasitoid systems, based on Drosophila melanogaster and pea aphids as hosts. Data from true insect-parasite systems mainly concern the costs of actual defence; evidence for the costs of standing defences is mostly circumstantial. In pea aphids, the costs of standing defences have so far proved elusive. Resistance amongst clones is not correlated with life-time fecundity, whether measured on good or poor quality plants. Successful defence by a D. melanogaster larva results in a reduction in adult size and fecundity and an increased susceptibility to pupal parasitoids. Costs of standing defences are a reduction in larval competitive ability though these costs only become important when food is limited. It is concluded that costs of resistance can play a pivotal role in the evolutionary and population dynamic interactions between hosts and their parasites.


The erbium micropeel: a prospective, randomized trial of the effects of two fluence settings on facial photoaging.
Recent studies have suggested that a series of low-energy, single-pass ablative laser resurfacing micropeels can reduce photoaging with decreased downtime. This randomized, prospective single-blinded trial sought to determine the ideal settings of sequential erbium:yttrium-aluminum-garnet (Er:YAG) laser treatments that maximize efficacy and patient satisfaction. Forty-six subjects with mild-to-moderate facial dyschromia and rhytides were evenly randomized to two Er:YAG treatment arms. Patients in the lower fluence (LF) (2.5 J/cm2) and higher fluence (HF) (3.8 J/cm2) groups each received three one-pass, full-face treatments one month apart. Patient and investigator assessments of rhytides, dyschromia and global appearance were performed at baseline and at four, eight and 20 weeks using a nominal scale from 1–4. Adverse events and patient satisfaction were also evaluated. Patient scores showed rhytid improvement only with HF treatments. Investigator scores at three months post-treatment showed dyschromia was significantly improved in both study arms, with a 24 and 36 percent reduction for the LF and HF groups, respectively. Global appearance scores improved by 25 and 32 percent, respectively. A trend towards greater post-procedure erythema and time-to-erythema resolution was observed in the HF group. Mild peeling was the most common adverse event. Individuals who underwent LF treatments were more likely to pursue future treatments. Both settings resulted in moderate but significant improvement in dyschromia, although only HF treatment improved rhytides. The decreased downtime of LF treatments made this the preferred choice of patients.


Biallelic Gene Targeting in Rice.
Sequence-specific nucleases (SSNs) have been used successfully in homology-directed repair (HDR)-mediated gene targeting (GT) in many organisms. However, break-induced GT in plants remains challenging due to inefficient delivery of HDR templates and SSNs into plant nuclei. In many plants, including rice, Agrobacterium-mediated transformation is the most practical means of transformation because this biotic transformation system can deliver longer and more intact DNA payloads with less incorporation of fragmented DNA compared with physical transformation systems such as polyethylene glycol, electroporation, or biolistics. Following infection with Agrobacterium, transfer of transfer DNA (T-DNA) to the nucleus and its integration into the plant genome occur consecutively during cocultivation, thus timing the induction of DNA double-strand breaks (DSBs) on the target gene to coincide with the delivery of the HDR template is crucial. To synchronize DSB induction and delivery of the HDR template, we transformed a Cas9 expression construct and GT vector harboring the HDR template with guide RNAs (gRNAs) targeting the rice acetolactate synthase (ALS) gene either separately or sequentially into rice calli. When gRNAs targeting ALS were transcribed transiently from double-stranded T-DNA containing the HDR template, DSBs were induced in the ALS locus by the assembled Cas9/gRNA complex and homologous recombination was stimulated. Contrary to our expectations, there was no great difference in GT efficiency between Cas9-expressing and nonexpressing cells. However, when gRNA targeting DNA ligase 4 was transformed with Cas9 prior to the GT experiment, GT efficiency increased dramatically and more than one line exhibiting biallelic GT at the ALS locus was obtained.


Technical note and results in the management of anatomical variants of renal vascularisation during endovascular aneurysm repair.
The revascularisation of large (>3 mm) renal arteries emerging from the proximal sealing zone or off the aneurismal wall can be challenging during endovascular aortic aneurysm repair. In this article, we describe various endovascular techniques using custom-made endografts to treat these complex variant anatomies. Nine patients deemed unfit for open repair with unusual renal vascularisation associated with aortic aneurysms were treated by endovascular means. After three-dimensional (3D) reconstructions on a dedicated workstation, custom-made devices were designed and manufactured. The revascularisation of multiple renal arteries and aberrant origins of renal arteries, associated or not with pelvic kidney or horseshoe kidney, was managed using fenestrated and branched endografts. All target vessels were patent on computed tomography (CT) scan and contrast-enhanced ultrasound evaluation before discharge as well as on the 6-month follow-up. One patient presented a decrease of postoperative glomerular filtration rate over 30% but did not require dialysis. No sac enlargement was depicted, and no reintervention was performed during follow-up. Three type 2 endoleaks were diagnosed. Endovascular treatment with fenestrated and branched endografts should be considered in challenging renal artery anatomies in patients unfit for open repair.


Generation of 9 MeV γ-rays by all-laser-driven Compton scattering with second-harmonic laser light.
Gamma-ray photons with energy >9 MeV were produced when second-harmonic-generated laser light (3 eV) inverse-Compton-scattered from a counterpropagating relativistic (~450 MeV) laser-wakefield-accelerated electron beam. Two laser pulses from the same laser system were used: one to accelerate electrons and one to scatter. Since the two pulses play very different roles in the γ-ray generation process, and thus have different requirements, a novel laser system was developed. It separately and independently optimized the optical properties of the two pulses. This approach also mitigated the deleterious effects on beam focusing that generally accompany nonlinear optics at high peak-power levels.


The Anti-Aggregation Holdase Hsp33 Promotes the Formation of Folded Protein Structures.
Holdase chaperones are known to be central to suppressing aggregation, but how they affect substrate conformations remains poorly understood. Here, we use optical tweezers to study how the holdase Hsp33 alters folding transitions within single maltose binding proteins and aggregation transitions between maltose binding protein substrates. Surprisingly, we find that Hsp33 not only suppresses aggregation but also guides the folding process. Two modes of action underlie these effects. First, Hsp33 binds unfolded chains, which suppresses aggregation between substrates and folding transitions within substrates. Second, Hsp33 binding promotes substrate states in which most of the chain is folded and modifies their structure, possibly by intercalating its intrinsically disordered regions. A statistical ensemble model shows how Hsp33 function results from the competition between these two contrasting effects. Our findings reveal an unexpectedly comprehensive functional repertoire for Hsp33 that may be more prevalent among holdases and dispels the notion of a strict chaperone hierarchy.


Multiplex detection of RNA expression in Drosophila embryos.
We present a fluorescence-based, multiplex in situ hybridization method that permits the simultaneous detection of five differently labeled antisense RNA probes and up to seven differ-ent transcripts in a single Drosophila embryo. We also show that it should be possible to increase the number of detected transcripts substantially with nascent transcript multiplex fluorescent in situ hybridization. These multiplex methods fill a current technological gap between high-resolution in situ hybridization with one or two fluorescently labeled probes and low-resolution but genome-wide microarray RNA profiling and should be of great utility in establishing gene networks.


Rack1 promotes epithelial cell-cell adhesion by regulating E-cadherin endocytosis.
E-cadherin and its cytoplasmic partners, catenins, mediate epithelial cell-cell adhesion. Disruption of this adhesion allows cancer cells to invade and metastasize. Aberrant activation of the Src tyrosine kinase disrupts cell-cell contacts through an E-cadherin/catenin-dependent mechanism. Previously we showed that Rack1 regulates the growth of colon cells by suppressing Src activity at G(1) and mitotic checkpoints, and in the intrinsic apoptotic and Akt cell survival pathways. Here we show that Rack1, partly by inhibiting Src, promotes cell-cell adhesion and reduces the invasive potential of colon cancer cells. Rack1 stabilizes E-cadherin and catenins at cell-cell contacts by inhibiting the Src phosphorylation of E-cadherin, the ubiquitination of E-cadherin by the E3 ligase Hakai and the endocytosis of E-cadherin. Upon depletion and restoration of extracellular calcium, Rack1 facilitates the re-assembly of E-cadherin-containing cell-cell contacts. Rack1 also blocks HGF-induced endocytosis of E-cadherin, disruption of cell-cell contacts and cell scatter. Our results uncover a novel function of Rack1 in maintaining the junctional homeostasis of intestinal epithelial cells by regulation of the Src- and growth factor-induced endocytosis of E-cadherin.


Burden of adhesions in abdominal and pelvic surgery: systematic review and met-analysis.
To estimate the disease burden of the most important complications of postoperative abdominal adhesions: small bowel obstruction, difficulties at reoperation, infertility, and chronic pain. Systematic review and meta-analyses. Searches of PubMed, Embase, and Central, from January 1990 to December 2012, without restrictions to publication status or language. All types of studies reporting on the incidence of adhesion related complications were considered. The primary outcome was the incidence of adhesive small bowel obstruction in patients with a history of abdominal surgery. Secondary outcomes were the incidence of small bowel obstruction by any cause, difference in operative time, enterotomy during adhesiolysis, and pregnancy rate after abdominal surgery. Subgroup and sensitivity analyses were done to study the robustness of the results. A random effects model was used to account for heterogeneity between studies. We identified 196 eligible papers. Heterogeneity was considerable for almost all meta-analyses. The origin of heterogeneity could not be explained by study design, study quality, publication date, anatomical site of operation, or operative technique. The incidence of small bowel obstruction by any cause after abdominal surgery was 9% (95% confidence interval 7% to 10%; I(2)=99%). the incidence of adhesive small bowel obstruction was 2% (2% to 3%; I(2)=93%); presence of adhesions was generally confirmed by emergent reoperation. In patients with a known cause of small bowel obstruction, adhesions were the single most common cause (56%, 49% to 64%; I(2)=96%). Operative time was prolonged by 15 minutes (95% confidence interval 9.3 to 21.1 minutes; I(2)=85%) in patients with previous surgery. Use of adhesiolysis resulted in a 6% (4% to 8%; I(2)=89%) incidence of iatrogenic bowel injury. The pregnancy rate after colorectal surgery in patients with inflammatory bowel disease was 50% (37% to 63%; I(2)=94%), which was significantly lower than the pregnancy rate in medically treated patients (82%, 70% to 94%; I(2)=97%). This review provides detailed and systematically analysed knowledge of the disease burden of adhesions. Complications of postoperative adhesion formation are frequent, have a large negative effect on patients' health, and increase workload in clinical practice. The quantitative effects should be interpreted with caution owing to large heterogeneity. The review protocol was registered through PROSPERO (CRD42012003180).


Biocatalytic synthesis of flavones and hydroxyl-small molecules by recombinant Escherichia coli cells expressing the cyanobacterial CYP110E1 gene.
Cyanobacteria possess several cytochrome P450s, but very little is known about their catalytic functions. CYP110 genes unique to cyanaobacteria are widely distributed in heterocyst-forming cyanobacteria including nitrogen-fixing genera Nostoc and Anabaena. We screened the biocatalytic functions of all P450s from three cyanobacterial strains of genus Nostoc or Anabaena using a series of small molecules that contain flavonoids, sesquiterpenes, low-molecular-weight drugs, and other aromatic compounds. Escherichia coli cells carrying each P450 gene that was inserted into the pRED vector, containing the RhFRed reductase domain sequence from Rhodococcus sp. NCIMB 9784 P450RhF (CYP116B2), were co-cultured with substrates and products were identified when bioconversion reactions proceeded. Consequently, CYP110E1 of Nostoc sp. strain PCC 7120, located in close proximity to the first branch point in the phylogenetic tree of the CYP110 family, was found to be promiscuous for the substrate range mediating the biotransformation of various small molecules. Naringenin and (hydroxyl) flavanones were respectively converted to apigenin and (hydroxyl) flavones, by functioning as a flavone synthase. Such an activity is reported for the first time in prokaryotic P450s. Additionally, CYP110E1 biotransformed the notable sesquiterpene zerumbone, anti-inflammatory drugs ibuprofen and flurbiprofen (methylester forms), and some aryl compounds such as 1-methoxy and 1-ethoxy naphthalene to produce hydroxylated compounds that are difficult to synthesize chemically, including novel compounds. We elucidated that the CYP110E1 gene, C-terminally fused to the P450RhF RhFRed reductase domain sequence, is functionally expressed in E. coli to synthesize a robust monooxygenase, which shows promiscuous substrate specificity (affinity) for various small molecules, allowing the biosynthesis of not only flavones (from flavanones) but also a variety of hydroxyl-small molecules that may span pharmaceutical and nutraceutical industries.


Asynchronous ovulation in mares: seasonal variations in frequency.
The mare's reproductive system is rarely capable of sustaining multiple pregnancies to term. Multiple pregnancies largely derive from multiple ovulations, most commonly double ovulations, hence, double ovulations are of significant concern to breeders/veterinarians. Double ovulations may be synchronous or asynchronous. Asynchrony of up to 96 hours may result in two embryonic vesicles of very different sizes, which are challenging to detect at early ultrasonic pregnancy detection. This study aims to (1) document the incidence of synchronous and asynchronous double ovulation and (2) determine whether this varies with month/season. 506 cycles from double ovulating mares were monitored at 8±1 hour intervals before expected ovulation until 96 hours post initial ovulation. Mares were grouped according to eight-hour ovulation intervals and month/season. When asynchrony was classed as greater than or equal to eight hours or greater than or equal to 24 hours apart, respectively, a significant (P<0.001) difference existed between the number of mares demonstrating asynchronous double ovulations (65.8 and 28.5 per cent) and synchronous double ovulations (34.2 and 71.5 per cent). Significantly (P<0.05), more asynchronous ovulations occurred in the seasonal transition periods. This study demonstrates that asynchronous double ovulation is common and emphasises the importance of closely monitoring mares, particularly at the extremes of the breeding season, for double ovulation up to or at 96 hours postinitial ovulation in order to minimise the chances of missing multiple pregnancy.


Epidemiology of Kawasaki Disease in Canada 2004 to 2014: Comparison of Surveillance Using Administrative Data vs Periodic Medical Record Review.
We have previously documented an increase in the incidence of Kawasaki disease (KD) in Ontario followed by a stabilization from 1995 to 2006. We sought to validate the estimation of incidence of KD using administrative data and to describe the epidemiology of KD across Canada from 2004 to 2014. We queried the Canadian Hospital Discharge Database for hospital admissions associated with a discharge diagnosis of KD. The data set was manually curated and estimates of incidence were compared with those obtained from the retrospective triennial surveillances of KD performed in 2007 and 2010. The average number of cases per year identified through administrative data was 245 ± 45 vs 229 ± 33 from retrospective surveillance. This overestimation, representing 7 ± 6%, is similar to the historical percentage of patients originally diagnosed with KD in whom the diagnosis is subsequently excluded. The annual incidence of KD in Canada was 19.6, 6.4, and 1.3 cases per 100,000 children younger than 5 years, 5-9 years, and 10-14 years old, respectively, with important regional and seasonal differences. The incidence remained stable over the study period in the youngest age group but increased in both older age categories. Coronary artery aneurysms affected 3.5% of all patients, and 0.8% experienced associated major cardiac complications. Reliance on administrative data to determine incidence of KD is feasible and accurate with manual curation of the data. The incidence of KD in Canada seems to have plateaued for younger children. Differences in annual incidence observed between provinces remain to be explained, and might reflect genetic or environmental differences.


Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure.
Recent reports indicated high miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL. Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of miltefosine exposure were explored for their relationship with treatment failure. The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure. Achieving a sufficient exposure to miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for miltefosine in the treatment of VL.


Physiological random processes in precision cancer therapy.
Many different physiological processes affect the growth of malignant lesions and their response to therapy. Each of these processes is spatially and genetically heterogeneous; dynamically evolving in time; controlled by many other physiological processes, and intrinsically random and unpredictable. The objective of this paper is to show that all of these properties of cancer physiology can be treated in a unified, mathematically rigorous way via the theory of random processes. We treat each physiological process as a random function of position and time within a tumor, defining the joint statistics of such functions via the infinite-dimensional characteristic functional. The theory is illustrated by analyzing several models of drug delivery and response of a tumor to therapy. To apply the methodology to precision cancer therapy, we use maximum-likelihood estimation with Emission Computed Tomography (ECT) data to estimate unknown patient-specific physiological parameters, ultimately demonstrating how to predict the probability of tumor control for an individual patient undergoing a proposed therapeutic regimen.


Caring at the end of life: do cancer caregivers differ from other caregivers?
Cancer is one of the most common health conditions in receipt of informal caregiving. This study compares key characteristics of caregivers who cared for someone with cancer until death with caregivers of people with other life-limiting illnesses and their care recipients irrespective of health service utilisation. Data were analysed from annual state-wide South Australian Health Omnibus Surveys (2000-2007) involving 14,624 respondents, regarding end of life care. Descriptive and comparative data are presented. Almost a third of respondents (32%; participation rate 72%) had someone close to them die from an 'expected' death in the preceding 5 years. One in 10 (10%) respondents reported providing hands-on care predominantly for someone with cancer. Compared with non-cancer caregivers, cancer caregivers cared for someone who was significantly younger (mean age 66 (95% CI 64 to 67) years vs 74 (95% CI 72 to 77) years; one-way analysis of variance p<0.0001) and were more likely to report having a hospice/palliative care service involved in the care of the deceased (65% (95% CI 63 to 67) compared with 39% (95% CI 37 to 42). In the Australian context, this may mean contact with inpatient, outpatient and community-based services.There were no differences between the needs which caregivers perceived to be unmet or the perceptions that no additional supports were required between the two groups. Informal caregivers perform a critical social and economic role in care provision. Cancer caregivers are a proportionally larger cohort than non-cancer caregivers. With the increasing incidence of cancer, the sustainability of a voluntary cancer caregiving workforce will be reliant upon minimising the burden of care.


Tempo and mode of allopatric divergence in the weakly electric fish Sternopygus dariensis in the Isthmus of Panama.
Spatial isolation is one of the main drivers of allopatric speciation, but the extent to which spatially-segregated populations accumulate genetic differences relevant to speciation is not always clear. We used data from ultraconserved elements (UCEs) and whole mitochondrial genomes (i.e., mitogenomes) to explore genetic variation among allopatric populations of the weakly electric fish Sternopygus dariensis across the Isthmus of Panama. We found strong genetic divergence between eastern and western populations of S. dariensis. Over 77% of the UCE loci examined were differentially fixed between populations, and these loci appear to be distributed across the species' genome. Population divergence occurred within the last 1.1 million years, perhaps due to global glaciation oscillations during the Pleistocene. Our results are consistent with a pattern of genetic differentiation under strict geographic isolation, and suggest the presence of incipient allopatric species within S. dariensis. Genetic divergence in S. dariensis likely occurred in situ, long after the closure of the Isthmus of Panama. Our study highlights the contribution of spatial isolation and vicariance to promoting rapid diversification in Neotropical freshwater fishes. The study of spatially-segregated populations within the Isthmus of Panama could reveal how genetic differences accumulate as allopatric speciation proceeds.


Two oligomeric forms of plasma ficolin have differential lectin activity.
Ficolins are plasma proteins with binding activity for carbohydrates, elastin, and corticosteroids. The ficolin polypeptide has a collagen-like domain that presumably brings three subunits together in a triple helical rod, a C-terminal fibrinogen-like domain (fbg) similar to that of tenascin, which presumably has the binding activities, and a small N-terminal domain that we find to be the primary site for forming the ficolin oligomer. By sedimentation equilibrium we determined that the main plasma form, which we call big ficolin, had mass of 827,000 Da, consistent with 24 subunits. Little ficolin, about half this size, was obtained after binding to a GlcNAc affinity column. Electron microscopy of little ficolin showed a parachute-like structure, with a small globe at one end, corresponding to the 12 N-terminal domains, and the fbg domains clustered together at the ends of the collagen rods. Big ficolin was formed by the face to face fusion of the fbg domains of two little ficolins, leaving the rods and N-terminal domains projecting at opposite ends. Little ficolin maintained a high affinity for the GlcNAc column, and big ficolin had a low affinity or none. The binding sites for ligands may be obscured in this big ficolin oligomer, providing a regulation of their activity.


What has changed since cannabis was legalized?
The Canadian government legalized non-medical cannabis use by adults in October 2018 in order to minimize associated harms and re-direct profits from criminals. Seven quarters of (NCS) data were combined into two groups: pre- and post-legalization periods - to examine changes in: cannabis use (overall, daily or almost daily (DAD)), source of product, driving after consumption and riding in a vehicle with a driver who had consumed. By 2019, overall cannabis use had increased (16.8% vs. 14.9%), particularly among: males, adults aged 25 and older, and in Newfoundland and Labrador, Nova Scotia, New Brunswick, and Alberta. DAD use, at 6.0%, remained stable, as did the prevalence of driving within 2 hours of consumption (13.2%). Riding in a vehicle with a driver who had used declined, overall (from 5.3% to 4.2%) and among: females, persons aged 25 and older, and in Newfoundland and Labrador, Ontario and Alberta. Where Canadians reported obtaining their cannabis also changed, with increasing percentages reporting getting some or all of their cannabis from legal sources, and fewer using illegal sources or relying on friends/family. Some provinces experienced more change than others. While too soon to observe the longer-term impacts associated with the Cannabis Act, early indications based on data collected in the months surrounding enactment suggests some cautions and also some assurances. Ongoing monitoring will be essential particularly given the 2.0 Act modifications and the ever-changing provincial retail and regulatory landscapes.


How does a comprehensive clinical performance examination relate to ratings on the medical school student performance evaluation?
U.S. medical schools have long used the Medical Student Performance Evaluation (MSPE) to represent overall student performance while comprehensive clinical performance exams (CPX) are beginning to emerge as a new standard for determining student competence. This study describes the association between the MSPE and CPX in their independent measures of student competence. We examined the relationship between CPX scores and student MSPE rating at our institution, which was completed independently of the CPX. Students with higher CPX scores had better MSPE rating, but the associations are small ranging from rs=.13 for history-taking skills to rs=.31 for interpersonal skills. CPX results are not strongly related to MSPE rating and, thus, they may provide information on clinical competencies that should be included in the MSPE.


Of mice and men: bridging the translational disconnect in CNS drug discovery.
The tremendous advances in transgene animal technology, especially in the area of Alzheimer's disease, have not resulted in a significantly better success rate for drugs entering clinical development. Despite substantial increases in research and development budgets, the number of approved drugs in general has not increased, leading to the so-called innovation gap. While animal models have been very useful in documenting the possible pathological mechanisms in many CNS diseases, they are not very predictive in the area of drug development. This paper reports on a number of under-appreciated fundamental differences between animal models and human patients in the context of drug discovery with special emphasis on Alzheimer's disease and schizophrenia, such as different affinities of the same drug for human versus rodent target subtypes and the absence of many functional genotypes in animal models. I also offer a number of possible solutions to bridge the translational disconnect and improve the predictability of preclinical models, such as more emphasis on good-quality translational studies, more pre-competitive information sharing and the embracing of multi-target pharmacology strategies. Re-engineering the process for drug discovery and development, in a similar way to other more successful industries, is another possible but disrupting solution to the growing innovation gap. This includes the development of hybrid computational models, based upon documented preclinical physiology and pharmacology, but populated and validated with clinical data from actual patients.


Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma.
Cyclooxygenase-2 (COX-2, PTGS2) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway. By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration. Strong (2+) COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515) than in hyperplastic polyps (4.2% = 1/24, p = 0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0% = 0/12, p = 0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515) than in hyperplastic polyps (13% = 3/24, p < 0.0001) and serrated polyps (SSAs and mixed polyps) (25% = 3/12, p = 0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (approximately 85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas. COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.


Land suitability for waste disposal in metropolitan areas.
Site selection for waste disposal is a complex task that should meet the requirements of communities and stakeholders. In this article, three decision support methods (Boolean logic, index overlay and fuzzy gamma) are used to perform land suitability analysis for landfill siting. The study was carried out in one of the biggest metropolitan regions of Italy, with the objective of locating suitable areas for waste disposal. Physical and socio-economic information criteria for site selection were decided by a multidisciplinary group of experts, according to state-of-the-art guidelines, national legislation and local normative on waste management. The geographic information systems (GIS) based models used in this study are easy to apply but require adequate selection of criteria and weights and a careful evaluation of the results. The methodology is arranged in three steps, reflecting the criteria defined by national legislation on waste management: definition of factors that exclude location of landfills or waste treatment plants; classification of the remaining areas in terms of suitability for landfilling; and evaluation of suitable sites in relation to preferential siting factors (such as the presence of quarries or dismissed plants). The results showed that more than 80% of the provincial territory falls within constraint areas and the remaining territory is suitable for waste disposal for 0.72% or 1.93%, according to the model. The larger and most suitable sites are located in peripheral areas of the metropolitan system. The proposed approach represents a low-cost and expeditious alternative to support the spatial decision-making process.


Interaction of meropenem with 'N' and 'B' isoforms of human serum albumin: a spectroscopic and molecular docking study.
Carbapenems are used to control the outbreak of β-lactamases expressing bacteria. The effectiveness of drugs is influenced by its interaction with human serum albumin (HSA). Strong binding of carbapenems to HSA may lead to decreased bioavailability of the drug. The non-optimal drug dosage will provide a positive selection pressure on bacteria to develop resistance. Here, we investigated the interaction between meropenem and HSA at physiological pH 7.5 (N-isoform HSA) and non-physiological pH 9.2 (B-isoform HSA). Results showed that meropenem quenches the fluorescence of both 'N' and 'B' isoforms of HSA (ΔG < 0 and binding constant ~10(4) M(-1)). Electrostatic interactions and van der Waal interactions along with H-bonds stabilized the complex of meropenem with 'N' and 'B' isoforms of HSA, respectively. Molecular docking results revealed that meropenem binds to HSA near Sudlow's site II (subdomain IIIA) close to Trp-214 with a contribution of a few residues of subdomain IIA. CD spectroscopy showed a change in the conformation of both the isoforms of HSA upon meropenem binding. The catalytic efficiency of HSA (only N-isoform) on p-nitrophenyl acetate was increased primarily due to a decrease in Km and an increase in kcat values. This study provides an insight into the molecular basis of interaction between meropenem and HSA.


An antibiotic stewardship program in a surgical ICU of a resource-limited country: financial impact with improved clinical outcomes.
Antibiotic resistance (ABX-R) is alarming in lower/middle-income countries (LMICs). Nonadherence to antibiotic guidelines and inappropriate prescribing are significant contributing factors to ABX-R. This study determined the clinical and economic impacts of antibiotic stewardship program (ASP) in surgical intensive care units (SICU) of LMIC. We conducted this pre and post-test analysis in adult SICU of Aga Khan University Hospital, Pakistan, and compared pre-ASP (September-December 2017) and post-ASP data (April-July 2018). January-March 2018 as an implementation/training phase, for designing standard operating procedures and training the team. We enrolled all the patients admitted to adult SICU and prescribed any antibiotic. ASP-team daily reviewed antibiotics prescription for its appropriateness. Through prospective-audit and feedback-mechanism changes were made and recorded. Outcome measures included antibiotic defined daily dose (DDDs)/1000 patient-days, prescription appropriateness, antibiotic duration, readmission, mortality, and cost-effectiveness. 123 and 125 patients were enrolled in pre-ASP and post-ASP periods. DDDs/1000 patient-days of all the antibiotics reduced in the post-ASP period, ceftriaxone, cefazolin, metronidazole, piperacillin/tazobactam, and vancomycin showed statistically significant (p < 0.01) reduction. The duration of all antibiotics use reduced significantly (p < 0.01). Length of SICU stays, mortality, and readmission reduced in the post-ASP period. ID-pharmacist interventions and source-control-documentation were observed in 62% and 50% cases respectively. Guidelines adherence improved significantly (p < 0.01). Net cost saving is 6360US$ yearly, mainly through reduced antibiotics consumption, around US$ 18,000 (PKR 2.8 million) yearly. ASP implementation with supplemental efforts can improve the appropriateness of antibiotic prescriptions and the optimum duration of use. The approach is cost-effective mainly due to the reduced cost of antibiotics with rational use. Better source-control-documentation may further minimize the ABX-R in SICU.


Acidic Bile Salts Induce Epithelial to Mesenchymal Transition via VEGF Signaling in Non-Neoplastic Barrett's Cells.
Metaplastic glands buried under squamous epithelium are frequently detected in patients with Barrett esophagus (BE). This subsquamous intestinal metaplasia might be responsible for cancers that develop despite endoscopic surveillance and for metaplasia recurrences after endoscopic ablation. To determine whether reflux induces BE cells to undergo an epithelial-to-mesenchymal transition (EMT) that produces subsquamous intestinal metaplasia, we assessed EMT in BE cells exposed to acidic bile salts and in rat and human esophageal tissues. We compared markers of EMT and cell motility in trans-well and 3-dimensional organotypic culture systems among dysplastic BE epithelial cell lines, nondysplastic telomerase-immortalized BE cell lines (BAR-T), and BAR-T cells exposed acutely or for 20 weeks to acidic bile salts. Vascular endothelial growth factor (VEGF) A was inhibited with a neutralizing antibody or CRISPR-Cas9n and VEGF receptor 2 was inhibited with SU1498 or shRNA, and cells were analyzed by immunohistochemistry, quantitative polymerase chain reaction, or immunoblotting for markers of VEGF signaling and EMT; cell motility was assessed by trans-well assay. We used immunohistochemistry and quantitative polymerase chain reaction to assess EMT markers in the columnar-lined esophagus of rats with surgically induced reflux esophagitis and in esophagectomy specimens from patients with BE. We detected features of EMT (decreased cadherin 1 [CDH1]; increased fibronectin 1, vimentin, and matrix metalloproteinase 2; and increased motility) in dysplastic BE epithelial cell lines and in BAR-T cells exposed for 20 weeks, but not in unexposed BAR-T cells. Acute acidic bile salt exposure induced expression of zinc finger E-box binding homeobox 1 and 2 (ZEB1/2) in BAR-T cells, which decreased their expression of CDH1 and increased motility; inhibitors of VEGF signaling blocked these effects. Columnar-lined esophagus of rats with reflux esophagitis had increased expression of ZEB1/2 and decreased expression of CDH1 compared with controls. Dysplastic BE tissues also had significantly increased levels of ZEB1 and significantly decreased levels of CDH1 compared with nondysplastic BE tissues. In BE cell lines, acidic bile salts induce EMT by VEGF signaling, which increases expression of ZEB1/2, repressors of CDH1. These observations suggest that reflux induces EMT in metaplastic BE tissues, which promotes development of subsquamous intestinal metaplasia.


Barriers to accessing surgical care in Pakistan: healthcare barrier model and quantitative systematic review.
Inadequate access to surgical services results in increased morbidity and mortality from a spectrum of conditions in Pakistan. We employed a modification of Andersen's model of health services utilization and developed a 'Healthcare Barrier Model,' to characterize the barriers to accessing health care in developing countries, using surgical care in Pakistan as a case study. We performed a literature search from MEDLINE, EMBASE, CINAHL, SCOPUS, Global Health Database, and Cochrane Central Register of Controlled Trials, and selected 64 of 3113 references for analysis. Patient-related variables included age (elderly), gender (female), preferential use of alternative health providers (Hakeem, traditional healers, others), personal perceptions regarding disease and potential for treatment, poverty, personal expenses for healthcare, lack of social support, geographic constraints to accessing a health facility, and compromised general health status as it relates to the development of surgical disease. Environmental barriers include deficiencies in governance, the burden of displaced or refugee populations, and aspects of the medicolegal system, which impact treatment and referral. Barriers relating to the health system include deficiencies in capacity (infrastructure, physical resources, human resources) and organization, and inadequate monitoring. Provider-related barriers include deficiencies in knowledge and skills (and ongoing educational opportunities), delays in referral, deficient communication, and deficient numbers of female health providers for female patients. The Healthcare Barrier model addresses this broad spectrum of barriers and is designed to help formulate a framework of healthcare barriers. To overcome these barriers will require a multidisciplinary, multisectoral effort aimed at strengthening the health system.


Structural and functional connectivity mapping of the human corpus callosum organization with white-matter functional networks.
The corpus callosum serves as a crucial organization for understanding the information integration between the two hemispheres. Our previous study explored the functional connectivity between the corpus callosum and white-matter functional networks (WM-FNs), but the corresponding physical connectivity remains unknown. The current study uses the resting-state fMRI of Human Connectome Project data to identify ten WM-FNs in 108 healthy subjects, and then independently maps the structural and functional connectivity between the corpus callosum and above WM-FNs using the diffusion tensor images (DTI) tractography and resting-state functional connectivity (RSFC). Our results demonstrated that the structural and functional connectivity between the human corpus callosum and WM-FNs have the following high overall correspondence: orbitofrontal WM-FN, DTI map = 89% and RSFC map = 92%; sensorimotor middle WM-FN, DTI map = 47% and RSFC map = 77%; deep WM-FN, DTI map = 50% and RSFC map = 79%; posterior corona radiata WM-FN, DTI map = 82% and RSFC map = 73%. These findings reinforce the notion that the corpus callosum has unique spatial distribution patterns connecting to distinct WM-FNs. However, important differences between the structural and functional connectivity mapping results were also observed, which demonstrated a synergy between DTI tractography and RSFC toward better understanding the information integration of primary and higher-order functional systems in the human brain.


Defective neuropeptide processing and ischemic brain injury: a study on proprotein convertase 2 and its substrate neuropeptide in ischemic brains.
Using a focal cerebral ischemia model in rats, brain ischemia-induced changes in expression levels of mRNA and protein, and activities of proprotein convertase 2 (PC2) in the cortex were examined. In situ hybridization analyses revealed a transient upregulation of the mRNA level for PC2 at an early reperfusion hour, at which the level of PC2 protein was also high as determined by immunocytochemistry and western blotting. When enzymatic activities of PC2 were analyzed using a synthetic substrate, a significant decrease was observed at early reperfusion hours at which levels of PC2 protein were still high. Also decreased at these reperfusion hours were tissue levels of dynorphin-A(1-8) (DYN-A(1-8)), a PC2 substrate, as determined by radioimmunoassay. Further examination of PC2 protein biosynthesis by metabolic labeling in cultured neuronal cells showed that in ischemic cells, the proteolytic processing of PC2 was greatly attenuated. Finally, in mice, an intracerebroventricular administration of synthetic DYN-A(1-8) significantly reduced the extent of ischemic brain injury. In mice those lack an active PC2, exacerbated brain injury was observed after an otherwise non-lethal focal ischemia. We conclude that brain ischemia attenuates PC2 and PC2-mediated neuropeptide processing. This attenuation may play a role in the pathology of ischemic brain injury.


Management of gastrojejunal anastomotic leaks after Roux-en-Y gastric bypass.
Anastomotic leaks after Roux-en-Y gastric bypass (RYGB) potentially result in considerable morbidity and mortality. In the present report we describe our experience with the management of gastrojejunal anastomotic leaks. Tachycardia and fever are considered early signs of anastomotic disruption. Patients weighing less than 350 pounds underwent radiographic testing to diagnose gastrojejunal disruption. Those with severe leaks or patients too large for radiographic evaluation underwent exploratory laparotomy. For severe anastomotic disruptions a retrograde transanastomotic jejunal sump drain was placed. Twenty-four (1.3%) anastomotic leaks occurred in 1789 RYGBs. Five of the leaks were classified as severe and required retrograde sump tube placement. There was one mortality and all of the other patients completely recovered. Aggressive and early intervention for anastomotic disruption after RYGB is necessary to ensure the best possible outcomes for patients with this complication. A high index of suspicion for leaks in postoperative RYGB patients with tachycardia is required if patients are to have good outcomes when complications develop.


Toward a new understanding of risk perception among young female BRCA1/2 "previvors".
The quantitative risk of cancer among BRCA1/2 gene mutation carriers is generally well-understood, and can be communicated clearly to potential and known mutation carriers during the genetic risk assessment, education, and testing process. The extent to which individual mutation carriers feel vulnerable to cancer is a more complex dynamic with a powerful effect on risk-management decision-making; however, these decisions are not the products of straightforward personal assessment of one's quantitative probability of being diagnosed with cancer. We undertook this National Cancer Institute study to broaden understanding of the lived experiences of women who learn early in the life course that they carry a BRCA1/2 mutation. Our data indicate that the relationship between perceived risk and risk-management decisions is not direct, that is, several nononcologic components of risk are also integral to women's management decision-making. High-risk women commonly utilize self-perceived cancer risk to shape their decision-making and communication about various tasks of young adulthood, including differentiation from family of origin, establishing a permanent couple relationship, and family formation. Risk-management is also an important domain in which they strive to take control of their lives by actively participating in management choices. By understanding how these complex dynamics fit together, care providers can better guide, counsel, and support high-risk women as they struggle to balance legitimate risk-reduction needs with the desire to live a normal life. Here we present data from our qualitative research to aid in this effort.


Aminoglycoside resistance and susceptibility testing errors in Acinetobacter baumannii-calcoaceticus complex.
Antimicrobial resistance is depleting the pharmacopeia of agents clinically useful against Gram-negative bacilli. As the number of active agents diminishes, accurate susceptibility testing becomes critical. We studied the susceptibilities of 107 isolates of the Acinetobacter baumannii-calcoaceticus complex to amikacin, gentamicin, and tobramycin using disk diffusion, Etest, as well as the Phoenix, Vitek 2, and MicroScan automated systems, and compared the results to those obtained by broth microdilution. Genes encoding aminoglycoside-modifying enzymes (AMEs) were detected by multiplex PCR, and clonal relationships were determined by pulsed-field gel electrophoresis. Tobramycin was the most active aminoglycoside (27.1% of isolates were susceptible). Disk diffusion and Etest tended to be more accurate than the Vitek 2, Phoenix, and MicroScan automated systems; but errors were noted with all methods. The Vitek 2 instrument incorrectly reported that more than one-third of the isolates were susceptible to amikacin (a very major error). Isolates were polyclonal, with 26 distinct strains, and carried multiple AME genes unrelated to the strain type. The presence of the ant(2")-Ia gene was statistically associated with resistance to each aminoglycoside. The AME genotype accounted for the resistance profile observed in a minority of isolates, suggesting the involvement of multiple resistance mechanisms. Hospital pharmacy records indicated the preferential use of amikacin over other aminoglycosides in the burn intensive care unit, where aminoglycoside resistance is prevalent. The resistance in that unit did not correlate with a predominant strain, AME genotype, or total annual aminoglycoside consumption. Susceptibility to tobramycin increased, even though susceptible isolates carried AME genotypes predicting the inactivation of tobramycin. Determination of the relative contribution of multiple concurrent resistance mechanisms may improve our understanding of aminoglycoside resistance in the Acinetobacter baumannii-calcoaceticus complex.


The Domestic Dog as a Laboratory Host for Brugia malayi.
Of the three nematodes responsible for lymphatic filariasis in humans, only Brugia malayi is actively maintained in research settings owing to its viability in small animal hosts, principal among which is the domestic cat. While the microfilaremic feline host is necessary for propagation of parasites on any significant scale, this system is plagued by a number of challenges not as pronounced in canine filarial models. For this reason, we investigated the capacity in which dogs may serve as competent laboratory hosts for B. malayi. We infected a total of 20 dogs by subcutaneous injection of 500 B. malayi third-stage larvae (L3) in either a single (n = 10) or repeated infection events (125 L3 per week for four weeks; n = 10). Within each group, half of the individuals were injected in the inguinal region and half in the dorsum of the hind paw. To track the course of microfilaremia in this host, blood samples were examined by microscopy biweekly for two years following infection. Additionally, to identify cellular responses with potential value as predictors of patency, we measured peripheral blood leukocyte counts for the first year of infection. A total of 10 of 20 dogs developed detectable microfilaremia. Peak microfilaria density varied but attained levels useful for parasite propagation (median = 1933 mL-1; range: 33-9950 mL-1). Nine of these dogs remained patent at 104 weeks. A two-way ANOVA revealed no significant differences between infection groups in lifetime microfilaria production (p = 0.42), nor did regression analysis reveal any likely predictive relationships to leukocyte values. The results of this study demonstrate the competence of the dog as a host for B. malayi and its potential to serve in the laboratory role currently provided by the cat, while also clarifying the potential for zoonosis in filariasis-endemic regions.


To each his own: isonitriles for all flavors. Functionalized isocyanides as valuable tools in organic synthesis.
The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed.


What factors are associated with abstinence amongst socioeconomically disadvantaged smokers? A cross-sectional survey of use of cessation aids and quitting approach.
This study aimed to compare current and ex-smokers' sociodemographic and psychosocial characteristics, use of cessation aids and abrupt versus gradual quitting approaches. A cross-sectional survey of financially disadvantaged adults attending a community service organisation was conducted in New South Wales, Australia, between February 2012 and December 2013. Sociodemographic and psychosocial factors, use of cessation aids and gradual versus abrupt quit approach were assessed. χ2 tests and logistic regression compared characteristics of current and ex-smokers. Of 905 individuals who completed the survey, 639 (71%) were current smokers and 107 (12%) were ex-smokers. Ex-smokers were older [odds ratio (OR) = 1.03, 95% confidence interval (CI) = 1.01, 1.05], had higher odds of being female (OR = 1.67, 95% CI = 1.06, 2.65), lower odds of being financially stressed (OR = 0.87, 95% CI = 0.76, 0.99), lower odds of anxiety and depression symptoms (OR = 0.91, 95% CI = 0.84, 0.98) and lower odds of having friends and family who were smokers (ORs ranged from 0.30-0.43). Ex-smokers had lower odds of using cessation aids and higher odds of reporting abrupt quitting during their last quit attempt (OR = 4.48, 95% CI = 2.66, 7.54). Lower levels of disadvantage, less smoking in social networks, less use of cessation aids and abrupt (vs. gradual) quitting approaches were associated with being an ex-smoker. Lower use of evidence based methods to quit by disadvantaged ex-smokers requires further exploration. [Twyman L, Bonevski B, Paul C, Bryant J, West R, Siahpush M, D'este C, Oldmeadow C, Palazzi K. What factors are associated with abstinence amongst socioeconomically disadvantaged smokers? A cross-sectional survey of use of cessation aids and quitting approach. Drug Alcohol Rev 2017;00:000-000].


PROCESS AND SYSTEMS: A cohort study to evaluate the impact of service centralisation for emergency admissions with acute heart failure.
The aim of our study was to describe the impact of emergency care centralisation on unscheduled admissions with a primary discharge diagnosis of acute heart failure (HF). We carried out a retrospective cohort study of HF admissions 1 year before and 1 year after centralisation of three accident and emergency departments into one within a single large NHS trust. Outcomes included mortality, length of stay, readmissions, specialist inpatient input and follow-up, and prescription rates of stabilising medication. Baseline characteristics were similar for 211 patients before and for 307 following reconfiguration. Median length of stay decreased from 8 to 6 days (p=0.020) without an increase in readmissions (4.7% versus 4.2%, p=0.813). The proportion with specialist follow-up increased (60% to 72%, p=0.036). There was a trend towards decreased mortality (32.2% versus 27.7% at 90 days; p=0.266). Contact with the cardiology team was associated with decreased mortality. In conclusion, centralisation of specialist emergency care was associated with greater service efficiency and a trend towards reduced mortality.


Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor-inhibitor treatment.
Epidermal growth factor receptor inhibitors (EGFRIs) are an increasingly important class of anticancer agents. Cutaneous toxicities, the most common adverse effects of EGFRI therapy, require dose modification or treatment cessation when moderate or severe and may compromise treatment compliance. To date, assessment has focused on physical symptoms associated with cutaneous toxicities; however, the psychosocial impact of those effects requires greater consideration. This article reviews current knowledge of assessment of cutaneous toxicities and identifies gaps in evidence, with particular focus on the psychosocial impact of cutaneous toxicities. Promising new assessment tools and approaches including the use of electronic patient-reported outcome measures are discussed, as well as implications for research in evaluating psychosocial interventions.


Epicardial fat thickness is associated with severity of disease in patients with chronic obstructive pulmonary disease.
Cardiovascular diseases (CVD) are common in patients with chronic obstructive pulmonary disease (COPD) and the BODE index is an important tool for the prognostic assessment of COPD patients. It is well known that epicardial fat thickness (EFT) is related to CVD. However, there are very few data about the relationship between EFT and BODE index. The aim of this study is to investigate the relationship between EFT and BODE index in patients with COPD. We prospectively included 157 patients with COPD and 45 controls in the present study. All patients underwent pulmonary function tests and six-minute walking test. EFT and other echocardiographic parameters were measured using transthoracic echocardiography on admission. Patients were divided into four quartiles according to the BODE index scores (Quartile-1 (Q1): 0-2 points; Quartile-2 (Q2): 3-4 points; Quartile-3 (Q3): 5-6 points; Quartile-4 (Q4): 7-10 points). High sensitive C-reactive protein (Hs-CRP) and other biochemical parameters were measured in all participants. COPD patients had higher EFT values compared with control group (p<0.05). When COPD patients were classified according to BODE index quartiles, the highest EFT values were observed in Q1 compared with other quartiles (p<0.05, for all). EFT values showed a decreasing trend from Q1 to Q4. Furthermore, EFT was independently associated with BODE index (β=0.405, p<0.001), Hs-CRP (β=0.300, p<0.001) and diabetes (β=0.338, p<0.001) in multivariate linear regression analysis. Our findings suggested that EFT is independently and negatively associated with the severity of disease as indicated by BODE index in patients with COPD.


Identification and molecular characterization of a marafivirus in Rubus spp.
An undescribed virus with isometric particles and a diameter of ca. 30 nm was identified in diseased samples of wild and cultivated Rubus species and molecularly characterized. Its genome was 6,463 nt, excluding the 3'-terminal poly(A) tail, and contained a single open reading frame coding for a 2,035-amino-acid-long precursor polypeptide (p223). The amino terminal portion of p223, identified as a replication-associated polyprotein, contained conserved motifs of methyltransferase, endopeptidase/protease, helicase and RNA-dependent RNA polymerase. The carboxy terminus of the large polypeptide is involved in the formation of two viral coat protein subunits with deduced molecular masses of 23 and 21 kDa. Pairwise comparisons and phylogenetic analyses showed closest relationships of this virus with oat blue dwarf virus and citrus sudden death-associated virus, sharing levels of genome sequence conservation far below the species demarcation level established for tymovirids. Our data indicate that this virus, for which the name blackberry virus S (BlVS) is proposed, is a hitherto undescribed species of the genus Marafivirus, family Tymoviridae. A survey conducted in Mississippi, USA, has shown that BlVS is also present in cultivated Rubus germplasm. This work represents the first report of a marafivirus infecting small fruits.


Securing the communication of medical information using local biometric authentication and commercial wireless links.
Medical information is extremely sensitive in nature - a compromise, such as eavesdropping or tampering by a malicious third party, may result in identity theft, incorrect diagnosis and treatment, and even death. Therefore, it is important to secure the transfer of medical information from the patient to the recording system. We consider a portable, wireless device transferring medical information to a remote server. We decompose this problem into two sub-problems and propose security solutions to each of them: (1) to secure the link between the patient and the portable device, and (2) to secure the link between the portable device and the network. Thus we push the limits of the network security to the edge by authenticating the user using their biometric information; authenticating the device to the network at the physical layer; and strengthening the security of the wireless link with a key exchange mechanism. The proposed authentication methods can be used for recording the readings of medical data in a central database and for accessing medical records in various settings.


Nanophotonic coherent imager.
An integrated silicon nanophotonic coherent imager (NCI), with a 4 × 4 array of coherent pixels is reported. In the proposed NCI, on-chip optical processing determines the intensity and depth of each point on the imaged object based on the instantaneous phase and amplitude of the optical wave incident on each pixel. The NCI operates based on a modified time-domain frequency modulated continuous wave (FMCW) ranging scheme, where concurrent time-domain measurements of both period and the zero-crossing time of each electrical output of the nanophotonic chip allows the NCI to overcome the traditional resolution limits of frequency domain detection. The detection of both intensity and relative delay enables applications such as high-resolution 3D reflective and transmissive imaging as well as index contrast imaging. We demonstrate 3D imaging with 15μm depth resolution and 50μm lateral resolution (limited by the pixel spacing) at up to 0.5-meter range. The reported NCI is also capable of detecting a 1% equivalent refractive index contrast at 1mm thickness.


DISEASE CLASSIFICATION AND PREDICTION VIA SEMI-SUPERVISED DIMENSIONALITY REDUCTION.
We present a new semi-supervised algorithm for dimensionality reduction which exploits information of unlabeled data in order to improve the accuracy of image-based disease classification based on medical images. We perform dimensionality reduction by adopting the formalism of constrained matrix decomposition of [1] to semi-supervised learning. In addition, we add a new regularization term to the objective function to better captur the affinity between labeled and unlabeled data. We apply our method to a data set consisting of medical scans of subjects classified as Normal Control (CN) and Alzheimer (AD). The unlabeled data are scans of subjects diagnosed with Mild Cognitive Impairment (MCI), which are at high risk to develop AD in the future. We measure the accuracy of our algorithm in classifying scans as AD and NC. In addition, we use the classifier to predict which subjects with MCI will converge to AD and compare those results to the diagnosis given at later follow ups. The experiments highlight that unlabeled data greatly improves the accuracy of our classifier.