Phytoplankton Distribution in Relation to Environmental Drivers on the North West European Shelf Sea.
The edge of the North West European Shelf (NWES) is characterised by a steep continental slope and a northward flowing slope current. These topographic/hydrographic features separate oceanic water and shelf water masses hence potentially separate phytoplankton communities. The slope current may facilitate the advective transport of phytoplankton, with mixing at the shelf edge supporting nutrient supply and therefore phytoplankton production. On the west Scottish shelf in particular, little is known about the phytoplankton communities in and around the shelf break and adjacent waters. Hence, to improve our understanding of environmental drivers of phytoplankton communities, biological and environmental data were collected on seven cross-shelf transects across the Malin and Hebridean Shelves during autumn 2014. Density profiles indicated that shelf break and oceanic stations had a 100 m deep mixed surface layer while stations on the shelf were generally well mixed. Analysis of similarity and multidimensional scaling of phytoplankton counts revealed that phytoplankton communities on the shelf were significantly different to those found at the shelf break and at oceanic stations. Shelf stations were dominated by dinoflagellates, with diatoms contributing a maximum of 37% of cells. Shelf break and oceanic stations were also dinoflagellate dominated but displayed a lower species diversity. Significant difference between shelf and shelf break stations suggested that the continental slope limited cross shelf phytoplankton exchange. Northern and southern phytoplankton communities on the shelf were approximately 15% dissimilar while there was no latitudinal gradient for stations along the slope current, suggesting this current provided south to north connectivity. Fitting environmental data to phytoplankton ordination showed a significant relationship between phytoplankton community dissimilarities and nutrient concentrations and light availability on the shelf compared to shelf break and oceanic stations in the study area.


The underlying factors controlling the Pd-catalyzed site-selective alkenylation of aliphatic amines.
The Pd(ii)-catalyzed site-selective δ-C(sp3)-H alkenylation in the presence of more accessible γ-C(sp3)-H bonds is investigated by DFT calculations. Migratory insertion is found to be both the rate-limiting and the selectivity-determining step. The origin of the unusual site-selectivity is originally attributed to the different steric repulsion between the alkyne and palladacycle; however, our theoretical results reveal that the inherent electronic effect instead of steric repulsion determines the site-selectivity. The proposal is further validated by model calculations involving the less sterically hindered 1,2-dimethyl acetylene and acetylene. In addition, a novel HCO3--assisted N-H activation mechanism is reported, and the origin of the regioselectivity of an unsymmetrical alkyne is also studied.


Hrp48 attenuates Sxl expression to allow for proper notch expression and signaling in wing development.
Different signaling pathways are deployed in specific developmental contexts to generate sexually dimorphic traits. Recently, Sex-lethal (Sxl), the female determinant in Drosophila melanogaster, was shown to down-regulate Notch (N) signaling to accomplish sex-specific patterning. Paradoxically, however, both Sxl and N are ubiquitously expressed in all of the female cells. This raises a key question as to how, during monomorphic female development, N signaling escapes the negative impact of Sxl. Here, we uncover a regulatory loop involving Hrp48, an abundant Drosophila hnRNP, Sxl and N. Phenotypic consequences of the partial loss of hrp48 resemble that of N but are more pronounced in females than in males. Likewise, N levels are drastically diminished only in females. Interestingly, monomorphic female tissues including wing, eye and antennal discs display considerable increase in Sxl amounts. Finally, female-specific attenuation of N signaling is rescued upon simultaneous removal of Sxl. Thus, our data demonstrate that in monomorphic contexts, Hrp48 functions as a moderator of Sxl expression to achieve adequate levels of N receptor production and signaling. We propose that it is critical to modulate the activities of the master determinant underling sexual dimorphism, to ensure that it does not function inappropriately in monomorphic tissues and disrupt their development.


Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSC of the ISTH.
Light transmission aggregometry (LTA) is the most common method used in clinical and research laboratories to assess platelet function. However, the method has never been standardized. As the first step towards development of methodological guidelines, the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) undertook a large, detailed, global survey of LTA practices. Members of ISTH and of External Quality Assurance in Thrombosis and Haemostasis organizations were invited to complete a 129 item, online questionnaire. Results were analyzed anonymously to participant identities. The online supplement for this article (http://www.isth.org/Publications/OfficialCommunications/PlateletPhysiology/LightTransmissionAggregometry/tabid/201/Default.aspx) contains the full details of the study findings. 359 (244 clinical, 115 research) laboratories from 48 countries participated in the survey. LTA was widely used to assess inherited or acquired bleeding disorders. Common practices were identified in sample collection, processing and analysis and although some are generally considered acceptable, others are not ideal. The agonist concentrations used for LTA varied, and many laboratories used ADP, collagen, epinephrine and Ristocetin, at more than one concentration, in addition to arachidonic acid. The parameters commonly used to assess LTA responses were maximal amplitude or % aggregation, which was considered particularly important, in addition to the presence of a 'secondary wave', deaggregation, shape change and a measure of the lag phase. However, many laboratories did not have appropriate reference intervals. This is the largest and most detailed survey of LTA practices ever undertaken. It shows a very high variability in LTA practices worldwide, and, as a consequence, methodological standardization is necessary. The information gathered in this survey will be helpful in the development of ISTH methodological guidelines for LTA.


Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data.
Rational medical decisions should be based on the best possible evidence. Clinical trial results, however, may not reflect conditions in actual practice. In hypertension, for example, trials indicate equivalent antihypertensive efficacy and safety for many medications, yet blood pressure frequently remains uncontrolled, perhaps owing to poor compliance. This paper examines the effect of initial choice of treatment on persistence with therapy in actual practice. The authors examined all outpatient prescriptions for antihypertensive medications filled in Saskatchewan between 1989 and 1994 by over 22,000 patients with newly diagnosed hypertension whose initial treatment was with a diuretic, beta-blocker, calcium-channel blocker or angiotensin-converting-enzyme (ACE) inhibitor. Rates of persistence over the first year of treatment were compared. After 6 months, persistence with therapy was poor and differed according to the class of initial therapeutic agent: 80% for diuretics, 85% for beta-blockers, 86% for calcium-channel blockers and 89% for ACE inhibitors (p < 0.001). These differences remained significant when age, sex and health status in the previous year were controlled for. Changes in the therapeutic regimen were also associated with lack of persistence. A relation not seen in clinical trials--between persistence with treatment and initial antihypertensive medication prescribed--was found in actual practice. This relation also indicates the importance of real-world studies for evidence-based medicine.


ProteMiner-SSM: a web server for efficient analysis of similar protein tertiary substructures.
Analysis of protein-ligand interactions is a fundamental issue in drug design. As the detailed and accurate analysis of protein-ligand interactions involves calculation of binding free energy based on thermodynamics and even quantum mechanics, which is highly expensive in terms of computing time, conformational and structural analysis of proteins and ligands has been widely employed as a screening process in computer-aided drug design. In this paper, a web server called ProteMiner-SSM designed for efficient analysis of similar protein tertiary substructures is presented. In one experiment reported in this paper, the web server has been exploited to obtain some clues about a biochemical hypothesis. The main distinction in the software design of the web server is the filtering process incorporated to expedite the analysis. The filtering process extracts the residues located in the caves of the protein tertiary structure for analysis and operates with O(nlogn) time complexity, where n is the number of residues in the protein. In comparison, the alpha-hull algorithm, which is a widely used algorithm in computer graphics for identifying those instances that are on the contour of a three-dimensional object, features O(n2) time complexity. Experimental results show that the filtering process presented in this paper is able to speed up the analysis by a factor ranging from 3.15 to 9.37 times. The ProteMiner-SSM web server can be found at http://proteminer.csie.ntu.edu.tw/. There is a mirror site at http://p4.sbl.bc.sinica.edu.tw/proteminer/.


Fat mass and obesity associated (FTO) gene influences skeletal muscle phenotypes in non-resistance trained males and elite rugby playing position.
FTO gene variants have been associated with obesity phenotypes in sedentary and obese populations, but rarely with skeletal muscle and elite athlete phenotypes. In 1089 participants, comprising 530 elite rugby athletes and 559 non-athletes, DNA was collected and genotyped for the FTO rs9939609 variant using real-time PCR. In a subgroup of non-resistance trained individuals (NT; n = 120), we also assessed structural and functional skeletal muscle phenotypes using dual energy x-ray absorptiometry, ultrasound and isokinetic dynamometry. In a subgroup of rugby athletes (n = 77), we assessed muscle power during a countermovement jump. In NT, TT genotype and T allele carriers had greater total body (4.8% and 4.1%) and total appendicular lean mass (LM; 3.0% and 2.1%) compared to AA genotype, with greater arm LM (0.8%) in T allele carriers and leg LM (2.1%) for TT, compared to AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes (back three and centre players) who are most reliant on LM rather than total body mass for success, compared to other rugby athletes (82%; P = 0.01, OR = 3.34) and controls (84%; P = 0.03, OR = 2.88). Accordingly, these athletes had greater peak power relative to body mass than other rugby athletes (14%; P = 2 x 10-6). Collectively, these results suggest that the T allele is associated with increased LM and elite athletic success. This has implications for athletic populations, as well as conditions characterised by low LM such as sarcopenia and cachexia.


The effects of torture-related stressors on long-term complex post-traumatic symptoms in South Korean torture survivors.
This study explored whether perceived distress from specific stressors during and after torture explain long-term complex post-traumatic symptoms of South Korean torture survivors. We conducted a cross-sectional survey of survivors who had been tortured by the homeland regime from the 1970s to the 2000s. Data from 206 survivors were gathered by key informants using target sampling and snowballing techniques. Project staff designed scales to encompass the specific types of stressors related to torture techniques used in Korea. Frequencies and distress ratings of exposure to torture, post-torture psychosocial stressors and physical damage related to torture were gathered. Psychological symptoms were assessed by the Impact of Event Scale-Revised-Korean version and subscales of the Symptom Checklist 90-Revised-Korean version. Perceived distress from torture stressors was mainly divided into factors representing physical, psychological and deprivation torture by adapting a principal axis factor analysis. Hierarchical regression analyses showed that distress from psychological torture explained post-traumatic stress disorder (PTSD) and that distress from deprivation explained PTSD and anxiety after controlling for demographic variables, psychological preparedness, time span since torture and distress from trauma other than torture. Among post-torture stressors, distress from physical damage related to torture and social exclusion were strong indicators of complex symptoms.


Acidosis of severe falciparum malaria: heading for a shock?
Severe Plasmodium falciparum malaria encompasses a complex syndrome affecting many organs and causing physiological perturbations that have many features in common with children with sepsis. Among these, metabolic acidosis has emerged as a central feature of severe malaria and is the best independent predictor of a fatal outcome in both adults and children. There is now clear evidence that intravascular hypovolaemia (shock) is common in children with malarial acidosis. How it should be treated presents a therapeutic dilemma because acidosis often coexists with impaired consciousness (cerebral malaria). We summarize the results of recent clinical trials examining the safety and efficacy of volume expansion in children with 'cerebral malaria' complicated by acidosis.


Normal sperm morphology and chromatin packaging: comparison between aniline blue and chromomycin A3 staining.
The successful implementation of ICSI has provided a unique means of allowing couples suffering from severe male infertility to achieve their reproductive goals. However, despite the great therapeutic advantages of the technique, ICSI often provides solutions to clinicians in the absence of an aetiological or pathophysiological diagnosis. The development of a sequential diagnostic schedule for patients consulting for fertility disturbances would be an ideal method of approach. Since sperm morphology recorded by strict criteria has often been correlated with fertilization failure, the present study aimed to evaluate the relationship between normal morphology and chromatin staining among fertile and subfertile men. Both chromomycin A3 (CMA3) and acidic aniline blue (AAB) were employed to record chromatin packaging quality among 58 men visiting the andrology laboratory. Intra- and interassay variations were initially recorded for fertile sperm donors. The coefficients of variation (CV) for all intra- and inter-assay assessments were < 12%. Chromatin packaging was significantly and negatively correlated with normal sperm morphology, namely r = 0.40 (P = 0.001) and r = 0.33 (P = 0.001) for CMA3 and AAB, respectively. Receiver operator characteristics illustrated sensitivity and specificity values of 75% and 82% for CMA3 and 60% and 91% for AAB, respectively. Significantly different CMA3 and AAB staining was recorded among men with severe teratozoospermia (< 4% normal forms) when compared with normozoospermic men (> 14% normal forms), namely 49% vs. 29% for CMA3 and 51% vs. 26% for AAB staining, respectively. Chromatin packaging assessments should be a valuable addition to the sequential diagnostic programme in an assisted reproduction arena.


Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice.
Hypomagnesemia has been reported up to 40% in asthma patients, and a relationship between hypomagnesemia and asthma severity has been previously characterized. However, the mechanism for hypomagnesemia in asthma patients is not clear. Transient receptor potential melastatin 6 (TRPM6) is a newly identified channel that is involved in active epithelial magnesium transport, and downregulation of TRPM6 in the kidney was related to reduced Mg2+ reabsorption in mouse model. The aim of the study was to investigate whether plasma and erythrocyte magnesium levels were correlated with renal expression of TRPM6 mRNA in C57BL/6 asthmatic mice. 48 healthy C57BL/6 mice were randomly divided into asthmatic group and control group with 24 mice in each group. Each group were randomly taken out 8 mice at 1d, 21d, 34d to detect plasma Mg2+, intracellular Mg2+ and renal TRPM6 mRNA expressions. There were no significant difference in plasma Mg2+, intracellular Mg2+ and TRPM6 mRNA expression of renal tissues between asthmatic group and control group at 1d. However, plasma Mg2+ and intracellular Mg2+ as well as TRPM6 mRNA of renal tissues in asthmatic group were significantly lower than that of control group at 21d and at 34d. Both plasma Mg2+ and intracellular Mg2+ were positively correlated with TRPM6 mRNA expression in the renal tissues. This study indicates that the consistently reduced expression of TRPM6 mRNA may play a role in the pathogenesis of hypomagnesemia in C57BL/6 asthmatic mice.


A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility.
The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH). A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single-nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays. We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01-1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52-0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation<0.0001). The mRNA expression and in-silico function prediction analyses have confirmed a regulatory potential for a majority of SNPs associated with EH susceptibility. Our pilot study was the first to show that gene-gene and gene-environment interactions in the AHR signaling pathway represent important determinants for the development of EH, and the pathway may become an attractive target for a pharmacological intervention in hypertensive patients in the future.


Nurse and physician perspectives on patients with cancer having online access to their laboratory results.
To compare the perspectives of oncology nurses and physicians regarding online access to laboratory results for patients with cancer pre- and postimplementation, and to evaluate the impact on workload. Pre- and postimplementation surveys distributed to nurses and physicians. In addition, a nursing workload study was conducted to measure the number of phone calls received from patients regarding laboratory results. The outpatient department of a comprehensive cancer center in a large, urban setting in the northeastern United States with more than 500,000 patient visits each year. 460 outpatient nurses and 349 attending physicians were surveyed; 10 of those nurses were invited to participate in the nursing workload study, as well. A survey was sent to nurses and physicians one month prior to implementation and then repeated six months postimplementation. A nursing workload study was conducted for 16 weeks beginning one month prior to implementation and completed three months postimplementation. Nurse and physician perspectives; nursing workload. Nurses demonstrated greater support than physicians with regard to patient access, their level of comfort with the patient access, and patients' ability to interpret results. Statistical significance was identified in all three questions (p<0.05). Perspectives on workload did not differ by role; nurses and physicians anticipated an increase in workload prior to implementation, but reported that workload decreased or stayed the same postimplementation (p<0.005). The nursing workload study supported that finding because no change was observed in the average number of phone calls per day during the implementation period. Oncology nurses and physicians have different perspectives on providing patients with cancer with online access to laboratory results. Concerns about increasing workload were not substantiated in the current study. Providing patients with online access to their laboratory results is a growing trend. Understanding the perspectives of oncology nurses can inform future directions for increasing health-record transparency for patients with cancer. Future research may explore the impact on the nurse-patient relationship.


Associations between injection risk and community disadvantage among suburban injection drug users in southwestern Connecticut, USA.
Increases in drug abuse, injection, and opioid overdoses in suburban communities led us to study injectors residing in suburban communities in southwestern Connecticut, US. We sought to understand the influence of residence on risk and injection-associated diseases. Injectors were recruited by respondent-driven sampling and interviewed about sociodemographics, somatic and mental health, injection risk, and interactions with healthcare, harm reduction, substance abuse treatment, and criminal justice systems. HIV, hepatitis B and C (HBV and HCV) serological testing was also conducted. Our sample was consistent in geographic distribution and age to the general population and to the patterns of heroin-associated overdose deaths in the suburban towns. High rates of interaction with drug abuse treatment and criminal justice systems contrasted with scant use of harm reduction services. The only factors associated with both dependent variables-residence in less disadvantaged census tracts and more injection risk-were younger age and injecting in one's own residence. This contrasts with the common association among urban injectors of injection-associated risk behaviors and residence in disadvantaged communities. Poor social support and moderate/severe depression were associated with risky injection practices (but not residence in specific classes of census tracts), suggesting that a region-wide dual diagnosis approach to the expansion of harm reduction services could be effective at reducing the negative consequences of injection drug use.


The negative mucosal potential: separating central and peripheral effects of NSAIDs in man.
We wanted to test whether assessment of both a central pain-related signal (chemo-somatosensory evoked potential, CSSEP) and a concomitantly recorded peripheral signal (negative mucosal potential, NMP) allows for separation of central and peripheral effects of NSAIDs. For this purpose, experimental conditions were created in which NSAIDs had previously been observed to produce effects on phasic and tonic pain by either central or peripheral mechanisms. According to a double-blind, randomised, controlled, threefold cross-over design, 18 healthy subjects (11 males, 7 females; mean age 26 years) received either placebo, 400 mg ibuprofen, or 800 mg ibuprofen. Phasic pain was applied by means of short pulses of CO2 to the nasal mucosa (stimulus duration 500 ms, interval approximately 60 s), and tonic pain was induced in the nasal cavity by means of dry air of controlled temperature, humidity and flow rate (22 degrees C, 0% relative humidity, 145 ml.s-1). Both CSSEPs as central and NMPs as peripheral correlates of pain were obtained in response to the CO2 stimuli. Additionally, the subjects rated the intensity of both phasic and tonic pain by means of visual analogue scales. As described earlier, administration of ibuprofen was followed by a decrease in tonic pain but-relative to placebo-an increase in correlates of phasic pain, indicating a specific effect of ibuprofen on the interaction between the pain stimuli under these special experimental conditions. Based on the similar behaviour of CSSEP and NMP, it was concluded that the pharmacological process underlying this phenomenon was localised in the periphery. By means of the simultaneous recording of interrelated peripheral and central electrophysiologic correlates of nociception, it was possible to separate central and peripheral effects of an NSAID. The major advantage of this pain model is the possibility of obtaining peripheral pain-related activity directly using a non-invasive technique in humans.


Loss of sensory discrimination after median nerve injury and activation in the primary somatosensory cortex on functional magnetic resonance imaging.
The aim of this study was to assess the effects of median nerve injury and regeneration on neuronal activation in the somatosensory cortex by means of functional magnetic resonance (fMR) imaging and somatosensory evoked potentials (SSEPs). Ten injured male patients (mean age 26 years) were examined 15 to 58 months after a total transection of the median nerve at the wrist that was repaired with epineural sutures. Two-point discrimination was lost in Digit II-III and sensory nerve conduction displayed decreased velocity (-29%) and amplitude (-84%) in the median nerve at the wrist. The fMR images were obtained during tactile stimulation (gentle strokes) performed separately on the volar surface of either Digit II-III or Digit IV-V (eight patients: two were excluded because of movement artifacts). The SSEPs were obtained using electrical stimulation proximal to the median nerve lesion. Patients with loss of sensory discrimination after median nerve damage and regeneration had larger areas of activation in fMR imaging near the contralateral central sulcus during tactile stimulation of the injured compared with the noninjured hand. The increase relative to the unaffected hand was 43% (p < 0.02) for Digit II-III stimulation and 46% (p < 0.02) for Digit IV-V stimulation. The SSEP data showed normal latency and amplitude. The enlarged area of cortical activation may be the result of reorganization, and it may indicate that larger cortical areas are involved in the discriminatory task after a derangement of the peripheral input.


A new way to integrate selection when both demography and selection gradients vary over time.
When both selection and demography vary over time, how can the long-run expected strength of selection on quantitative traits be measured? There are two basic steps in the proposed new analysis: one relates trait values to fitness components and the other relates fitness components to total fitness. We used one population projection matrix for each state of the environment together with a model of environmental dynamics, defining total fitness as the stochastic growth rate. We multiplied environment-specific, stage-specific mean-standardized selection gradients by environment-specific, stage-specific elasticities of the stochastic growth rate, summing over all relevant life history and environmental paths. Our two example traits were floral tube length in a rainforest herb and the timing of birth in Red Deer. For each species, we constructed two models of environmental dynamics, including one based on historical climate records. We found that total integrated selection, as well as the relative contributions of life-history pathways and environments, varied with environmental dynamics. Temporal patterning in the environment has selective consequences. Linking models of environmental change to relevant short term data on demography and selection may permit estimation of the force of selection over the long-term in variable environments.


Mode of Transmission Determines the Virulence of Black Queen Cell Virus in Adult Honey Bees, Posing a Future Threat to Bees and Apiculture.
Honey bees (Apis mellifera) can be infected by many viruses, some of which pose a major threat to their health and well-being. A critical step in the dynamics of a viral infection is its mode of transmission. Here, we compared for the first time the effect of mode of horizontal transmission of Black queen cell virus (BQCV), a ubiquitous and highly prevalent virus of A. mellifera, on viral virulence in individual adult honey bees. Hosts were exposed to BQCV either by feeding (representing direct transmission) or by injection into hemolymph (analogous to indirect or vector-mediated transmission) through a controlled laboratory experimental design. Mortality, viral titer and expression of three key innate immune-related genes were then quantified. Injecting BQCV directly into hemolymph in the hemocoel resulted in far higher mortality as well as increased viral titer and significant change in the expression of key components of the RNAi pathway compared to feeding honey bees BQCV. Our results support the hypothesis that mode of horizontal transmission determines BQCV virulence in honey bees. BQCV is currently considered a benign viral pathogen of adult honey bees, possibly because its mode of horizontal transmission is primarily direct, per os. We anticipate adverse health effects on honey bees if BQCV transmission becomes vector-mediated.


1,3,7-Triethyl-substituted xanthines--possess nanomolar affinity for the adenosine A1 receptor.
Adenosine A1 receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A1 receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to discover potential selective adenosine A1 receptor antagonists. Several analogs of 8-(3-phenylpropyl)xanthines (3), 8-(2-phenylethyl)xanthines (4) and 8-(phenoxymethyl)xanthines (5) were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that the 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d), among each series, displayed the highest affinity for the adenosine A1 receptor with Ki values in the nanomolar range. This ethyl-substitution pattern was previously unknown to enhance adenosine A1 receptor binding affinity. The 1,3,7-triethyl-substituted analogs (3d, 4d, and 5d) behaved as adenosine A1 receptor antagonists in GTP shift assays performed with either rat cortical or whole brain membranes expressing adenosine A1 receptors. Further, in vivo evaluation of 3d showed reversal of adenosine A1 receptor agonist-induced hypolocomotion. In conclusion, the most potent evaluated compound, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (3d), showed both in vitro and in vivo activity, and therefore represent a novel adenosine A1 receptor antagonist that may have potential as a drug candidate for dementia disorders.


Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial.
Across many observational studies, herpes simplex virus type 2 (HSV-2) infection is associated with two-fold to three-fold increased risk for HIV-1 infection. We investigated whether HSV-2 suppression with aciclovir would reduce the risk of HIV-1 acquisition. We undertook a double-blind, randomised, placebo-controlled phase III trial in HIV-negative, HSV-2 seropositive women in Africa and men who have sex with men (MSM) from sites in Peru and the USA. Participants were randomly assigned by block randomisation to twice daily aciclovir 400 mg (n=1637) or matching placebo (n=1640) for 12-18 months, and were seen monthly for dispensation of study drug, adherence counselling and measurement by pill count and self-reporting, and risk reduction counselling, and every 3 months for genital examination and HIV testing. The primary outcome was HIV-1 acquisition and secondary was incidence of genital ulcers. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00076232. 3172 participants (1358 women, 1814 MSM) were included in the primary dataset (1581 in aciclovir group, 1591 in control group). The incidence of HIV-1 was 3.9 per 100 person-years in the aciclovir group (75 events in 1935 person-years of follow-up) and 3.3 per 100 person-years in the placebo group (64 events in 1969 person-years of follow-up; hazard ratio 1.16 [95% CI 0.83-1.62]). Incidence of genital ulcers on examination was reduced by 47% (relative risk 0.53 [0.46-0.62]) and HSV-2 positive genital ulcers by 63% (0.37 [0.31-0.45]) in the aciclovir group. Adherence to dispensed study drug was 94% in the aciclovir group and 94% in the placebo group, and 85% of expected doses in the aciclovir group and 86% in the placebo group. Retention was 85% at 18 months in both groups (1028 of 1212 in aciclovir group, 1030 of 1208 in placebo group). We recorded no serious events related to the study drug. Our results show that suppressive therapy with standard doses of aciclovir is not effective in reduction of HIV-1 acquisition in HSV-2 seropositive women and MSM. Novel strategies are needed to interrupt interactions between HSV-2 and HIV-1.


Deciphering elapsed time and predicting action timing from neuronal population signals.
The proper timing of actions is necessary for the survival of animals, whether in hunting prey or escaping predators. Researchers in the field of neuroscience have begun to explore neuronal signals correlated to behavioral interval timing. Here, we attempt to decode the lapse of time from neuronal population signals recorded from the frontal cortex of monkeys performing a multiple-interval timing task. We designed a Bayesian algorithm that deciphers temporal information hidden in noisy signals dispersed within the activity of individual neurons recorded from monkeys trained to determine the passage of time before initiating an action. With this decoder, we succeeded in estimating the elapsed time with a precision of approximately 1 s throughout the relevant behavioral period from firing rates of 25 neurons in the pre-supplementary motor area. Further, an extended algorithm makes it possible to determine the total length of the time-interval required to wait in each trial. This enables observers to predict the moment at which the subject will take action from the neuronal activity in the brain. A separate population analysis reveals that the neuronal ensemble represents the lapse of time in a manner scaled relative to the scheduled interval, rather than representing it as the real physical time.


A comparative study of ripening among berries of the grape cluster reveals an altered transcriptional programme and enhanced ripening rate in delayed berries.
Transcriptional studies in relation to fruit ripening generally aim to identify the transcriptional states associated with physiological ripening stages and the transcriptional changes between stages within the ripening programme. In non-climacteric fruits such as grape, all ripening-related genes involved in this programme have not been identified, mainly due to the lack of mutants for comparative transcriptomic studies. A feature in grape cluster ripening (Vitis vinifera cv. Pinot noir), where all berries do not initiate the ripening at the same time, was exploited to study their shifted ripening programmes in parallel. Berries that showed marked ripening state differences in a véraison-stage cluster (ripening onset) ultimately reached similar ripeness states toward maturity, indicating the flexibility of the ripening programme. The expression variance between these véraison-stage berry classes, where 11% of the genes were found to be differentially expressed, was reduced significantly toward maturity, resulting in the synchronization of their transcriptional states. Defined quantitative expression changes (transcriptional distances) not only existed between the véraison transitional stages, but also between the véraison to maturity stages, regardless of the berry class. It was observed that lagging berries complete their transcriptional programme in a shorter time through altered gene expressions and ripening-related hormone dynamics, and enhance the rate of physiological ripening progression. Finally, the reduction in expression variance of genes can identify new genes directly associated with ripening and also assess the relevance of gene activity to the phase of the ripening programme.


Electron affinity and excited states of methylglyoxal.
Using photoelectron imaging spectroscopy, we characterized the anion of methylglyoxal (X2A″ electronic state) and three lowest electronic states of the neutral methylglyoxal molecule: the closed-shell singlet ground state (X1A'), the lowest triplet state (a3A″), and the open-shell singlet state (A1A″). The adiabatic electron affinity (EA) of the ground state, EA(X1A') = 0.87(1) eV, spectroscopically determined for the first time, compares to 1.10(2) eV for unsubstituted glyoxal. The EAs (adiabatic attachment energies) of two excited states of methylglyoxal were also determined: EA(a3A″) = 3.27(2) eV and EA(A1A″) = 3.614(9) eV. The photodetachment of the anion to each of these two states produces the neutral species near the respective structural equilibria; hence, the a3A″ ← X2A″ and A1A″ ← X2A″ photodetachment transitions are dominated by intense peaks at their respective origins. The lowest-energy photodetachment transition, on the other hand, involves significant geometry relaxation in the X1A' state, which corresponds to a 60° internal rotation of the methyl group, compared to the anion structure. Accordingly, the X1A' ← X2A″ transition is characterized as a broad, congested band, whose vertical detachment energy, VDE = 1.20(4) eV, significantly exceeds the adiabatic EA. The experimental results are in excellent agreement with the ab initio predictions using several equation-of-motion methodologies, combined with coupled-cluster theory.


The Physical Activity Patterns of Pregnant Taiwanese Women.
Physical activity reduces the risk of maternal disorders during pregnancy. However, many pregnant women reduce their levels of physical activity while pregnant. The purpose of this study was to examine and compare the physical activity (total amount, intensity, type) of Taiwanese women during each trimester. This cross-sectional survey used purposive sampling to enroll 581 Taiwanese women as participants. The physical activity of participants was measured using the Mandarin version of the Pregnancy Physical Activity Questionnaire. The levels of household/caregiving activity and occupational activity differed significantly across trimesters. Household/caregiving (43.2%-54.5%) and occupational activity (42.0%-54.0%) accounted for the largest percentages of total energy expenditure for all three trimesters. In terms of total and household/caregiving activities, multiparous women had significantly higher mean energy expenditures than their primiparous peers. Moreover, income had a pervasive influence on all types and amounts of physical activity and energy expenditures, respectively, with the exception of sports/exercise. Further careful assessment of the types and intensities of physical activity that are suitable for pregnant women in different parity and income categories in Taiwan is necessary. Furthermore, healthcare providers should encourage pregnant women to use strategies that promote their more regular participation in enjoyable physical activities. One of these potential strategies is to do activities together with children, family members, or friends.


Single-voxel (1)H spectroscopy in the human hippocampus at 3 T using the LASER sequence: characterization of neurochemical profile and reproducibility.
The hippocampus is crucial for long-term episodic memory and learning. It undergoes structural change in aging and is sensitive to neurodegenerative and psychiatric diseases. MRS studies have seldom been performed in the hippocampus due to technical challenges. The reproducibility of MRS in the hippocampus has not been evaluated at 3 T. The purpose of the present study was to quantify the concentration of metabolites in a small voxel placed in the hippocampus and evaluate the reproducibility of the quantification. Spectra were measured in a 2.4 mL voxel placed in the left hippocampus covering the body and most of the tail of the structure in 10 healthy subjects across three different sessions and quantified using LCModel. High-quality spectra were obtained, which allowed a reliable quantification of 10 metabolites including glutamate and glutamine. Reproducibility of MRS was evaluated with coefficient of variation, standard errors of measurement, and intraclass correlation coefficients. All of these measures showed improvement with increased number of averages. Changes of less than 5% in concentration of N-acetylaspartate, choline-containing compounds, and total creatine and of less than 10% in concentration of myo-inositol and the sum of glutamate and glutamine can be confidently detected between two measurements in a group of 20 subjects. A reliable and reproducible neurochemical profile of the human hippocampus was obtained using MRS at 3 T in a small hippocampal volume.


A Live Bio-Therapeutic for Mastitis, Containing Lactococcus lactis DPC3147 With Comparable Efficacy to Antibiotic Treatment.
Bovine mastitis is an ongoing significant concern in the dairy and agricultural industry resulting in substantial losses in milk production and revenue. Among the predominant etiological agents of bovine mastitis are Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, and Escherichia coli. Currently, the treatment of choice for bovine mastitis involves the use of commercial therapeutic antibiotic formulations such as TerrexineTM, containing both kanamycin and cephalexin. Such antibiotics are regularly administered in more than one dose resulting in the withholding of milk for processing for a number of days. Here, we describe the optimization of a formulation of Lactococcus lactis DPC3147, that produces the two-component bacteriocin lacticin 3147, in a liquid paraffin-based emulsion (formulation hereafter designated 'live bio-therapeutic') for the first time and compare it to the commercial antibiotic formulation TerrexineTM, with a view to treating cows with clinical/sub-clinical mastitis. Critically, in a field trial described here, this 'ready-to-use' emulsion containing live L. lactis DPC3147 cells exhibited comparable efficacy to TerrexineTM when used to treat mastitic cows. Furthermore, we found that the L. lactis cells within this novel emulsion-based formulation remained viable for up to 5 weeks, when stored at 4, 22, or 37°C. The relative ease and cost-effective nature of producing this 'live bio-therapeutic' formulation, in addition to its enhanced shelf life compared to previous aqueous-based formulations, indicate that this product could be a viable alternative therapeutic option for bovine mastitis. Moreover, the single-dose administration of this 'live bio-therapeutic' formulation is a further advantage, as it can expedite the return of the milk to the milk pool, in comparison to some commercial antibiotics. Overall, in this field trial, we show that the live bio-therapeutic formulation displayed a 47% cure rate compared to a 50% cure rate for a commercial antibiotic control, with respect to curing cows with clinical/sub-clinical mastitis. The study suggests that a larger field trial to further demonstrate efficacy is warranted.


Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions.
Cytidine deaminases of the APOBEC3 family all have specificity for single-stranded DNA, which may become exposed during replication or transcription of double-stranded DNA. Three human APOBEC3A (hA3A), hA3B, and hA3H genes are expressed in keratinocytes and skin, leading us to determine whether genetic editing of human papillomavirus (HPV) DNA occurred. In a study of HPV1a plantar warts and HPV16 precancerous cervical biopsies, hyperedited HPV1a and HPV16 genomes were found. Strictly analogous results were obtained from transfection experiments with HPV plasmid DNA and the three nuclear localized enzymes: hA3A, hA3C, and hA3H. Thus, stochastic or transient overexpression of APOBEC3 genes may expose the genome to a broad spectrum of mutations that could influence the development of tumors.


DNA polymerase delta is required for the replication feedback control of cell cycle progression in Schizosaccharomyces pombe.
DNA replication and DNA repair are essential cell cycle steps ensuring correct transmission of the genome. The feedback replication control system links mitosis to completion of DNA replication and partially overlaps the radiation checkpoint control. Deletion of the chk1/rad27 gene abolishes the radiation but not the replication feedback control. Thermosensitive mutations in the DNA polymerase delta, cdc18 or cdc20 genes lead cells to arrest in the S phase of the cell cycle. We show that strains carrying any of these mutations enter lethal mitosis in the absence of the radiation checkpoint chk1/rad27. We interpret these data as an indication that an assembled replisome is essential for replication dependent control of mitosis and we propose that the arrest of the cell cycle in the thermosensitive mutants is due to the chk1+/rad27+ pathway, which monitors directly DNA for signs of damage.


Resting Heart Rate and Long-term Outcomes Among the African American Population: Insights From the Jackson Heart Study.
Increased resting heart rate is associated with worse outcomes in studies of mostly white populations, but its significance is not well established in African Americans persons whose cardiac comorbidities and structural abnormalities differ. To study the prognostic utility of heart rate in a community-based African American cohort in the Jackson Heart Study. A total of 5261 participants in the Jackson Heart Study, a prospective, community-based study in Jackson, Mississippi, were evaluated. Baseline heart rate was assessed by quintiles and as a continuous variable. All participants with baseline heart rate documented by a 12-lead electrocardiogram without pacing or atrial fibrillation noted on their baseline Jackson Heart Study examination were included in the study. Follow-up began September 26, 2000, and was completed December 31, 2011. Data analysis was performed from July to October 2015. Unadjusted and adjusted associations between heart rate and all-cause mortality and heart failure hospitalization using Cox proportional hazards regression models. Of the 5261 individuals included in the analysis, 1921 (36.5%) were men; median (25th-75th percentile) age was 55.7 (45.4-64.8) years. Median (25th-75th percentile) baseline heart rate was 63 beats per minute (bpm) (57-71 bpm). The highest heart rate quintile (73-118 bpm) had higher rates of diabetes (398 [37.4%]; P < .001) and hypertension (735 [69.1%]; P < .001), higher body mass index (median [IQR], 32.4 [28.1-38.3]; P < .001), less physical activity (0 hours per week, 561 [52.8%]; P < .001), and lower β-blocker use (73 [6.9%]; P < .001) compared with lower quintiles. Caffeine intake (from 80.7 to 85.5 mg/d; P = .57) and left ventricular ejection fraction (from 62% to 62.3%; P = .01) were similar between groups. As a continuous variable, elevated heart rate was associated with increased mortality and heart failure hospitalizations, with adjusted hazard ratios for every 5-bpm increase of 1.14 (95% CI, 1.10-1.19) and 1.10 (95% CI, 1.05-1.16), respectively. Similar patterns were observed in comparisons between the highest and lowest quintiles. Higher baseline heart rate was associated with increased mortality and heart failure hospitalizations among African American participants in the Jackson Heart Study. These findings are similar to those seen in white populations, but further study is needed to understand whether African American individuals benefit from interventions targeting heart rate reduction.


Accuracy of a continuous blood pressure monitor based on arterial tonometry.
A validation study of the continuous noninvasive tonometric blood pressure monitor called JENTOW was performed in 20 normotensive subjects and 10 hypertensive patients. Tonometric and intra-arterial blood pressures were simultaneously recorded at supine rest and during a Valsalva maneuver and tilting test. The results of the strict evaluation of the instrument's capacity for reproducing intra-arterial blood pressure were as follows: 1) The overall frequency response of the transcutaneous blood pressure-monitoring system based on arterial tonometry was flat, with negligible delay to intra-arterial blood pressure in the range of 0-5 Hz. 2) The largest discrepancy between intra-arterial and tonometric pressure waveforms was found at the early systolic phase; except for this phase, the tonometric waveform was almost equal to the intra-arterial waveform. 3) The beat-to-beat variability of tonometric pressure corresponded to that of intra-arterial pressure almost perfectly in the physiologically significant frequency range of 0-0.5 Hz. 4) During resting conditions, the averages of the systolic and diastolic values measured tonometrically corresponded well to those measured intra-arterially. 5) The changes in the between-method discrepancy of blood pressure values during the Valsalva maneuver were statistically significant but small (< 5 mm Hg). 6) No significant effect of postural tilting was found on the between-method discrepancy. We conclude that this method is clinically acceptable and reliable except for its limited capacity for recording the higher frequency intra-arterial waveform and for responding to the relatively rapid and large transient changes in blood pressure.


A retrospective comparison of 1,022 implants: immediate versus nonimmediate.
The aim of this study was to compare the survival of implants placed in mature bone with the survival of implants placed in fresh extraction sockets in the same patients. A retrospective study of patients treated simultaneously with at least one immediate and one nonimmediate implant was carried out for the period 2005 to 2008. Data were recorded for patient age and sex; implant length, diameter, and position; and, for postextraction implants, distance between the implant and the alveolar bone. One thousand twenty-two implants were placed in 150 patients; 480 were placed immediately and 542 were placed in mature bone. The mean implant survival rate was 93.4%; survival rates were 93.8% for immediate implants and 93.2% for nonimmediate implants. The failure rate in the maxilla was 5.2% and in the mandible it was 2.8%. The failure rate for immediate implants in the posterior maxilla was 8.5%, which was statistically significantly higher than for implants placed elsewhere. Of the failed implants, 72% were early failures. The survival rate of implants placed in fresh extraction sockets was similar to that of implants placed in mature bone. A statistically significantly higher failure rate was seen with immediate implants placed in the posterior maxilla.


Association of suprascapular neuropathy with rotator cuff tendon tears and fatty degeneration.
The mutual influence of suprascapular neuropathy (SSN) and rotator cuff tendon tears on muscle pathology is unclear. Debate continues as to how retracted cuff tears can lead to SSN and whether SSN or tendon retraction causes muscle fatty degeneration. A cohort of 87 patients suspected of having SSN was identified from a prospectively collected registry. All underwent electromyography/nerve conduction velocity study (EMG/NCV) and magnetic resonance imaging (MRI) of their shoulders. EMG/NCVs were performed and interpreted by electrodiagnosticians, and MRI cuff tendon quality and muscle fatty degeneration were interpreted by two surgeons. Out of 87 patients, 32 patients had SSN on EMG/NCV, and 55 patients had normal suprascapular nerve. MRI showed that 59 of 87 supraspinatus had no fatty degeneration or mild fatty streaks (Goutallier grades 0 and 1), and 28 patients had significant fatty degeneration (grades 2-4); infraspinatus fatty degeneration was similar. Review of supraspinatus tendon showed 41 patients with intact tendons or partial tears, and 46 with full tears. Infraspinatus tendons pathology was similar. Tendon pathology and fatty degeneration were related (P-value<.001), with more severe tendon pathology leading to higher degree of fatty degeneration. Infraspinatus tendon tears were associated with SSN (P = .01), but SSN was not related to fatty degeneration of either supraspinatus or infraspinatus (P-values .65, .54). The exact association and etiology of SSN in patients with rotator cuff pathology remain unclear. SSN is correlated to tendon tear size, but it does not have significant influence on fatty degeneration of either supraspinatus or infraspinatus.


Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate.
The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.


Modeling the Cost-Effectiveness of Doula Care Associated with Reductions in Preterm Birth and Cesarean Delivery.
One in nine US infants is born before 37 weeks' gestation, incurring medical costs 10 times higher than full-term infants. One in three infants is born by cesarean; cesarean births cost twice as much as vaginal births. We compared rates of preterm and cesarean birth among Medicaid recipients with prenatal access to doula care (nonmedical maternal support) with similar women regionally. We used data on this association to mathematically model the potential cost-effectiveness of Medicaid coverage of doula services. Data came from two sources: all Medicaid-funded, singleton births at hospitals in the West North Central and East North Central US (n = 65,147) in the 2012 Nationwide Inpatient Sample, and all Medicaid-funded singleton births (n = 1,935) supported by a community-based doula organization in the Upper Midwest from 2010 to 2014. We analyzed routinely collected, de-identified administrative data. Multivariable regression analysis was used to estimate associations between doula care and outcomes. A probabilistic decision-analytic model was used for cost-effectiveness estimates. Women who received doula support had lower preterm and cesarean birth rates than Medicaid beneficiaries regionally (4.7 vs 6.3%, and 20.4 vs 34.2%). After adjustment for covariates, women with doula care had 22 percent lower odds of preterm birth (AOR 0.77 [95% CI 0.61-0.96]). Cost-effectiveness analyses indicate potential savings associated with doula support reimbursed at an average of $986 (ranging from $929 to $1,047 across states). Based on associations between doula care and preterm and cesarean birth, coverage reimbursement for doula services would likely be cost saving or cost-effective for state Medicaid programs.


Risk Mitigation of Emerging Zoonoses: Hendra Virus and Non-Vaccinating Horse Owners.
Hendra virus was identified in horses and humans in 1994, in Queensland, Australia. Flying foxes are the natural host. Horses are thought to acquire infection by direct or indirect contact with infected flying fox urine. Humans are infected from close contact with infected horses. To reduce risk of infection in horses and humans, Australian horse owners are encouraged to vaccinate horses against the virus and adopt property risk mitigation practices that focus on reducing flying fox horse contact and contamination of horses' environment with flying fox bodily fluids. This study investigates uptake of four Hendra virus risk mitigation practices in a sample of non- and partially vaccinating horse owners living close to previous Hendra virus cases. Protection motivation theory was used to develop a conceptual model to investigate risk perception and coping factors associated with uptake of risk mitigation practices. An online survey was administered via Facebook pages of veterinary clinics close to previous Hendra virus cases. Factors associated with uptake of risk mitigation practices were investigated using univariate and multivariate binary logistic regression. Belief that a risk mitigation practice would be effective in reducing Hendra virus risk was significantly associated with the uptake of that practice. Issues around the practicality of implementing risk mitigation practices were found to be the greatest barrier to uptake. Factors that relate to risk immediacy, such as nearby infection, were identified as more likely to trigger uptake of risk mitigation practices. The role of veterinarians in supporting Hendra risk mitigation was identified as more influential than that of respected others or friends. Findings from this study are being used to assist stakeholders in Australia responsible for promotion of risk mitigation practice in identifying additional pathways and reliable influencing factors that could be utilized for engaging and communicating with horse owners to promote Hendra virus risk mitigation behaviour.


Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion.
To characterize the voltage-gated ion channels in human beta-cells from nondiabetic donors and their role in glucose-stimulated insulin release. Insulin release was measured from intact islets. Whole-cell patch-clamp experiments and measurements of cell capacitance were performed on isolated beta-cells. The ion channel complement was determined by quantitative PCR. Human beta-cells express two types of voltage-gated K(+) currents that flow through delayed rectifying (K(V)2.1/2.2) and large-conductance Ca(2+)-activated K(+) (BK) channels. Blockade of BK channels (using iberiotoxin) increased action potential amplitude and enhanced insulin secretion by 70%, whereas inhibition of K(V)2.1/2.2 (with stromatoxin) was without stimulatory effect on electrical activity and secretion. Voltage-gated tetrodotoxin (TTX)-sensitive Na(+) currents (Na(V)1.6/1.7) contribute to the upstroke of action potentials. Inhibition of Na(+) currents with TTX reduced glucose-stimulated (6-20 mmol/l) insulin secretion by 55-70%. Human beta-cells are equipped with L- (Ca(V)1.3), P/Q- (Ca(V)2.1), and T- (Ca(V)3.2), but not N- or R-type Ca(2+) channels. Blockade of L-type channels abolished glucose-stimulated insulin release, while inhibition of T- and P/Q-type Ca(2+) channels reduced glucose-induced (6 mmol/l) secretion by 60-70%. Membrane potential recordings suggest that L- and T-type Ca(2+) channels participate in action potential generation. Blockade of P/Q-type Ca(2+) channels suppressed exocytosis (measured as an increase in cell capacitance) by >80%, whereas inhibition of L-type Ca(2+) channels only had a minor effect. Voltage-gated T-type and L-type Ca(2+) channels as well as Na(+) channels participate in glucose-stimulated electrical activity and insulin secretion. Ca(2+)-activated BK channels are required for rapid membrane repolarization. Exocytosis of insulin-containing granules is principally triggered by Ca(2+) influx through P/Q-type Ca(2+) channels.


Gastrointestinal nurse navigation: implementation of a novel role.
Gastrointestinal (GI) cancer is the second most frequent cancer diagnosis in the United States, and the care for patients with GI cancer is multifaceted, with each clinical encounter impacting patients' overall experience. Patients and families often navigate this complicated journey on their own with limited resources and knowledge; therefore, innovative, patient-centered, and quality-focused programs must be developed. The purpose of this article is to discuss the development of GI nurse navigators (NNs) and the important role they have in providing coordinated evidence-based cancer care and in the benchmarking of quality metrics to allow more transparency and improve GI cancer care. This article provides a foundation for developing a GI NN role within the context of a newly developed multidisciplinary GI cancer program, and identifies the importance of tracking specific quality metrics. This innovative model is useful for healthcare organizations and nursing practice because it identifies the importance of a nurse in the navigator role, as well as highlights the numerous functions the NN can provide to the GI multidisciplinary team and patients.


Current review and a simplified "five-point management algorithm" for keratoconus.
Keratoconus is a slowly progressive, noninflammatory ectatic corneal disease characterized by changes in corneal collagen structure and organization. Though the etiology remains unknown, novel techniques are continuously emerging for the diagnosis and management of the disease. Demographical parameters are known to affect the rate of progression of the disease. Common methods of vision correction for keratoconus range from spectacles and rigid gas-permeable contact lenses to other specialized lenses such as piggyback, Rose-K or Boston scleral lenses. Corneal collagen cross-linking is effective in stabilizing the progression of the disease. Intra-corneal ring segments can improve vision by flattening the cornea in patients with mild to moderate keratoconus. Topography-guided custom ablation treatment betters the quality of vision by correcting the refractive error and improving the contact lens fit. In advanced keratoconus with corneal scarring, lamellar or full thickness penetrating keratoplasty will be the treatment of choice. With such a wide spectrum of alternatives available, it is necessary to choose the best possible treatment option for each patient. Based on a brief review of the literature and our own studies we have designed a five-point management algorithm for the treatment of keratoconus.


Gymnastic-Based Movement Therapy for Children With Neurodevelopmental Disabilities: Results From a Pilot Feasibility Study.
Background: Developmental and behavioral issues often limit the participation of children with neurodevelopmental disabilities (NDD) in community-based activities with their peers, which decreases opportunities for their social learning and development. Parents of children with NDD seek out programs that address physical and psychosocial development. Several studies already support the positive effects for the child to attend physical activity programs (PAPs). However, these studies are highly prone to biases and Hawthorne effect. In the planning stage of a large prospective study to assess the effectiveness of PAPs we reviewed the records of children who participated in a gymnastic-based program, the Empowering Steps Movement Therapy (ESMT). Besides generating useful data for developing the prospective study we thought these data reflect the rate of changes in context of normal practice in a naturalistic environment; therefore protected from Hawthorne effect and other biases. Design: This is a historical cohort: the files of 67 children with NDD were examined across a 2-year period (Jan 2011 to Jan 2013). As part of standard practice, the ESMT therapists document changes in motor function every 6 months, using the ESMT's proprietary motor scale. Parents also completed a parental questionnaire in June 2011 regarding their perceptions of changes in their child's physical and psychosocial function, as well as family functioning since their child started the program. Results: Linear Mixed Effects Model clearly identified three groups according to changes in motor function: the ones with rapid changes (mostly functional children with autism spectrum disorder: n = 13), the ones with moderate changes (different types of NDD diagnoses: n = 41) and the ones that did not change or even decreased motor skills over the follow-up (children with complex diseases or uncontrolled epilepsy despite treatment: n = 13). Parental questionnaires (n = 39) reported improvement in most of the children's physical and psychosocial abilities; they also indicated improvement in some of the family parameters. There was no association between the changes in children's motor functions and parents' responses to the questionnaire. Conclusion: Despite limitations due to the retrospective nature of the study, the absence of a control group and the absence of validated measurement tools, the observed positive effects of attending movement therapy center on motor performance and psychosocial development confirm in a naturalistic environment what has been shown in context of clinical trials or quasi-experimental studies. These results are not conclusive. They warrant further, rigorous investigation using validated instruments, independent assessors, and control groups.


Tungsten diselenide for all-fiber lasers with the chemical vapor deposition method.
Two-dimensional materials have become the focus of research for their photoelectric properties, and are employed as saturable absorption materials. Currently, the challenge is how to further improve the modulation depth of saturable absorbers (SAs) based on two-dimensional materials. In this paper, three kinds of WSe2 films with different thicknesses are prepared using the chemical vapor deposition method. The nonlinear optical responses of the WSe2 films including the nonlinear saturable absorption and nonlinear refractive index are characterized by the double-balanced detection method and Z-scan experiments. Different modulation depths are successfully obtained by controlling the thickness of the WSe2 films. We further incorporate them into an all-fiber laser to generate mode-locked pulses. The mode-locked fiber lasers with a pulse duration of 185 fs, 205.7 fs and 230.3 fs are demonstrated when the thickness of the WSe2 films is measured to be 1.5 nm, 5.7 nm and 11 nm, respectively. This work provides new prospects for WSe2 in ultrafast photonic device applications.


Reconstruction of normal sounding speech for laryngectomy patients through a modified CELP codec.
Whispered speech can be useful for quiet and private communication, and is the primary means of unaided spoken communication for many people experiencing voice-box deficiencies. Patients who have undergone partial or full laryngectomy are typically unable to speak anything more than hoarse whispers, without the aid of prostheses or specialized speaking techniques. Each of the current prostheses and rehabilitative methods for post-laryngectomized patients (primarily oesophageal speech, tracheo-esophageal puncture, and electrolarynx) have particular disadvantages, prompting new work on nonsurgical, noninvasive alternative solutions. One such solution, described in this paper, combines whisper signal analysis with direct formant insertion and speech modification located outside the vocal tract. This approach allows laryngectomy patients to regain their ability to speak with a more natural voice than alternative methods, by whispering into an external prosthesis, which then, recreates and outputs natural-sounding speech. It relies on the observation that while the pitch-generation mechanism of laryngectomy patients is damaged or unusable, the remaining components of the speech production apparatus may be largely unaffected. This paper presents analysis and reconstruction methods designed for the prosthesis, and demonstrates their ability to obtain natural-sounding speech from the whisper-speech signal using an external analysis-by-synthesis processing framework.


Active surveillance to determine the impact of methicillin-resistant Staphylococcus aureus colonization on patients in intensive care units of a Veterans Affairs Medical Center.
The impact of methicillin-resistant Staphylococcus aureus (MRSA) colonization on mortality has not been well characterized. We sought to describe the impact of MRSA colonization on patients admitted to intensive care units (ICUs) in the Birmingham Veterans Affairs Medical Center (VAMC). We conducted a retrospective cohort study of ICU patients at the Birmingham VAMC during 2005 to evaluate the predictors of MRSA colonization and determine its effect on clinical outcomes. Surveillance cultures for MRSA were performed on admission to the ICU and weekly thereafter. Clinical findings, the incidence of MRSA infection, and mortality within 3 months after ICU admission were recorded. Predictors of mortality and S. aureus colonization were determined using multivariable models. S. aureus colonization was present in 97 (23.3%) of 416 patients screened, of whom 67 (16.1%) were colonized with methicillin-susceptible S. aureus (MSSA) and 30 (7.2%) with MRSA. All-cause mortality at 3 months among MRSA-colonized patients was significantly greater than that among MSSA-colonized patients (46.7% vs 19.4%; P = .009). MRSA colonization was an independent predictor of death (adjusted odds ratio [OR], 3.7 [95% confidence interval [CI], 1.5-8.9]; P = .003) and onset of MRSA infection after hospital discharge (adjusted OR, 7.6 [95% CI, 2.48-23.2]; P < .001). Risk factors for MRSA colonization included recent antibiotic use (adjusted OR, 4.8 [95% CI, 1.9-12.2]; P = .001) and dialysis (adjusted OR, 18.9 [95% CI, 2.1-167.8]; P = .008). Among ICU patients, MRSA colonization is associated with subsequent MRSA infection and an all-cause mortality that is greater than that for MSSA colonization. Active surveillance for MRSA colonization may identify individuals at risk for these adverse outcomes. Prospective studies of outcomes in MRSA-colonized patients may better define the role of programs for active MRSA surveillance.


Development and validation of simulated virtual patients to impart early clinical exposure in endocrine physiology.
In the country presently, preclinical medical students are not routinely exposed to real patients. Thus, when they start clinical postings, they are found to have poor clinical reasoning skills. Simulated virtual patients (SVPs) can improve clinical skills without endangering real patients. This pilot study describes the development of two SVPs in endocrine physiology and their validation in terms of acquisition of clinical knowledge and student engagement. Two SVPs, Nandini Sharma (unintentional weight gain) and Sunil Yadav (polyuria), were created and published on the i-Human Patients platform through an iterative, interdisciplinary, and transdisciplinary collaborative process using the conceptual framework of Kim et al. (Kim S, Phillips WR, Pinsky L, Brock D, Phillips K, Keary J. Med Educ 40: 867-876, 2006). After internal and external peer validation, the SVPs were piloted on 40 students (20 students per virtual patient) over 2 wk. A cognitive pretest was conducted before exposure, and a posttest soon after. Faculty and student feedback were collected. Faculty found SVPs authentic, helpful as teaching-learning tools, and useful for giving feedback and for assessment. Students found SVPs more engaging than paper cases and helpful in developing clinical reasoning and in imparting clinical exposure. Pretest and posttest scores indicated knowledge gain ( P < 0.01). Although challenging to create, SVPs created on the i-Human Patients platform improved learning in endocrine physiology and were well accepted by students and faculty as a means to provide early clinical exposure. More SVPs can be developed through collaboration between stakeholder departments and integrated into the curriculum for greater benefit.


Free Energy Landscape of Lipid Interactions with Regulatory Binding Sites on the Transmembrane Domain of the EGF Receptor.
Lipid molecules can bind to specific sites on integral membrane proteins, modulating their structure and function. We have undertaken coarse-grained simulations to calculate free energy profiles for glycolipids and phospholipids interacting with modulatory sites on the transmembrane helix dimer of the EGF receptor within a lipid bilayer environment. We identify lipid interaction sites at each end of the transmembrane domain and compute interaction free energy profiles for lipids with these sites. Interaction free energies ranged from ca. -40 to -4 kJ/mol for different lipid species. Those lipids (glycolipid GM3 and phosphoinositide PIP2) known to modulate EGFR function exhibit the strongest binding to interaction sites on the EGFR, and we are able to reproduce the preference for interaction with GM3 over other glycolipids suggested by experiment. Mutation of amino acid residues essential for EGFR function reduce the binding free energy of these key lipid species. The residues interacting with the lipids in the simulations are in agreement with those suggested by experimental (mutational) studies. This approach provides a generalizable tool for characterizing the interactions of lipids that bind to specific sites on integral membrane proteins.


The ethics of deep brain stimulation (DBS).
Deep brain stimulation (DBS) is an invasive technique designed to stimulate certain deep brain regions for therapeutic purposes and is currently used mainly in patients with neurodegenerative disorders, such as Parkinson's disease. However, DBS is also used increasingly for other experimental applications, such as the treatment of psychiatric disorders (e.g. severe depression), weight reduction. Apart from its therapeutic potential, DBS can cause severe adverse effects, some that might also have a significant impact on the patient's personality and autonomy by the external stimulation of DBS which effects lie beyond the individual's control and free will. The article's purpose is to outline the procedures of DBS currently used in therapeutic and experimental applications and to discuss the ethical concerns regarding this procedure. It will address the clinical benefit-risk-ratio, the particular ethics of research in this field, and the ethical issues raised by affecting a patient's or an individual's personality and autonomous behaviour. Moreover, a potential ethical guideline, the Ulysses contract is discussed for the field of clinical application as well as the question of responsibility.


Tyrosine kinase inhibitors in the treatment of systemic sclerosis: from animal models to clinical trials.
Efficient antifibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential antifibrotic therapies for SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib, and dasatinib demonstrated strong antifibrotic effects. Imatinib not only prevented fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse-1 model but also reduced established fibrosis in a modified bleomycin model. Open-label, proof-of-concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and lung fibrosis compared with baseline measures. However, whether this reflects the natural course of the disease or is a result of treatment effects is unclear and needs to be analyzed in larger, multicenter, randomized, placebo-controlled trials. Toxicity is expected from cancer trials with frequent mild to moderate adverse events.


MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis.
Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution. In human carotid plaques, MerTK cleavage correlated with plaque necrosis and the presence of ischemic symptoms. Moreover, in fat-fed LDL receptor-deficient (Ldlr-/-) mice whose myeloid cells expressed a cleavage-resistant variant of MerTK, atherosclerotic lesions exhibited higher macrophage MerTK, lower levels of the cleavage product soluble Mer, improved efferocytosis, smaller necrotic cores, thicker fibrous caps, and increased ratio of proresolving versus proinflammatory lipid mediators. These findings provide a plausible molecular-cellular mechanism that contributes to defective efferocytosis, plaque necrosis, and impaired resolution during the progression of atherosclerosis.


Observation of Multiplicity Dependent Prompt χ_{c1}(3872) and ψ(2S) Production in pp Collisions.
The production of χ_{c1}(3872) and ψ(2S) hadrons is studied as a function of charged particle multiplicity in pp collisions at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 2 fb^{-1}. For both states, the fraction that is produced promptly at the collision vertex is found to decrease as charged particle multiplicity increases. The ratio of χ_{c1}(3872) to ψ(2S) cross sections for promptly produced particles is also found to decrease with multiplicity, while no significant dependence on multiplicity is observed for the equivalent ratio of particles produced away from the collision vertex in b-hadron decays. This behavior is consistent with a calculation that models the χ_{c1}(3872) structure as a compact tetraquark. Comparisons with model calculations and implications for the binding energy of the χ_{c1}(3872) state are discussed.


Body mass index and healthcare costs: a systematic literature review of individual participant data studies.
Excess weight is associated with increased total healthcare costs, but it is less well known how the associations between excess weight and costs vary across different types of healthcare service. We reviewed studies using individual participant data to estimate associations between body mass index and healthcare costs, and summarized how annual healthcare costs for overweight (body mass index 25 to <30 kg/m2 ) and obese (≥30 kg/m2 ) individuals compared with those for healthy weight individuals (18.5 to <25 kg/m2 ). EMBASE and MEDLINE were searched from January 1990 to September 2016, and 75 studies were included in the review. Of these, 34 studies presented adequate information to contribute to a quantitative summary of results. Compared with individuals at healthy weight, the median increases in mean total annual healthcare costs were 12% for overweight and 36% for obese individuals. The percentage increases in costs were highest for medications (18% for overweight and 68% for obese), followed by inpatient care (12% and 34%) and ambulatory care (4% and 26%). Percentage increases in costs associated with obesity were higher for women than men. The substantial costs associated with excess weight in different healthcare settings emphasize the need for investment to tackle this major public health problem.


Lentivirus production is influenced by SV40 large T-antigen and chromosomal integration of the vector in HEK293 cells.
Currently, lentiviral vectors for research and gene therapy are produced from 293-T cells that are transiently transfected with plasmids encoding the vector and helper functions. However, transiently transfected vectors as well as the presence of SV40 virus large T-antigen (T-Ag) cause serious technical and safety considerations. We aimed to exploit single copy integration sites in the HEK293 genome supporting lentiviral vector production. We found that lentiviral vectors result in minimal infectious particle production from single copy integrants in HEK293. Moreover, once this cell line harbors single copy integrations of lentiviral vectors, its ability to transiently produce lentiviral vectors becomes strongly impaired. T-Ag has a dramatic effect on virus production. Low levels of constitutive T-Ag expression can overcome the production restriction imposed by integrated lentiviral vectors copies. Interestingly, T-Ag does not exert its role at the level of transcriptional activity of the vector; rather, it seems to impose an indirect effect on the cell thereby enabling lentiviral vector production. Altogether, our study highlights the restrictions for integrated lentiviral vectors that are relevant for the establishment of stable and safe producer cell lines.


A retinal neuronal developmental wave of retinoschisin expression begins in ganglion cells during layer formation.
Mutations in the retinoschisin gene, RS-1, cause juvenile X-linked retinoschisis (XLRS), a dystrophy characterized by delamination of the inner retinal layers, leading to visual impairment. Although the retinoschisin protein (RS) is expressed most abundantly in photoreceptors in the outer retina, XLRS disease affects the innermost retinal layers, including the nerve fiber layer that contains retinal ganglion cells (RGCs). Considering the histopathological and electrophysiological characteristics of the clinical disease, the present study was conducted to evaluate the local cellular expression of RS-1 during retinal development. RS protein and RS-1 mRNA were localized to specific retinal cell types in embryonic to adult mice by immunohistochemistry, confocal immunofluorescence microscopy, catalyzed reporter deposition in situ hybridization, and laser capture microdissection/RT-PCR. RS-1 mRNA was expressed first in RGCs by postnatal day (P)1, after terminal differentiation. Expression then moved posteriorly through the retina in a spatial and temporal developmental wave, as additional neuronal classes were born and synaptic layers were formed. RS was expressed by bipolar cells at a time when these neurons were establishing functional synapses with photoreceptors, evidenced by the appearance of the electroretinogram b-wave between P12 and P14. All major classes of adult retinal neurons, with the possible exception of horizontal cells, express RS protein and mRNA, strongly suggesting that retinoschisin in the inner retina is synthesized locally rather than being transported, as earlier proposed, from distal retinal photoreceptors. Continued expression of RS by mature inner-retinal neurons supports the possibility of a therapeutic strategy of protein replacement to treat both infants and adults with XLRS.


The Genome of Dendrobium officinale Illuminates the Biology of the Important Traditional Chinese Orchid Herb.
Dendrobium officinale Kimura et Migo is a traditional Chinese orchid herb that has both ornamental value and a broad range of therapeutic effects. Here, we report the first de novo assembled 1.35 Gb genome sequences for D. officinale by combining the second-generation Illumina Hiseq 2000 and third-generation PacBio sequencing technologies. We found that orchids have a complete inflorescence gene set and have some specific inflorescence genes. We observed gene expansion in gene families related to fungus symbiosis and drought resistance. We analyzed biosynthesis pathways of medicinal components of D. officinale and found extensive duplication of SPS and SuSy genes, which are related to polysaccharide generation, and that the pathway of D. officinale alkaloid synthesis could be extended to generate 16-epivellosimine. The D. officinale genome assembly demonstrates a new approach to deciphering large complex genomes and, as an important orchid species and a traditional Chinese medicine, the D. officinale genome will facilitate future research on the evolution of orchid plants, as well as the study of medicinal components and potential genetic breeding of the dendrobe.


Analytical subcellular fractionation studies on enterocytes from the jejunum and ileum of the rat and some properties of brush-border alkaline phosphatase.
1. Enterocytes, isolated from the proximal jejinum and distal ileum of the rat, were homogenized and their organelles separated by isopycnic centrifugation on continuous sucrose density gradients. The distributions of marker enzymes for the principal organelles, RNA and protein were determined in the sucrose gradients and related to the activities per entercocyte. 2. In the jejunum the modal equilibrium densities of the various organelles were: brush borders (1.20), lysosomes (1.20), peroxisomes (1.19), mitochondria (1.17) and basal-lateral membranes (1.13). The values were not significantly different in the ileum. The activities of brush-border enzymes, soluble and mitochondrial malate dehydrogenase, soluble and membrane-associated lactate dehydrogenase and particulate protein content, however, were greater in the jejunal than the ileal enterocytes. 3. Detergent exposed latent alkaline phosphatase activity in jejunal enterocytes and indicated that this enzyme is present not only in the brush border but also in the basal-lateral membrane and soluble fractions of the cell. 4. Isolated jejunal brush-border preprations showed latent activities of both alkaline phosphatase and gamma-glutamyltransferase whereas the activities of alpha-glucosidase and leucyl-beta-naphylamidase were not affected by detergent. Mechanical disruption of these preparations suggested the presence of two forms of alkaline phosphatase in the brush border and provides a technique to assess membrane fragility.


Cost-effectiveness modelling of recombinant FSH versus urinary FSH in assisted reproduction techniques in the UK.
The purpose of this study was to undertake an economic evaluation to compare the cost-effectiveness of recombinant (r)FSH with urinary (u)FSH for attaining clinical pregnancy with assisted reproduction. Mathematical modelling was utilized incorporating a Markovian decision framework and a Monte Carlo simulation. Statistical representations of recurrent events over time were incorporated into a decision analysis involving fresh and frozen cycles in any sequence (after the first fresh embryo transfer cycle) over three successive assisted reproduction attempts. The mean values of transition probabilities were derived from randomized controlled clinical trials and published reports. The distributions of these transition probabilities were agreed upon by a panel of experts. Cost data for procedures and drugs were derived and validated according to the perspectives of the National Health Service and private clinics in the UK. The study involved 5000 Monte-Carlo simulations of treatment on a Markov cohort of 100 000 patients. The total number of pregnancies attained was significantly higher in the rFSH (40 575) compared with the uFSH (37 358) group. The cost per successful pregnancy was significantly lower for rFSH (5906 pounds sterling) compared with uFSH (6060 pounds sterling) and overall, fewer cycles of treatment were required with rFSH to achieve an ongoing pregnancy. The incremental cost-effectiveness ratio is 4148 pounds sterling for each additional clinical pregnancy with rFSH. In addition to the increased effectiveness of rFSH in ART, this study demonstrated that it is more cost-effective and more efficient than uFSH in attaining an ongoing pregnancy.


Measuring interprofessional competencies and attitudes among health professional students creating family planning virtual patient cases.
The Virtual Interprofessional Patients-Computer-Assisted Reproductive Health Education for Students (VIP-CARES) Project took place during the summers of 2010-2012 for eight weeks each year at the University of British Columbia (UBC). Undergraduate health care students worked collaboratively to develop virtual patient case-based learning modules on the topic of family planning. The purpose of this study was to evaluate the changes in perception towards interprofessional collaboration (IPC) among the participants, before and after the project. This study utilized a mixed methods evaluation using self-assessment survey instruments, semi-structured interviews, and reflective essays. Pre- and post- project surveys were adapted from the Canadian Medical Education Determinants (CanMEDS) and Canadian Interprofessional Health Collaborative (CIHC) frameworks, as well as the Memorial University Interprofessional Attitudes (IPA) questionnaire. The survey results were analyzed as mean (M) and standard deviation (SD) on Likert scales. The non-parametric Wilcoxon signed-rank test was used to determine if any significant changes were measured between each participant's differences in score (p ≤ 0.05). Post-project interview transcripts and essays were analyzed using recursive abstraction to elicit any themes. Altogether, 26 students in medicine, pharmacy, nursing, midwifery, dentistry, counselling psychology, and computer science participated in VIP-CARES, during the three years. Student attitudes toward IPC were positive before and after the project. At the project's conclusion, there was a statistically significant increase in the participants' self-assessment competency scores in the CanMEDS roles of health advocate (p = 0.05), manager (p = 0.02), and medical expert (p = 0.03), as well as the CIHC domains of interprofessional communication (p = 0.04), role clarification (p = 0.01), team functioning (p = 0.05), and collaborative leadership (p = 0.01). Qualitative evaluations yielded three major themes: communication and respect as key to team functioning, importance of role clarification within the team, and existence of inherent challenges to IPC. From the reflections, students generally felt more comfortable with their improvements in the CIHC domains of interprofessional communication, team functioning, and role clarification. After working within an interdisciplinary team developing virtual patient learning modules on family planning, the student participants of the VIP-CARES Project indicated general improvement in the skills necessary for effective interprofessional collaboration. Triangulation of the overall data suggests this was especially observed within the areas of interprofessional communication, team functioning, and role clarification.


Examination of age-dependent effects of fetal ethanol exposure on behavior, hippocampal cell counts, and doublecortin immunoreactivity in rats.
Ethanol is known as a potent teratogen having adverse effects on brain and behavior. However, some of the behavioral deficits caused by fetal alcohol exposure and well expressed in juveniles ameliorate with maturation may suggest some kind of functional recovery occurring during postnatal development. The aim of this study was to reexamine age-dependent behavioral impairments in fetal-alcohol rats and to investigate the changes in neurogenesis and gross morphology of the hippocampus during a protracted postnatal period searching for developmental deficits and/or delays that would correlate with behavioral impairments in juveniles and for potential compensatory processes responsible for their amelioration in adults. Ethanol was delivered to the pregnant dams by intragastric intubation throughout 7-21 gestation days at daily dose of 6 g/kg. Isocaloric intubation and intact control groups were included. Locomotor activity, anxiety, and spatial learning tasks were applied to juvenile and young-adult rats from all groups. Unbiased stereological estimates of hippocampal volumes, the total number of pyramidal and granular cells, and double cortin expressing neurons were carried out for postnatal days (PDs) PD1, PD10, PD30, and PD60. Alcohol insult during second trimester equivalent caused significant deficits in the spatial learning in juvenile rats; however, its effect on hippocampal morphology was limited to a marginally lower number of granular cells in dentate gyrus (DG) on PD30. Thus, initial behavioral deficits and the following functional recovery in fetal-alcohol subjects may be due to more subtle plastic changes within the hippocampal formation but also in other structures of the extended hippocampal circuit. Further investigation is required.


Efficacy And Safety of Dabigatran Etexilate Utilization With Concomitant Dual Antiplatelet Therapy In Atrial Fibrillation.
The necessity to add two antiplatelet agents to an oral anticoagulant (OAC) often arises in patients with atrial fibrillation (AF) in routine clinical practice. The majority of AF patients have an indication for continuous OAC, and coronary artery disease co-exists in 25% of these patients. The increasing use of drug-eluting stents to minimize intrastent restenosis necessitates long-term dual antiplatelet therapy with Aspirin plus Clopidogrel to reduce the risk of early and late stent thrombosis. Combined aspirin-clopidogrel therapy, however, is less effective in preventing stroke compared with OAC alone in AF patients, and OAC alone is insufficient to prevent stent thrombosis. The management of AF patients presenting with an acute coronary syndrome poses similar management complexities. Since AF and coronary artery disease with stent placement are common, it is relatively frequent to treat patients with both these conditions, where triple antithrombotic therapy with Aspirin, Clopidogrel and an OAC would be needed. Dabigatran etexilate, an oral direct thrombin inhibitor, has shown that compared with Warfarin given at a dose of 150 mg twice daily significantly reduces stroke with less intracranial bleeding, and at a dose of 110 mg twice daily has similar efficacy with less bleeding. Although, Dabigatran maintained its overall favorable profile compared with Warfarin in patients on dual antiplatelet therapy, we should always bear in mind for the sake of our AF patients that combining dual antiplatelet therapy with chronic anticoagulation with Dabigatran, as well as with Warfarin, significantly increases bleeding risk. This triple therapy association should be evaluated in the individual patient after carefully balancing bleeding versus thrombotic risk.


Health economic studies of colorectal cancer and the contribution of administrative data: A systematic review.
Several forces are contributing to an increase in the number of people living with and surviving colorectal cancer (CRC). However, due to the lack of available data, little is known about the implications of these forces. In recent years, the use of administrative records to inform research has been increasing. The aim of this paper is to investigate the potential contribution that administrative data could have on the health economic research of CRC. To achieve this aim, we conducted a systematic review of the health economic CRC literature published in the United Kingdom and Europe within the last decade (2009-2019). Thirty-seven relevant studies were identified and divided into economic evaluations, cost of illness studies and cost consequence analyses. The use of administrative data, including cancer registry, screening and hospital records, within the health economic research of CRC is commonplace. However, we found that this data often come from regional databases, which reduces the generalisability of results. Further, administrative data appear less able to contribute towards understanding the wider and indirect costs associated with the disease. We explore several ways in which various sources of administrative data could enhance future research in this area.